Insulin secretion in type 2 diabetes mellitus gevolgen,treatment for early diabetes uk,mflor stalen - 2016 Feature


Diabetes mellitus, kurz auch nur als Diabetes oder Zuckerkrankheit bezeichnet, ist eine Erkrankung des Stoffwechsels, fur welche ein erhohter Blutzuckerspiegel kennzeichnend ist. Die Zuckerkrankheit (Diabetes mellitus Typ 1) beruht auf einer hormonellen Storung der Regulation des Blutzuckerspiegels. Diabetes Typ I, von dem etwa nur funf Prozent der Diabetiker betroffen sind, entsteht in der Regel dadurch, dass bestimmte Zellen der Bauchspeicheldruse zerstort werden.
Bei diesen Menschen wird zur Konstanthaltung des Blutzuckerspiegels mehr Insulin benotigt als die Bauchspeicheldruse produziert. Bei der Diabetes vom Typ II wiederum wird zwar genugend Insulin ausgeschuttet, dieses kann jedoch von den Zellen nicht richtig verarbeitet werden und der Blutzuckerspiegel steigt ebenfalls an. Obwohl diese Form der Diabetes vor allem altere Menschen betrifft, konnen durchaus auch Kinder und Jugendliche an dieser Form der Zuckerkrankheit leiden. Diabetes mellitus ist eine Stoffwechselerkrankung, die zu einem Anstieg des Blutzuckerspiegels fuhrt.
Die im Blut vorhandene Glucose wird nicht mehr zu den Leber- und Muskelzellen transportiert und demzufolge auch nicht in ihnen zur Speicherform Glykogen umgewandelt. Wegen des Traubenzuckermangels in den Zellen wird der Energiebedarf vermehrt durch den Fett- und Eiwei?abbau gedeckt. Durch den stark erhohten Eiwei?- und Fettabbau sowie den erhohten Glucosespiegel im Blut konnen tiefgrundige Stoffwechselstorungen auftreten. Die Zuckerkrankheit (Diabetes) au?ert sich in einem erhohten Blutzuckerspiegel sowie in einer Erhohung der Harnmenge. Um Organ- und Spatschaden zu vermeiden, ist es bei beiden Diabetesformen, Typ 1 und 2, entscheidend, dass eine Diagnose so fruh als moglich gestellt wird. Die Verdachtsdiagnose eines Pradiabetes oder manifesten Diabetes mellitus kann in der Arztpraxis oft schon anhand der Leitsymptome Polyurie und Polydipsie erfolgen. Eine Anwesenheit von Glucose im Urin ist daher diagnostisch stets als pathologisch im Sinne eines manifesten Diabetes mellitus anzusehen. Die Behandlung von Diabetes mellitus soll dafur sorgen, dass sich die Lebensqualitat der Betroffenen verbessert. Die unterschiedlichen Behandlungsziele werden zwischen dem Patienten und dem Arzt gemeinsam vereinbart. Ubergewicht ist einer der gro?ten Risikofaktoren fur Diabetes - daher sollte man fettreiches Essen weitestgehend meiden und sich hauptsachlich von Obst, Gemuse und Vollkornprodukten ernahren. Jedoch kann jeder von dieser Krankheit getroffen werden; nicht selten spielen auch die Gene eine Rolle. Achtet man nicht auf einen ausgeglichenen Blutzuckerspiegel, kann Diabetes schlimmstenfalls weitere Folgeerkrankungen mit sich bringen. Diabetes ist zwar nicht heilbar, jedoch kann man mit der richtigen und konsequenten Behandlung durchaus ein beschwerdefreies Leben fuhren. Science, Technology and Medicine open access publisher.Publish, read and share novel research.
Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 DiabetesJixin Zhong1, 2[1] Department of Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, China[2] Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio, USA1. Espino-Paisan L, Urcelay E, Concha EGdl, Santiago JL: Early and Late Onset Type 1 Diabetes: One and the Same or Two Distinct Genetic Entities?
Zhong J, Xu J, Yang P, Liang Y, Wang C-Y: Innate immunity in the recognition of beta-cell antigens in type 1 diabetes.
Schroder,M, Friedl,P: Overexpression of recombinant human antithrombin III in Chinese hamster ovary cells results in malformation and decreased secretion of recombinant protein. Martinez,IM, Chrispeels,MJ: Genomic analysis of the unfolded protein response in Arabidopsis shows its connection to important cellular processes. Type 1 and type 2 diabetes each have similarities in that both types of diabetes involve insulin from the pancreas not working properly as it should. Many people with type 2 diabetes start out by diet and exercise, trying to lower their weight to improve their sugars before trying any oral anti-diabetic medications.
Type 1 diabetes, once it is discovered, will need to take insulin right away in order to live, otherwise they will die without it if not taken when they are supposed to.
Any diabetic needs to check blood sugars often when they are on insulin, pills, or a combination of both. Understanding the Effects of Roux-en-Y Gastric Bypass (RYGB) Surgery on Type 2 Diabetes MellitusRaymond G. Why there is this discordant finding between HOMA-IR measures and insulin clamp studies is unclear.
Grundsatzlich werden zwei Arten dieser Erkrankung unterschieden: Diabetes vom Typ I und Diabetes Typ II. Hier sind die Ursachen in einer meist schweren Schadigung der Bauchspeicheldruse zu finden, so dass das erforderliche Insulin durch Spritzen verabreicht werden muss. Diese produzieren das lebenswichtige Hormon Insulin; dieses sorgt im Normalfall dafur, dass der uber die Nahrung aufgenommene Zucker in die Zellen gelangt und dort verarbeitet wird. Doch auch Erbfaktoren sowie Virusinfektionen konnen durchaus eine Ursache fur die Diabetes Typ I sein. Der Insulinmangel ist bei ihnen demzufolge noch starker ausgepragt und die Blutzuckerregulation wird noch problematischer. Diese Insulinresistenz ruhrt in vielen Fallen daher, dass dem Korper ein Uberschuss an Nahrung zugefuhrt wird.
Dies ist vor allem auf schlechte Ernahrungsgewohnheiten zuruckzufuhren - so ist es nicht weiter verwunderlich, dass vor allem in Europa besonders viele Menschen an dieser Form der Diabetes leiden.
Infolge ungenugender oder volligem Ausfall der Insulinproduktion in der Bauchspeicheldruse ist der Glucosegehalt des Blutes standig zu hoch.
Insulinmangel erhoht auch noch zusatzlich den Glykogenabbau in den Zellen und die Glucoseneubildung aus Fett und Eiwei?. Durch entsprechende Laboruntersuchungen des Blutes und des Harns kann festgestellt werden, ob eine Zuckerkrankheit vorliegt. Dem Korper geht sehr viel Flussigkeit verloren, was sich auch in einem uberma?ig gro?es Durstgefuhl zeigt und zum standigen Trinken animiert.
Die Symptome verlaufen beim juvenilen Diabetes mellitus oft dramatischer als beim Altersdiabetes, deshalb erfolgt hier die Diagnose in der Regel fruhzeitiger. Darunter wird ein Harndrang mit vermehrtem Wasserlassen bei gleichzeitig permanent vorhandenem Durstgefuhl verstanden.
In beiden Korperflussigkeiten konnen bei Diabetes mellitus erhohte Glucosewerte nachgewiesen werden. Um Diabetes Vorstufen zu diagnostizieren, wird der sogenannte orale Glucose-Toleranztest eingesetzt. Wahrend Typ I Patienten meist nicht ohne Insulinspritzen auskommen, haben Typ II Patienten haufig noch die Moglichkeit, das Voranschreiten der Krankheit mit einer gesunden Lebensweise aufzuhalten. Selbst wenn die Krankheit bereits weiter vorangeschritten ist, helfen oft noch Medikamente.
Herz-Kreislauf-Erkrankungen, wie Durchblutungsstorungen und im weiteren Verlauf ein Herzinfarkt oder Schlaganfalle konnen ebenso die Folge sein wie Erektionsstorungen oder Dysfunktionen der Nieren.
Regulation of glucose-stimulated insulin secretion by nutrients, hormones and neurotransmitters. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide. The body launches an attack on its own immune system, in which the insulin productive cells are destroyed.
They also need to follow their diets, exercise, and both types need to monitor their sugars regularly.
Weight loss over 15 years between control groups (blue), gastric banding (orange), vertical banded gastroplasty (purple), and gastric bypass (green).3. Are there available studies that compare effective calorie restriction versus RYGB in terms of diabetes improvement? Although HOMA-IR is an index of insulin sensitivity, it may also be used as a surrogate for hepatic insulin sensitivity.
Relationship Between Obesity and Diabetes in a US Adult Population Findings from the National Health and Nutrition Examination Survey, 1996-2006.
Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals with type 2 diabetes: one year results of the look AHEAD trial. Comparison of Glucostatic Pamaeters After Hypocaloric Diet or Bariatric Surgery and Equivalent Weight Loss. Effect of Weight Loss by Gastric bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes. Propsective Study Of Gut Hormone and Metabolic Changes after Adjsutable Gastric Banding and Roux-en-Y Gastric Bypass. Re-emergence of diabetes after gastric bypass after gastric bypass in patients with mid to long term follow up. Refractory and new-onset diabetes more than 5 years after gastric bypass for morbid obesity. Improvement of Type 2 Diabetes Mellitus After Bariatric Surgery-Who Fails in the Early Postoperative Course? Auch die Nahrungsaufnahme sollte zu festgelegten Zeiten passieren, damit der Energiebedarf standig gedeckt ist. Typische Symptome, die besonders bei der Diabetes Typ I auftreten, sind uberma?iger Durst, vermehrtes Wasserlassen sowie Hei?hunger. Aufgrund dessen gewinnen Glucagon und Adrenalin an Bedeutung und begunstigen somit die hohe Traubenzuckerbelastung unserer Korperflussigkeit. Eine weitere Folge ist ein Gewichtsverlust, bedingt durch den Abbau von Fett und Eiwei? in den Geweben. Durch die Filtrationstatigkeit der Nieren kann Blutzucker erst ab einer Schwelle von 180 Milligramm pro Milliliter Blut in den Urin ubergehen, man spricht hier auch von der sogenannten Nierenschwelle.
Au?erdem wird jeder neudiagnostizierte Diabetiker einer erweiterten Diagnostik im Hinblick auf eventuell bereits vorhandene Spatschaden zugefuhrt.
Wenn die Krankheit rechtzeitig erkannt wird, kann der gestorte Glukosestoffwechsel ohne Medikamente normalisiert werden. Naturlich muss man sich an einige Regeln halten - besonders auf die Ernahrung ist zu achten. Glucose enters the cell by glucose transporters (GLUT2 in rodents, GLUT1 in humans) and is then phosphorylated for its metabolism through glycolysis and oxidation. Therefore, maintaining glucose levels within a normal range is essential for life in vertebrates. The body’s cells are starved for insulin, and since they are getting insulin or insulin sensitive, it creates a dry mouth and thirst. High blood sugars in either type 1 or type 2 diabetes are damaging to blood vessels, and this leads to retinal damage in the eyes. When the whole body is experiencing higher sugar levels than is normal, then skin infections can come up as gangrene, which is scary in both types of diabetes. This type of diabetes will also lead into diabetic ketoacidosis which is very life threatening, and type 2 does not, although, if sugars become too high in type 2, it can lead to what is known as hyperosmolar hyperglycemic state.
Most of the time over the years, insulin secretion becomes smaller and smaller with type 2 diabetes, leading to a dependency on insulin injections.
Brathwaite1 and Louis Ragolia3[1] Department of Bariatric Surgery, Winthrop University Hospital, Mineola, New York, USA[2] Department of Endocrinology and Metabolism, Winthrop University Hospital, Mineola, New York, USA[3] Department of Vascular Biology, Winthrop University Hospital, Mineola, New York, USA1. While most accurate in assessment of glucose uptake of in vivo systems, it requires experienced and skilled personnel often not readily available.
Therefore, one may observe there are more rapid improvements of hepatic insulin sensitivity than that seen with peripheral insulin sensitivity. Wahrend vom Typ I eher junge Menschen betroffen sind, kommt es bei alteren Patienten eher zu Diabetes vom Typ II.
Es kommt zu Ermudungserscheinungen, zum Leistungsabfall und zu einer herabgesetzten Abwehrreaktion gegenuber Infektionserkrankungen.
Dazu gehoren beispielsweise die Analyse der Nervenleitgeschwindigkeit oder des Augenhintergrundes. Bei der Behandlung stehen zwei Arten von Insulin zur Verfugung, namlich Normalinsulin und Insulinanaloga. The generation of ATP by glycolysis, the Krebs cycle and the respiratory chain closes the ATP-sensitive K+ channel (KATP), allowing sodium (Na+) entry without balance. Apoptotic beta-cells undergoing secondary necrosis may release beta-cell antigens, which would activate the antigen presenting cells. Glucose homeostasis in the organism is tightly regulated by insulin, a hormone that acts on the major glucose metabolic tissues such as muscle, liver and adipose tissue. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. When it is not being secreted at all, or we are resistant to it due to obesity as in type 2 diabetes, it causes us to feel tiredness easily.
Type 1 diabetic people lose weight no matter how much they eat, it is burned right off in the body. Other skin infections involve Acanthosis Nigricans, Vitilgo, and cellulitis, a staph type of infection.
One such study by Plum et al demonstrated greater improvement in diabetes in RYGB subjects when compared to low calorie diets over three months [13]. The small body of literature that uses clamp data in gastric bypass subjects supports that insulin sensitivity in the post-operative period correlates with weight loss [31, 33], and therefore, is not a weight independent event in both diabetics and non-diabetics. It is possible glycemic variability is a precursor to the metabolic complication post-gastric bypass hypoglycemia. These two events depolarizethe membrane and open voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels. Glucose metabolism by the Krebs Cycle also renders a series of metabolic coupling factors that may initiate and sustain insulin secretion.
Insulin’s main effects include promoting glucose uptake, glycogen synthesis in the liver and muscle, triglyceride formation to be stored in adipocytes, and protein synthesis.
In type 1 diabetes, there is no more secretion or very very little of the essential insulin.
If you are having a lot of dry, itchy skin with breakouts, you need to speak with your doctor about diabetes as a possibility. Both groups had similar amounts of weight loss, suggestive that RYGB has weight independent effects on diabetes.The surgical obesity procedure known as the gastric band may be perceived as a superior “control group” to dietary weight loss. Only Kashyap et al [34] demonstrated a slight increase of insulin sensitivity using clamp studies at one week following surgery for subjects that underwent gastric bypass as compared to gastric banding. HOMA-IR and peripheral insulin sensitivity were assessed through clamp studies, with individuals undergoing RYGB one month following surgery by Lima et al [36].
Our laboratory is involved in trials studying this effect.There are a greater number of studies examining the changes of insulin resistance in those that undergo RYGB and caloric restriction. Na+ and Ca2+ entry further depolarizes the membrane and L-type and maybe other voltage-dependent calcium channels (VDCC) open. These metabolic coupling factors participate in mitochondrial shuttles, involving NADPH, pyruvate, malate, citrate, isocitrate, acyl-CoAs, and glutamate. When T cells reencounter the islet-antigens, they are retained in the islet, releasing inflammatory factors and inducing insulitis. Insulin secretion is held by the pancreatic beta-cells, and it is modulated by glucose levels.
Type 1 diabetes mellitus, used to known as juvenile diabetes, is typically developed in children and juveniles.
The gastric band is an anatomically enforced form of caloric restriction and can be difficult to “cheat.” Diabetes remission in subjects who had the gastric band has been shown to be directly related to weight loss, and was superior to conventional therapy programs [8]. However, as with all control groups, it is unclear if the oral intake of gastric band subjects was equivalent to the RYGB study group. They demonstrated that there was no improvement of peripheral insulin resistance despite weight loss, although HOMA-IR did improve. There are far fewer studies comparing these two groups and assessing for differences in beta cell function. This activation increases intracellular Ca2+ ([Ca2+]i), which leads to fusion of insulin-containing secretory granules with the plasma membrane and the first phase insulin secretion. Signaling pathways that contribute to maintaining or increasing glucose-stimulated insulin secretion include PKA and PKC. Inflammatory cytokines activate transcription factors NF?? and STAT-1, which decrease PDX1 and GLUT1 expression, leading to insufficient insulin production and secretion. Insufficient insulin secretion and consequent impairment of insulin’s actions lead to Diabetes Mellitus.Diabetes is a group of metabolic diseases characterized by hyperglycemia, caused by a defect on insulin production, insulin action or both.
It contributes to significant morbidity and mortality including heart disease, stroke, cancer, arthritis and sleep apnea. However, prospective longitudinal studies comparing RYGB to gastric banding have demonstrated that RYGB promotes greater insulin sensitivity along with superior weight loss at one year [16].
Further molecular studies in rodent models that have undergone RYGB support the notion that insulin sensitivity is weight dependent.
Dunn et al used more dynamic and definitive methods for assessing hepatic insulin resistance using hyperinsulinemic euglycemic clamp studies with isotropic tracers, while also collecting data to asses for peripheral insulin resistance. One study by Hofso D et al [50] compared RYGB to “intensive lifestyle intervention” as the nearest appropriate control. A sustained second phase of insulin secretion is held when the granules from the readily releasable pool are converted to the immediately releasable pool, an ATP-dependent process termed “priming”. Glucagon, glucagon-Like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) act through PKA pathway, while acetylcholine and cholecystokinine act through the PKC pathway. Type 1 diabetes in particular is due to an autoimmune destruction of the insulin producing pancreatic beta-cell, which usually leads to absolute insulin deficiency (ADA 2009). Although most commonly presented in childhood, type 1 diabetes also accounts for 5-10% cases of adult diabetes (1). Additional other types of studies have validated the potency of RYGB on diabetes through the use of other controls. GLUT4 mRNA expression in skeletal muscle and adipose tissue of rodents that have undergone RYGB, does not increase until 28 days after surgery [35].
They also demonstrated that there was also improvement in hepatic insulin sensitivity as compared to no improvement of peripheral insulin sensitivity at one month [37]. However, as expected, RYGB achieved superior weight loss, with significantly improved beta cell function. Betroffene mussen regelma?ig zur arztlichen Kontrolle, um den Verlauf der Krankheit zu beobachten. Fatty acids may contribute to insulin secretion through the PKC pathway through formation of diacylglycerol (DAG) or through protein acylation. This type of diabetes accounts for 5-10% of the total cases of diabetes worldwide, and although its onset is commonly during childhood and adolescence, it can occur at any age, even during late adulthood.
Recent epidemiologic studies revealed that the incidence for type 1 diabetes in most regions of the world has increased by 2-5% (2). One such study by Adams et al [17] was a large retrospective study of several thousand, comparing RYGB subjects to weight matched controls. The reason for this requires further research.Although RYGB and insulin secretion will be discussed in a later section, there are few studies that have measured hepatic glucose output in subjects that have undergone RYGB. There are no available or appropriate weight matched trials to compare diet to RYGB on beta cell function.The anatomic and histologic changes brought on by RYGB on the pancreas are also not well studied, due to the inability to easily access pancreatic tissue. Aminoacids may stimulate insulin release by increasing ATP production from the Krebs Cycle, by membrane depolarization, or by participating in intracellular calcium increase.
As the loss of beta-cells is determinant for the development of overt type 1 diabetes, understanding beta-cell’s normal physiology, namely insulin secretion, and how it may be affected during the progression of this disease is essential.
Unlike type 2 diabetes, which is caused by the loss of insulin sensitivity, type 1 diabetes is caused by insulin deficiency following destruction of insulin-producing pancreatic ? cells.
Results from various studies have shown that weight reduction significantly reduces the risk of developing T2DM in obese individuals [3], as well as improving glycemic control in those already with T2DM [4,5]. Because insulin clamp studies are the gold standard in assessment of peripheral insulin sensitivity, the rapid glycemic improvement seen immediately following surgery appears not due to increased peripheral glucose uptake.
Dunn et al [37] demonstrated decreased hepatic glucose production using clamp studies as described earlier. The body of literature of known histologic or molecular changes within the pancreas that have been observed are restricted to rodent models, or those afflicted with post-gastric bypass hypoglycemia.
Moreover, the development of new therapeutic interventions for type 1 diabetes, such as islet transplantation, beta cell maintenance and replacement, or stem cell therapy, requires a profound knowledge of how the presence of different nutrients and signals may regulate insulin secretion and beta-cell mass. Autoimmune-mediated ? cell death has been considered as the major cause of ?-cell loss in type 1 diabetes. Long term medical therapy for obesity is often unsuccessful for the majority of patients in clinical practice.
Despite the overall lack of prospectively randomized control trials, there has been compelling data to demonstrate RYGB effectively treats hyperglycemia and the diabetic state.
One may expect hyperinsulinemia, especially in the setting of a marked peak in the postprandial insulin level. In this chapter we aim to review the mechanisms involved in normal beta-cell function and beta-cell mass regulation, and how this function may be modulated by glucose, nutrients and signals in the beta-cell milieu. Bariatric weight loss surgery has remained the most effective means of achieving and maintaining weight loss. Only in 2012 were the first prospectively, randomized, non blinded controlled studies made available, comparing weight loss surgery to medical weight loss therapy. Contrary to these findings, Camastra et al [33] showed no improvement of endogenous glucose production one week following surgery against BMI matched controls. However, if the AUC of postprandial insulin levels are unchanged from prior to surgery, it is difficult to assess what cellular changes would occur if the same quantity of insulin was made by the beta cell.
We also review how these mechanisms may be affected by the onset and progression of type 1 diabetes. Accumulating evidence suggests an involvement of endoplasmic reticulum (ER) stress in multiple biological processes during the development of type 1 diabetes. Schauer et al [18] compared the RYGB and gastric sleeve surgical procedures to medical therapy in the STAMPEDE study (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently). Because of these discrepant findings, the precise characterization of how RYGB affects hepatic glucose output also requires additional studies.The clinical observation amongst practitioners in bariatric surgery is that in the immediate post-operative period after gastric bypass there is a rapid decrease of fasting glucose levels.
In rodents that have undergone RYGB, there has been a demonstrated increase in pancreatic beta cell area [51], less beta cell apoptosis [52], and increased beta cell proliferation [53]. Pancreatic ? cells exhibit exquisite sensitivity to ER stress due to their high development in order to secrete large amounts of insulin.
The Roux-en-Y gastric bypass (RYGB) is a type of bariatric surgery that involves the creation of a smaller stomach with a connection to the middle portion of the small intestine, bypassing the duodenum and a portion of the jejunum (see figure 1). Mingrone et al [19] compared RYGB and biliopancreatic diversion (BPD) procedures to medical therapy.
However, dietary caloric restriction alone has been shown to decrease hepatic glucose output without affecting whole body glucose disposal [38-39]. Normal function of the beta-cell - glucose stimulated insulin secretionThe pancreas is an endocrine and exocrine gland.
There is also evidence supporting that ER stress regulates the immune cell functionality and cytokine production that is relevant to autoimmune processes in type 1 diabetes. The two studies had similar findings of greater “normalization” of glucose levels in the surgical patients as compared to medical therapy.
People who undergo RYGB often have a post-operative decrease in appetite, anatomically imposed caloric restriction, and healing gastrointestinal anastomoses that require smaller nutrient boluses to allow for healing.
The exocrine portion corresponds to acinar tissue, responsible for secreting digestive enzymes into the pancreatic juice, while the endocrine portion comprises the pancreatic islets, which consist of several cell types secreting different hormones: -cells (insulin), -cells (glucagon), -cells (somatostatin), PP-cells (pancreatic polypeptide) and -cells (ghrelin).
Furthermore, ? cell loss caused by autoimmune attack results in an increased ER burden on the rest pancreatic ? cells and induces unfolded protein response (UPR) and ER stress, which further exacerbates ? cell death.
One limb, referred to as the alimentary or Roux limb, is where nutrient boluses pass from the stomach pouch. However, there was still greater weight loss in the surgical groups, contributing to the greater glycemic improvement. In caloric restriction, the improvement of the endogenous glucose production (EGP) appears to be due to reduced glycogenolysis [40]. Much may also be learned of how RYGB affects the pancreas by the associated complication known as post-gastric bypass hypoglycemia (reviewed further in”Antidiabetic effect gone too far? Here I will summarize the functional involvement of ER stress in the pathogenesis of type 1 diabetes and the potential underlying mechanisms.2. The other limb, which is the bypassed portion of the gastrointestinal tract, is known as the biliopancreatic limb. Schauer et al [18] further demonstrated that the post-operative weight loss appeared to have no correlation with glucose control. This finding is consistent with a study by Isbell et al [30] demonstrating comparable liver improvements (HOMA-IR) between RYGB subjects and calorie restricted subjects. Therefore, the rapid alterations in hepatic metabolism seen immediately following gastric bypass may be from calorie reduction alone and not alterations brought on by the surgery itself.Further molecular studies have supported the notion that RYGB does not induce a weight independent effect on peripheral insulin sensitivity. Meier et al [54] demonstrated in human subjects who are afflicted with hyperinsulinemic post-gastric bypass hypoglycemia, the pancreatic beta cell area was not increased as compared to obese or even lean control subjects. Blood glucose regulation by pancreasThe major cause of type 1 diabetes is loss of insulin-secreting pancreatic ? cell and insulin inadequacy (3;4). Most remarkably, many obese diabetic patients who undergo RYGB are relieved of their anti-diabetic medications in a matter of days. Time-dependent GLUT4 expression in skeletal and adipose cells in rodents after RYGB and weight loss was discussed earlier [35]. They did demonstrate increased beta cell nuclear diameter in those afflicted with post-gastric bypass hypoglycemia compared to BMI-matched controls, suggestive of altered insulin production and secretion. For a better understanding of the pathogenesis of type 1 diabetes, the regulatory mechanisms of blood glucose by pancreaswill briefly introduced. Before discussing the antidiabetic mechanisms behind RYGB, a further discussion of the meaning of diabetes remission will be explored. Intramuscular lipid content has also been noted to decrease one year following surgery by as much as 44%, which also contributes to enhanced insulin action [41].
One may therefore hypothesize that the decreased weight in response to the elevated insulin levels in RYGB subjects may be the responsible factor that improves glycemic control.
Beta-cells are responsible for secreting insulin in response to rises in blood nutrient levels during the postprandial state. Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs.
A seemingly simple concept, we wish to elaborate on the meaning of “diabetes remission,” as well as discuss the associated complexities. These observations alone suggest why peripheral insulin sensitivity is delayed and appears to be affected only by the presence of adiposity.
Despite these studies, further characterization is needed to understand how the pancreas responds to RYGB in T2DM independent of weight loss. Alteration in gut hormone levels have been strongly implicated as a cause for the metabolic improvement seen in RYGB subjects, but has not clearly been associated with the changes in altered insulin sensitivity. Beta cell dysfunction is considered a hallmark of T2DM, often with hyperinsulinemia and gradual insulinopenia. The process by which glucose promotes insulin secretion requires its sensing and metabolism by the beta-cell, a process called glucose-stimulated insulin secretion. Islets of Langerhans are clusters of pancreatic cells that execute the endocrine function of pancreas. Roux-en-Y gastric bypass and remission of type 2 diabetes mellitusMany subjects who undergo RYGB surgery and have T2DM observe a rapid normalization of their glucose levels, leading them to believe they have been “cured” of their diabetes. The effect of GLP-1 on peripheral tissue has demonstrated some effect on glucose uptake in adipocytes and skeletal muscle cells [42-43]. The altered post-prandial insulin profile seen after RYGB suggests beta cell function has only been altered, and not necessarily restored to appropriate physiologic function. Insulin is secreted in a pulsatile and biphasic fashionGlucose-stimulated insulin secretion is biphasic and pulsatile (Stagner, J.I. They contain the following 4 types of cells, in order of abundance: ? cells, ? cells, ? cells, and ? cells. Improvement or remission of T2DM was thought to be due to weight loss in obese subjects [3, 5].
While these authors feel the term “cure” is incorrect, we cannot deny, and in fact pleasantly enjoy, watching the marked improvement in hyperglycemia following surgery. However, the authors feel the effect of GLP-1 has more clinically significant effects on pancreatic function. Pancreatic ? cells and ? cells make up about 70% and 17% of islet cells respectively, and both of them are responsible for the blood glucose regulation by producing insulin (? cells) and glucagon (? cells) (6). This was further supported by studies with gastric banding, a form of enforced caloric restriction [8]. The role of GLP-1 is discussed further in the section “Identifying anti-diabetic factors of gastric bypass.”It is of interest that RYGB and other weight loss surgeries have differential effects on insulin sensitivity and insulin secretion.
Identifying anti-diabetic factors of gastric bypassAlterations of insulin secretion itself is a contributing factor that ameliorates the diabetic state in RYGB. Pancreatic ? cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production.
However, clinicians began to observe that glucose levels were significantly lower in RYGB subjects as compared to weight matched controls [7].
Buse et al had [20] recently defined prolonged diabetes remission as hyperglycemia that is below the diagnostic threshold for diabetes for at least five years, while on no active pharmacologic therapy for diabetes. The biliopancreatic diversion (BPD), a more malabsorptive surgery with a more extensive bypass, is often reserved for the super-obese population.
The secretory pulses of beta-cells are associated with synchronous Ca2+ oscillations in response to glucose stimulus (Bergsten, P. Pancreatic ? cells secrete pancreatic polypeptide that is responsible for reducing appetite. Although malabsorption also likely contributes to the improved dysglycemia, there are other hormonal changes that are likely contributing to this effect. The increasing number of diabetes remissions after RYGB surgery has caused practitioners to revisit the definition.Mingrone and Schauer’s studies included similar definitions of diabetes remission in their trials, although their studies were less than five years in duration.
However, this surgery been suggested to improve glycemia through normalization of insulin sensitivity [44]. Several investigators have proposed various intestinal mediators that may induce euglycemia, none of which have fully explained the clinical potency of RYGB.
This contrasts to RYGB, which we have discussed here, in that it does not appear to rely on insulin sensitivity for rapid improvement of hyperglycemia.
Earlier studies suggested that exclusion of the proximal gut was responsible for the improvement of hyperglycemia, implying a potential “diabetogenic factor.” Rubino et al [55] was the first to support this concept, by performing a duodenal-jejunal exclusion in diabetic rodents known as Goto-Kakizaki rodents.
1994), and they have been suggested to be coupled to glycolysis oscillations of the beta cell (Kar, S. They keep blood glucose level in a normal range by coordinating with each other (Figure 1). These are hormones that are secreted by enteroendocrine cells from the stomach, pancreas, and small intestine. We have demonstrated here that peripheral insulin sensitivity improves as a function of weight loss, independent of RYGB, whereas hepatic insulin sensitivity improves as a function of caloric restriction. This was a surgery that led to preservation of gastric volume, with a pure exclusion of proximal intestinal absorptive surfaces. After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose.
Neural based mechanisms have also been implied as contributors to the glycemic improvement, although much is still not understood. The initial excitement of his findings surrounded the premise that there was greater glycemic control as compared to calorie restricted rodents, simply by removing a portion of the intestine without creating caloric restriction. The glucose is then absorbed across the intestinal wall and travel to the circulating bloodstream. This is a well accepted phenomenon seen with RYGB subjects, and is believed to contribute significantly to this improvement of hyperglycemia in diabetics. Born from this procedure was the concept of the “foregut theory.” From this, it was perceived that there was a “diabetogenic factor” in this region of the intestine. Pancreatic ? cells sense increased blood glucose level by taking up glucose through GLUT2, a glucose transporter. To better understand how RYGB affects those with T2DM, we will review the changes that occur with RYGB in key glucoregulatory organ systems within the body.
Are the diabetic microvascular complications also reversed and should practitioners stop following these patients if they do go into remission? Effects of gastric bypass surgery on pancreatic functionT2DM is characterized by both peripheral insulin resistance, as well as pancreatic beta cell dysfunction. However, this concept was later challenged by the “hindgut theory.” The “hindgut theory,” perhaps more popular, operated on the premise that there were factors in the distal intestine that became elevated and had potent anti-diabetogenic effects.
In the ensuing sections, we will discuss in detail, the changes of peripheral insulin sensitivity and insulin secretion brought on by gastric bypass, and their effects on hyperglycemia.
If there is complete reversal, why not use the term “cure?” Most important, has the characteristic pancreatic beta cell dysfunction reversed itself?
For this reason, understanding how RYGB affects the pancreas may allow us to better understand why diabetes improves after the surgery. The resulting increase of intracellular calcium concentration promotes the secretion of insulin into circulation of blood. These are questions proposed by these authors, some of which will be addressed in later sections.
The majority of available studies involve dynamic biochemical measurements involving nutrient challenges.
Further support for this are studies performed with feeding tubes placed in the gastric remnant of the intestine following RYGB. Circulating insulin then acts on cells in a variety of tissues including liver, muscle, and fat through interacting with insulin receptor on the cell membrane.
We will also discuss the role that caloric restriction and gut hormone elevation may have in this process. Despite these questions, it is very hard to ignore the potent clinical effect the surgery has on diabetes. The impetus for study of these nutrient challenges, such as mixed meal testing, is based on the link between RYGB and postprandial gut hormone hypersecretion [45].
Hansen et al [56] demonstrated that using gastric feeding tubes led to increased gut hormones, as well as via oral (jejunal) routes.
Insulin signaling induces the translocation of glucose transporter GLUT4 to cell membrane of muscle cells and adipocytes, leading to the uptake of glucose into cells as an energy source. For those physicians and health care practitioners who struggle with uncontrolled diabetic patients, it is a seemingly effective and attractive solution. Exaggerated gut hormone secretion appears to occur because of the altered transit of nutrient boluses caused by the gastric bypass, and is a well accepted phenomenon.
The similar alterations in insulin sensitivity between the two nutrient routes suggest the exclusion of nutrients from the foregut is not significant. In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver. Cumulatively, this will permit the reader to develop an understanding of the relationship of how RYGB affects diabetes.


The metabolic potency of RYGB has even been addressed by the International Diabetes Federation (IDF) in a statement published in 2011 [21]. Several gut hormones have been suggested to also alter insulin secretion, and are termed “incretins.” The incretin effect relates to the ability of an oral glucose load to result in an enhanced insulin response as compared to a similar intraveous glucose load. Instead, distal gut factors such as GLP-1 may more likely be the cause.GLP-1 physiology will not be covered here in depth.
Therefore, insulin lowers blood glucose level by promoting glycogenesis and glucose uptake by peripheral tissues (7). The distal gut hormone GLP-1 has been shown to be primarily responsible for mediating this effect, although other possible contributing anti-diabetic factors have yet to be characterized. Its anti-diabetic effect in gastric bypass has been demonstrated in rodent models that underwent RYGB [57]. In contrast, a drop in blood glucose caused by starving or other situations like extreme exercise suppresses the secretion of insulin by ? cells and stimulates ? cells of pancreas to release glucagon.
While a compelling argument can be made for this, we caution practitioners that not all RYGB subjects experience diabetes remission. There have been surprisingly few studies that have addressed the impact of RYGB on the release of insulin secretion and its relation to other gut hormones.
There are a small, but significant number of patients that have T2DM and undergo RYGB, but remain hyperglycemic post-operatively.
We will first characterize the pancreatic secretory alterations brought on by the surgery, and then further explain associated hormonal and pancreatic cellular changes.Le Roux CW, Aylwin SJ, Batterham RL et al.
Shortly after glucose stimulus, a first burst of insulin secretion occurs, followed by a decrease in the rate of secretion. Roux-en-Y Gastric Bypass (RYGB) and its weight independent effect on T2DMSince the early portion of the 21st century, there has been a growing interest in bariatric surgeries and their effect on ameliorating the diabetic state. In a retrospective review by DiGiorgi et al [22], as much as 24% of T2DM who had undergone RYGB had recurrence of their diabetes over a three year period, while a longer five year study demonstrated 31% recurrence [23].
Gut Hormone Profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters.
A second sustained phase of insulin secretion can be observed just after this decrease, which can continue for up to several hours until euglycemia is achieved (Curry, D.L. Pories et al was arguably the first to describe remission of diabetes following gastric bypass. Use of GLP-1 agonists or GLP-1 continuous infusions increased basal insulin secretion, often leading to an improved second phase of insulin secretion [58, 59]. The metabolism of glucose in ? cells promotes the secretion of insulin into circulation of blood. He reported gastric bypass not only caused weight loss, it also led to normalization of blood sugars in over 80% of his diabetic patients [9]. Because fasting GLP-1 levels do not increase following surgery, many questions remain regarding its postprandial effects.
Circulating insulin then increases the glucose uptake by a variety of tissues including liver, muscle, and fat. Initially, the normalization of blood sugars was thought to be directly caused by the weight loss.
Higher BMI’s, age, prior use of antidiabetic medications, and male gender were identified as factors associated with diabetes recurrence [23, 24]. The majority of studies also demonstrate a postprandial rise of insulin concentration that has a higher and earlier peak than seen pre-operatively [32-34, 46-48]. Perhaps the most important evidence that there are other factors besides GLP-1 in RYGB that contribute to the anti-diabetic effect, is that the pharmacologic use of GLP-1 agonists have not led to the equivalent potency of RYGB surgery alone.
In liver, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis. However, it has subsequently been noted that blood glucose control improves immediately following the surgery, prior to any significant weight loss. A similar study in Chinese subjects demonstrated that diabetes duration, BMI, and fasting C-peptide were predictors for diabetes remission at one year.
While this suggests a possible restoration of the first phase of insulin secretion, this remains unclear.
Both glycogenesis and glucose uptake by peripheral tissues can lead to a decrease of glucose level in blood stream. The concept that weight loss alone was not the reason for diabetes improvement after RYGB was a paradigm shift in the world of weight loss surgery, as well as the world of diabetes.
Mechanisms involved in the first phase of insulin secretion - the triggering pathwayThe first phase of glucose-stimulated insulin secretion is a multistep process that requires transport and oxidation of glucose, electrophysiological changes and fusion of insulin-containing secretory granules with the beta-cell plasma membrane (Figure 1).
In contrast, a drop of blood glucose level suppresses the secretion of insulin by ? cells and stimulates ? cells to release glucagon. These investigators were the first to suggest predictors and possible cutoffs in assessing the glycemic responses to RYGB. The insulin peak also does not appear to be as marked as the postprandial GLP-1 elevations. Roux-en-Y gastric bypass, satiety, and the central nervous systemThe importance in assessment of decreased caloric intake with diabetes remission has already been discussed, in particular those that undergo gastric banding [8]. Glucose enters the cell by facilitated diffusion mediated by glucose transporters (GLUT2 in rodents, GLUT1 in humans).
Determining how to use RYGB in diabetes management is still in the early stages of development. The insulin peak is typically followed by a rapid decrease of insulin and glucose levels following the peak. Similarly, the RYGB involves creation of a small stomach size, causing similar restriction.
Pancreatic ? cells and insulin biosynthesisEither insulin deficiency or insulin inefficiency can cause diabetes.
It is remarkable that subjects that undergo RYGB actually appear to have a markedly decreased appetite as compared to their gastric band counterparts. This enzyme plays a critical role in glucose-stimulated insulin secretion and is considered the glucosensor of the pancreatic beta cell. As the only cell type producing insulin, ? cell plays a critical role in the development of diabetes. However, the insulin area under the curve (AUC), based on these prior studies, is either unchanged or decreased as compared to pre-operative measurements.
Because postprandial elevation of gut hormones is a distinguishing factor of RYGB from gastric banding, investigation of their orexogenic and anorexogenic tendencies have recently begun to be characterized. Due to its kinetic characteristics, glucokinase is a determining factor for glucose phosphorylation (Matschinsky, F.M. In type 1 diabetes, autoimmune-mediated destruction of ? cell leads to insufficient insulin production and inability of cells to take up glucose. Figure 4 demonstrates an example of post-prandial insulin levels in subjects that underwent gastric band and RYGB, as compared to control obese and lean subjects. Earlier prospective studies generally demonstrated RYGB induced altered satiety [45, 60-62], although the field appears to be lacking trials that are appropriately controlled.The evidence continues to mount for this gut brain communication effect, with several biochemical mechanisms that affect neural signaling of hunger and satiety being discovered. The SOS trial is one of the largest prospective data collections to date that studies the clinical effects of various types of bariatric surgery. Since 1991, the National Institutes of Health used both BMI and the presence of obesity-related comorbidities as the criteria for surgical weight loss. The control obese subjects were matched to the pre-operative BMI of the surgical patients, and the subjects that underwent either operation had an equivalent post-operative BMI.
Therefore, RYGB has effects on satiety that are independent of the physical limitations imposed by the formation of the gastric pouch.
The generation of ATP by glycolysis, the Krebs cycle and the respiratory chain leads to closure of the ATP-sensitive K+ channel (KATP), a hetero-octamer comprised of four subunits of the sulphonylurea 1 receptor (SUR1) and four subunits of the inwardly rectifying K+ channel Kir6.2 (Aguilar-Bryan, L. In response to insulin resistance, the body secretes more insulin to overcome the impaired insulin action. The SOS data demonstrates durable weight loss by as much 25% reduction at 10 years with various surgery types.
Here, RYGB subjects exhibit the largest post-prandial insulin peak as compared to the gastric band and the remaining non-surgical subjects. The effect gut hormones have on the neural circuitry are most studied specifically within the hypothalamus [63], with the balance of orexogenic and anorexogenic hormones. However, pancreatic ? cells fail to secrete sufficient insulin to overcome insulin resistance in some individuals, resulting in type 2 diabetes (8;9). The greatest weight loss is observed with RYGB [6] as compared to gastric banding, and a modified restrictive surgery known as vertical banded gastroplasty, (see figure 3). Prime hormonal candidates for these changes include insulin, leptin, GLP-1, peptide YY (PYY), and ghrelin [61-62, 64-65]. Therefore, dysfunction of ? cell exists in both types of diabetes.Pancreatic ? cell is specialized for production of insulin to control blood glucose level. Since SOS, additional studies of obese subjects that have undergone RYGB have verified that weight loss from the surgery is durable and long lasting [10, 11].
We have already pointed out that post-operative weight loss does not always seem to correlate with glycemic control [18]. Decreased insulin levels following RYGB was generally believed to be the case with the perceived notion that insulin sensitivity was improved. While findings with ghrelin have been mixed, there is growing evidence that the other aforementioned hormones may play a significant role.
In response to hyperglycemia, insulin is secreted from a readily available pool in ? cells.
While durability of the surgery continues to be validated in ongoing trials, its weight independent effect on diabetes was initially uncertain during the infancy of bariatric surgery. However, as mounting evidence shows that peripheral insulin sensitivity is not immediately improved, these alterations in insulin secretion may hold more significance. These two events depolarize the membrane to a range that allows the opening of voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels. This uncertainty was at least partially due to the absence of appropriate “control groups” in various studies. Potential changes in alpha cell secretion of glucagon was then investigated to see if that had a possible role in these glycemic changes, namely if levels were decreased. Origins of these mediators come from multiple different organ systems, which subsequently affect neurons within the arcuate nucleus and other hypothalamic regions.
Insulin is first synthesized as preproinsulin with a signal peptide in the ribosomes of the rough endoplasmic reticulum.
For instance, the SOS data demonstrated reduced incidence of diabetes in surgically treated groups, but this was compared to non-standardized medically treated groups [12]. Seeing such high rates of diabetes remission in a lower BMI range reinforces the concept of weight-independent effects of surgery on diabetes.
Their activation triggers action potentials that increase in intracellular Ca2+ ([Ca2+]i) (Hiriart, M. Preproinsulin is translocated into ER lumen by interaction of signal peptide with signal recognition particle on the ER membrane.
Medical weight loss therapy can be difficult to implement effectively, and therefore, comparison to surgical subjects is often imbalanced. As most obese individuals fall within this BMI range, clinicians may even consider recommending surgery at an earlier BMI. Why hyperglucagonemia would be present during the glycemic improvement seen after RYGB is unclear, and needs further studies to validate these findings.Based on the postprandial insulin concentration profile demonstrated in figure 4, the glycemic effects do not clearly show why there would be an improvement of hyperglycemia.
Research into these anti-obesity mechanisms for pharmacologic uses are still being investigated. Preproinsulin is converted to proinsulin by removing the signal peptide forming three disulfide bonds in the ER. Increasing evidence shows that BMI alone is not an adequate measure to predict successful health outcomes after RYGB. Available studies do not demonstrate consistently how postprandial glucose levels behave in response to these insulin secretory changes. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules that are close to the cell membrane. Some have demonstrated significantly elevated postprandial glucose levels with a subsequent decrease [32], while others mostly show the postprandial decrease [8]. Roux-en-Y gastric bypass, type 2 diabetes mellitus, and the central nervous systemAutonomic nerve regulation has often been the target for pharmacologic weight loss therapy.
Together with calcium mobilized from intracellular stores, this Ca2+ increase leads to fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin into the circulation (Rorsman, P. In the secretory granules, proinsulin is cleaved into equal amounts of insulin and C-peptide (Figure 2). We have mentioned that assessing for adequate beta cell function [25] could be used as criteria for successful diabetes remission.
Inconsistency may have to do with varying nutritional content of test meals and timing after the surgery.
Therefore, there has been renewed interest in the role of the vagus nerve within bariatric surgical procedures to determine its role in weight loss. Additional evidence has suggested that those who have most benefited from surgery have elevated insulin levels, or insulin resistance [28, 29]. Using other methods in assessment of glycemic changes with RYGB, continuous glucose monitoring (CGM) has revealed unusual patterns. When the ? cell is appropriately stimulated, insulin is secreted from the cell by exocytosis (11).
The simultaneous improved cardiovascular effects observed from the surgery [28] may also highlight the intrinsic relationship between insulin resistance and cardiovascular disease, often referred to as the metabolic syndrome. In a group of RYGB subjects, CGM revealed increased glycemic variability using a calculation parameter known as “mean amplitude of glycemic excursions” (MAGE) [49]. An intact vagus nerve with RYGB appears to have a significant and improved effect on food intake and weight loss [70]. Following glucose metabolism, the rate-limiting-step for the first phase lies in the rate of signal transduction between sensing the rise in [Ca2+]i and exocytosis of the immediately releasable granules (Straub, S.G. As the major site for protein synthesis, ER plays an important role in insulin biosynthesis. As clinicians and scientists, it is critical for us to evaluate the effects of RYGB surgery beyond simple weight loss. However, the beneficial effect appears to carry over to improved glucose metabolism that also appears to be weight independent.
To fulfill the requirement for secreting large amount of insulin, the pancreatic ? cells are equipped with highly developed ER, leading to the vulnerability of ? cell to ER stress (12). Obese and diabetic rodent models studies have demonstrated that hepatic vagotomy will worsen glucose metabolism [71-72].
In type 1 diabetes, the loss of ? cell increases the burden of insulin secretion on the residual ? cells.
In the remaining portion of this chapter we will characterize the basic driving forces for T2DM and how the surgery brings about an improved glucose effect. This further highlights the necessary role of the vagus for helping attain euglycemia via hepatic-mediated mechanisms. This is not without some conflicting studies such as by Shin et al [73], although their focus was on food intake, body weight, and energy expenditure. Mechanisms involved in the second phase insulin secretion - the amplifying pathwayThe existence of a second phase of insulin secretion was first reported in the 1960s.
On the other hand, it also increases the ER burden of residual ? cells, which further exacerbates ? cell death. In the ribosomes of rough endoplasmic reticulum, insulin is first synthesized as a precursor, preproinsulin. Effects of gastric bypass surgery on insulin resistanceInsulin action has a key role in regulating glucose homeostasis, facilitating glucose uptake in various tissue types. The source of this neuroendocrine regulation may suggest that hepatic glucose metabolism is uniquely regulated by a hypothalamic source.Pocai A et al [74] demonstrated that activation of potassium-ATP channels within the hypothalamus appears to lower blood glucose through hepatic gluconeogenesis.
Preproinsulin has a signal peptide that directs it to translocate into ER lumen by interacting with signal recognition particle on the ER membrane.
Its inability to cause glucose uptake is believed to be a key step in the pathogenesis of T2DM. This was a significant advance in better understanding the mechanisms that may mediate hepatic gluconeogenesis.
1968) observed that, in total pancreas perfusion with glucose, insulin release showed an early and rapid increase at 2 min after glucose infusion, peaking at 4 min. In ER lumen, preproinsulin is converted to proinsulin by removing the signal peptide and forming three disulfide bonds. Similarly, insulin presence near the hypothalamus has also been demonstrated to suppress lipolysis [75], which directly affects insulin resistance and T2DM. A second or “slow” phase, characterized by an increasing rate of insulin secretion was sustained during the whole period of glucose infusion. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules where it is cleaved into equal amounts of insulin and C-peptide. Additional characterization of the hypothalamic and vagal mediated effects may also help us to better understand the role of the nervous system in glucose and lipid regulation. On the other hand, when the pancreas was perfused with tolbutamide, a sulfonylurea that blocks the potassium channels, only the first rapid release peak was observed, suggesting this biphasic insulin secretion is only generated in glucose-stimulated insulin secretion (Curry, D.L. After synthesis, insulin is stored in the secretory granules and secreted from the cell until the ? cell is appropriately stimulated.3.
Glucose transport is maintained primarily through insulin-regulated glucose transporters, such as GLUT4. Commonly proposed theories that may mediate insulin resistance include impaired insulin signaling defects, GLUT transporter dysfunction, as well as increased availability of circulating free fatty acids. PYY) may not only have anorexogenic effects that modify caloric intake, but they may also directly mediate glucose regulation via central nervous system mechanisms. Both environmental and molecular factors may contribute to the development of insulin resistance.
Further identification of where gut hormone receptors exist are needed to better understand this potentially significant glucose-governing mechanism. It was until the 1990s that evidence of mechanisms for glucose-stimulated insulin secretion independent of ionic action (i.e. As featured by its name, RER looks bumpy and rough under a microscope due to the ribosomes on the outer surfaces of the cisternae.
Obesity, as an environmental source, is believed to be a very common contributor.Insulin resistance has been significantly observed at the level of the liver, skeletal muscle, adipose tissue, and pancreas.
But it is skeletal muscle and adipose tissue that account for over 80% of total body glucose uptake.
The newly synthesized proteins are folded into 3-dimensional structure in RER and sent to Golgi complex or membrane via small vesicles. Because the reversal of diabetes immediately following gastric bypass is so profound, an alteration of peripheral tissue insulin sensitivity was thought to be the mechanism for achieving normoglycemia. Postgastric bypass hypoglycemiaPerhaps best described by the title of the article by Patti ME et al “Hypoglycemia following gastric bypass surgery-diabetes remission in the extreme?”[76] the condition of post-gastric bypass hypoglycemia has been an increasingly observed phenomenon. In contrast, SER appears to have a smooth surface under the microscope as it does not have ribosomes on its cisternae. With RYGB having superior weight loss, it has been well accepted that improved insulin sensitivity in surgical patients is also superior. Contrasting mechanisms of how this occurs have been proposed, with the initial reports suggesting islet cell hyperplasia [77].
SER is responsible for the synthesis of lipids and steroids, regulation of calcium concentration, attachment of receptors on cell membrane proteins, and detoxification of drugs. However, the timing of when peripheral insulin sensitivity improves has been an area of uncertainty. However, follow up studies suggested there was no change in beta cell mass, although there was an increase in beta cell nuclear diameter [54]. Answering when peripheral insulin sensitivity begins after RYGB will also help to elucidate if it is a weight independent event.The most frequently used measure of insulin resistance is the Homeostasis Model Assessment Insulin-Resistance (HOMA-IR). The increase in beta cell diameter may be more of a function of increased nuclear transcriptional activity of insulin production.
Since then, the concept of a rapid first phase glucose-stimulated insulin secretion, caused by a triggering pathway (or KATP-dependent mechanism), followed by a sustained second phase due to an amplifying pathway (or KATP-independent mechanism) has developed (Aizawa, T. The ease of obtaining measurable glucose parameters have made this a popular method for quantifying insulin sensitivity. This would coincide with those afflicted with this condition may have hypersecretion of insulin.
Several sources cite RYGB improves HOMA-IR from four days to two weeks following surgery in diabetic and non-diabetic subjects [30-31]. Hypersecretion of insulin at disproportionate levels to the decreased BMI following surgery may potentially lead to clinically significant hypoglycemia.
It is found in smooth and striated muscle, and is important for the regulation of calcium levels.
In a non-weight controlled study, HOMA-IR was also decreased at three days following surgery [32].
If we recall the changes in peak of insulin secretion discussed earlier brought on by RYGB [32-34, 46-48], a comparison to BMI-matched subjects afflicted with hypoglycemia demonstrated a greater post prandial peak of insulin secretion [78].
Biphasic insulin secretion has been explained by the existence of different pools of insulin-containing granules inside the beta cell (Aizawa, T. Unfolded protein response and ER stressER stress is defined as the cellular responses to the disturbances of normal function of ER. However, these same sources demonstrate that HOMA-IR in RYGB subjects has comparable improvement to that of diet controlled subjects at similar time intervals while on calorie restriction [30-31]. This may lead to increased glycemic variability, which has been demonstrated in subjects who are afflicted with post-gastric bypass hypoglycemia [40]. While this is suggestive that RYGB may induce hypoglycemia via pancreatic mediated mechanisms, the question of the contribution of peripheral insulin sensitivity to hypoglycemia was answered by Kim et al [79].
ER is the place where newly produced proteins fold into 3-dimensional conformation which is essential for their biological function.
These findings are suggestive that immediate changes in HOMA-IR following RYGB are possibly related to caloric restriction alone.
Using intravenous glucose infusions in BMI matched controls, Kim et al [80] showed that those who are afflicted with hypoglycemia demonstrated appropriate insulin secretion rates in response to intravenous glucose challenges. The sensitive folding environment could be disturbed by a variety of pathological insults like environmental toxins, viral infection, and inflammation.
Therefore, it appears the hypoglycemia is only brought on by ingestion of nutrient boluses which elicits an abnormal insulin response. In addition to pathological insults, it can also be induce by many physiological processes such as overloaded protein biosynthesis on ER, For example, in case of type 1 diabetes, increased insulin synthesis in residual ? cell exceeds the folding capacity of ER, resulting in the accumulation of unfolded insulin. While the response may be effective in mediating improved glucose control, it is unclear why some subjects develop hypoglycemia and others do not. There is a reserve pool of granules located in the cytoplasm which accounts for approximately 94% of the total granules, and a releasable pool of granules which are docked to the plasma membrane. The accumulation of unfolded or mis-folded proteins in the ER leads a protective pathway to restore ER function, termed as unfolded protein response (UPR). Possible causes may have to do with prior history of diabetes and residual insulin resistance. It has been suggested that the docked granules have different ability to be released and therefore constitute two subsets, the readily releasable pool, and the immediately releasable pool. Because of the increasing number of bariatric surgeries being performed, this is an area that is in urgent need of further study. The granules from the immediately releasable pool are the first to be secreted in response to intracellular Ca2+ increase during the triggering pathway, leading to the first phase of insulin secretion.
A special type of proteins called chaperones is used as a quality control mechanism in the ER. Understanding how this condition develops will also likely shed light on how the surgery helps improve hyperglycemia.
At the lowest point of secretion in between the two phases, the granules from the readily releasable pool are converted to the immediately releasable pool, an ATP-dependent process termed “priming”.
Currently, our laboratory is involved with ongoing clinical trials to better understand the mechanisms behind this clinically significant phenomena.
This priming has been suggested to be the rate-limiting step for exocytosis, and the target process for signals involved in the amplifying pathway that leads to the sustained second phase of insulin secretion (Straub, S.G. The unfolded proteins usually have a higher number of hydrophobic surface patches than that of proteins with native conformation (17). Thus, unfolded proteins are prone to aggregate with each other in a crowed environment and directed to degradative pathway (18). Molecular chaperones in the ER preferentially interact with hydrophobic surface patches on unfolded proteins and create a private folding environment by preventing unfolded proteins from interaction and aggregation with other unfolded proteins. Given the glucose-stimulated nature of biphasic insulin secretion and the ATP-dependence of priming, most of these signals are proposed to be derived from glucose metabolism.
In addition, the concentration of Ca2+ in ER also impairs protein folding by inhibiting the activity of ER-resident chaperones and foldases (19-22). The growing popularity of the bariatric weight loss surgery known as the sleeve gastrectomy is worthy of discussion.
The procedure involves the removal of the antrum of the stomach, with a creation of a sleeve-like structure. Transcription factors regulating beta cell functionTranscription factors in the beta-cell act in a cooperative manner, forming transcriptional networks, to induce not only insulin expression, but also the expression of other genesFigure 1.Mechanism of biphasic glucose-stimulated insulin secretion. The potency of the sleeve gastrectomy on diabetes has been demonstrated by Schauer et al [18].
While the improvement of hemoglobin A1c reduction was greater in those that underwent RYGB, the sleeve gastrectomy had a similar reduction of almost 3% at one year following surgery. Exhaustion of the protein folding machineries or insufficient energy supply increases the accumulation of unfolded or mis-folded proteins in ER, which is responsible for the activation of UPR.
The question remains if there is a weight-independent effect of diabetes improvement with this surgery?Earlier prospective studies of the sleeve gastrectomy, as compared to the RYGB, demonstrated that weight loss and glucose homeostasis was also similarly improved between the two [80-81]. However, they also demonstrated increased postprandial elevation of GLP-1, PYY, and insulin levels, although generally slightly less than RYGB. Short term (6 weeks) and long term (1 year) follow up demonstrated comparable GLP-1 responses to mixed meal challenges [82-83].
Some physiological processes such as the differentiation of B lymphocytes into plasma cells along with the development of highly specialized secretory capacity can also cause unfolded protein accumulation and activate UPR (29-31). The alterations of GLP-1 and PYY secretion is confusing and remains not well explained within the literature.
In response to those physiological and pathological insults, cells initiate UPR process to get rid of the unfolded or mis-folded proteins. RYGB has been associated with earlier transit of nutrients to the distal intestine, stimulating an elevation of the “hindgut hormones.” These elevations may potentially explain the glycemic improvement. For instance, UPR can increase the folding capacity by up-regulating ER chaperones and foldases, as well as attenuate the biosynthetic burden through down-regulating the expression of secreted proteins (32-34).
However, these observations do not explain why the postprandial hormone elevation with the sleeve gastrectomy occurs. In addition, UPR also eliminates unfolded or mis-folded proteins by activating ER associated degradation process (35-37).
The literature still lacks a satisfactory mechanism of the stimulating mechanism for these elevations. Some of these factors include PDX-1, HNF4?, MAFA, FOXA2 and NeuroD1 (Lazo-de-la-Vega-Monroy, M.L.
However, once the stress is beyond the compensatory capacity of UPR, the cells would undergo apoptosis. However, the clinical effects of the sleeve gastrectomy on diabetes remains difficult to ignore.
Disruption of those post-translational modifications can also result in the accumulation of incorrectly folded proteins and thereby induce UPR or ER stress. The mechanism remains elusive, and many questions remain about the effects of the sleeve gastrectomy.
PDX-1 is one of the most important transcription factors regulating the insulin gene transcription. ER stress pathwaysAs a protective mechanism during ER stress, UPR initiates a variety of process to ensure the homeostasis of ER. UPR can be mediated by three major pathways, which are initiated by the three transmembrane signaling proteins located on the ER membrane. Those transmembrane proteins function as a bridge linking cytosol and ER with their C-terminal in the cytosol and N-terminal in the ER lumen. The N-terminal is usually engaged by an ER resident chaperone BiP (Grp78) to avoid aggregation.
Many of the target genes for pdx1 are crucial for glucose-induced insulin secretion, such as glucose transporter glut2 (Ahlgren, U.
When unfolded proteins accumulate in ER, chaperons are occupied by unfolded proteins and release those transmembrane signaling proteins. The lack of an intestinal bypass prevents associated malabsorption and the plethora of micronutrient deficiencies.
There are three axes of signals that are initiated by the pancreatic endoplasmic reticulum kinase (PERK), the inositol-requiring enzyme 1 (IRE1), and the activating transcription factor 6 (ATF6) respectively.
Despite these appealing features, we would advise practitioners to evaluate their patients carefully when considering a bariatric surgical method for weight loss.
Little to no long-term studies are currently available on their clinical potency, and the lack of understanding how the surgery affects diabetes should give practitioners pause. Under normal condition, PERK, IRE1, and ATF6 binding to the ER chaperone BiP to remain inactive state. However, the surgery is still very promising with apparently little metabolic complications. Upon the accumulation of unfolded proteins, BiP preferentially binds to the unfolded proteins, leading to the release of PERK, IRE1, and ATF6.
The authors are excited about the growing role of the sleeve gastrectomy in weight loss procedures.6.
PERK becomes oligomerized and activated once released from BiP, and subsequently phosphorylates eIF2?.
ConclusionRYGB unquestionably ameliorates the hyperglycemic state in many of those with T2DM. Many who undergo the surgery gain significant health benefits, and achieve remission of their diabetes. Investigators are attempting to understand the clinical impact of diabetes remission on RYGB patients, as well as the mechanism of how this is achieved.
The improvement of peripheral insulin sensitivity appears to be weight dependent, while hepatic insulin sensitivity seems to be a function of caloric restriction. However, alterations in pancreatic function are reflected in the robust postprandial insulin secretion profile, and appear to be a direct result of RYGB. The detachment of ATF6 from BiP results in the translocation of ATF6 to the Golgi apparatus and cleavage of ATF6.
Understanding the condition of the pancreas’ endogenous insulin producing ability and the whole body insulin resistance may allow us to predict who will achieve diabetic remission.The increasing clinical phenomenon of post-gastric bypass hypoglycemia may be a result of an undesired overenhancement of the alterations brought on by surgery.
This condition needs further study to better aide those afflicted with this potentially debilitating condition. PDX1 plays a role in the maintenance and proliferation of beta-cells as well (Holland, A.M. In response to ER stress, the binding of unfolded proteins to BiP leads to the release of PERK from BiP. As a possible alternative, the sleeve gastrectomy may potentially be an alternative weight loss surgery that appears to have lesser metabolic complications than are associated with RYGB. However, understanding of how it mediates its effect on diabetes is still not understood, and also is in great need of additional research.7. As a result, PERK inactivates eukaryotic initiation factor 2? (eIF2?) by the phosphorylation of Ser51 to inhibit mRNA translation and protein load on ER (34;40). Itsoverexpression in diabetic mice (Irs2 knockouts) participates in beta-cell mass recovery and helps ameliorate glucose tolerance (Kushner, J.A.
Deficiency of PERK results in an abnormally elevated protein synthesis in response to the accumulation of unfolded proteins in ER. IRE1? is expressed in most cells and tissues, while IRE1? is restricted in intestinal epithelial cells (42;43).
PDX1 decrease has also been associated with apoptosis and reduced expression of the anti-apoptotic genes BclXL and Bcl-2 (Johnson, J.D. Activated IRE1 possesses endoribonuclease activity and cleaves 26 nucleotides from the mRNA encoding X-box binding protein-1 (XBP-1), resulting in the increased production of XBP-1 (44).
2006), defects in post-translational processing of insulin, inhibition of GLP-1 receptor expression (Wang, H.
XBP-1 is a transcriptional factor belonging to basic leucine zipper transcription factorfamily. It heterodimerizes with NF-Y and enhances gene transcription by binding to the ER stress enhancer and unfolded protein response element in the promoters of targeted genes involved in ER expansion, protein maturation, folding and export from the ER, and degradation of mis-folded proteins (44-49). In addition, IRE1? also mediates the degradation of ER-targeted mRNAs, thus decreasing the ER burden (50). Unlike PERK and IRE1 which oligomerize upon UPR, ATF6 translocates into the Golgi apparatus after released from BiP. The 50-kDa cleaved ATF6 is relocated into the nucleus where it binds to the ER stress response element CCAAT(N)9CCACG to regulate the expression of targeted genes. For example, once released from the ER membrane, ATF6 enhances the transcription of XBP-1 mRNA which is further regulated by IRE1 (44). ER stress and innate immune responseThe importance of innate immunity was highlighted in the pathophysiology of type 1 diabetes (54-57). However, glucose metabolism can also render a series of signals, or metabolic coupling factors, that may initiate and sustain the second phase of insulin secretion, presumably by favoring mobilization of the insulin granules form the reserve pool and the replenishment of the immediately releasable pool of insulin granules.
Type 1 diabetes was initially considered a T-cell-mediated autoimmune disease (58), in which T-cell was believed as the major immune cell causing ? cell destruction while the involvement of innate immune response has been ignored for a long time.
Some of these metabolic coupling factors participate in mitochondrial shuttles, involving NADPH, pyruvate, malate, citrate, isocitrate, acyl-CoAs, and glutamate (Jitrapakdee, S. However, recent studies suggest a critical role of innate immune responses in the development of type 1 diabetes (54;55). As the first line of defense mechanism, innate immunity is implicated in the initiation as well as the progression of autoimmune responses against pancreatic ? cell.
There are also various signaling pathways that, when activated, may contribute to maintaining or increasing glucose-stimulated insulin secretion, including the CaMKII (Calcium-Calmodulin-Dependent Protein Kinase II), PKA (Protein Kinase A), PKC (Protein Kinase C) and PKG (Protein kinase G) pathways. For example, Cyclic-AMP-responsive-element-binding protein H(CREBH), an ER stress-associated transcription factor, regulates the expression of serum amyloid P-component and C-reactive protein, the two critical factors implicated in innate immune responses. Mitochondrial signallingThe role of mitochondria in the second phase of glucose-induced insulin secretion has been established by several studies in cell lines and humans (Jitrapakdee, S.
In response to ER stress, CREBH release an N-terminal fragment and transit to nucleus to regulate the expression of target genes.


Innate immune response, in turn, regulates the expression of CREBH through inflammatory cytokines such as IL-1? and IL-6 (60). The development of dendritic cells, the major innate immune cells, is also regulated by ER stress response (61). High levels of mRNA splicing for XBP-1 are found in dendritic cell, and mice deficient in XBP-1 show defective differentiation of dendritic cell. Both conventional (CD11b+ CD11c+) and plasmacytoid dendritic cells (B220+ CD11c+) are decreased by >50%.
There is even evidence of an uncommon subform of diabetes, mitochondrial diabetes, where mutations in mitochondrial DNA causepancreatic beta-cell dysfunction (Maechler, P. Moreover, the secretion of inflammatory cytokine IL-23 by dendritic cell also involves ER stress response.
ER stress combined with Toll-like receptor (TLR) agonists was found to markedly increase the mRNA of IL-23 p19 subunit and the secretion of IL-23, while knockdown of CHOP suppressed the induction of IL-23 by ER stress and TLR signaling (62).
Pyruvate, the end product of glycolysis, plays an important role in this process, as it participates in several cycles whose final products constitute amplifying signals for insulin secretion.
The association of ER stress with innate immune response is confirmed in many disease models. Particularly, NADPH, GTP, Malonyl-CoA, long-chain acyl-CoA, and glutamate have been suggested to sustain insulin secretion, although the exact mechanisms by which they have their effects remain to be elucidated (Jitrapakdee, S.
2010).Once entering the mitochondria, pyruvate may be either converted to Acetyl-CoA by pyruvate dehydrogenase, or carboxylated to oxalacetate by pyruvate carboxylase, and therefore enter the Krebs cycle (Figure 2). Notably, there is a high expression of pyruvate carboxylase in the pancreatic islets comparable to that in gluconeogenic tissues, but islets lack phosphoenolpyruvate carboxykinase (PEPCK), the first enzyme in the glyconeogenic pathway (MacDonald, M.J.
In consistent with that, polymorphisms of XBP-1 gene were found to be associated with Crohn’s disease and ulcerative colitis in humans (64), the two autoimmune diseases share similar properties with type 1 diabetes. Lack of XBP-1 in intestinal epithelial cells may induce Paneth cell dysfunction which further results in impaired mucosal defense to Listeria monocytogenes and increased sensitivity to colitis (64). Moreover, several studies have correlated pyruvate carboxylation with insulin secretion (Han, J. ER stress and adaptive immune responseThe presence of ? cell specific autoantibodies is a marker for autoimmune diabetes (66). IRE1 is necessary for the Ig gene rearrangement, production of B cell receptors, and lymphopoiesis.
The expression multiple UPR components including BiP, GRP94, and XBP-1 is up-regulated during the differentiation of B cells (67).
Mice with a deficiency of IRE1 in hematopoietic cells have a defective differentiation of pro-B cells towards pre-B cells (68).
XBP-1, an IRE1 downstream molecule, is also involved in the differentiation of B cell and antibody production by mature B cells. It was found that the engagement of B-cell receptor induces ubiquitin-mediated degradation of BCL-6, a repressor for B-lymphocyte-induced maturation protein 1 (69), while B-lymphocyte-induced maturation protein 1 negatively regulates the expression of B-cell-lineage-specific activator protein (70), a repressor for XBP-1 (71).
In line with these results, B lymphocytes deficient in B-lymphocyte-induced maturation protein 1 failed to express XBP-1 in response to LPS stimulation (72).
As the pancreatic islet is not a lipogenic tissue, the fact that acetyl-CoA activity is high in this tissue may indicate that malonyl-CoA can also act as a metabolic coupling factor for insulin secretion (Prentki, M. The expression of XBP-1 is rapidly up-regulated when B cells differentiate into plasma cells.
Furthermore, XBP-1is able to initiate plasma cell differentiation when introduced into B-lineage cells. XBP-1-deficient lymphoid chimeras have a defective B-cell-dependent immune response due to the absence of immunoglobulin and plasma cells (30). Isocitrate, for example, is converted to ?-ketoglutarate by the NADP-dependent isocitrate dehydrogenase, rendering NADPH. TCR engagement, the first T cell activation signal, induces the expression of ER chaperons including BiP and GRP94. Glutamate has been suggested to be another metabolic coupling factor for insulin secretion, possibly by entering insulin secretory granules and promoting exocytosis (Maechler, P. Finally, GTP may be produced by an isoform of the succinyl-CoA synthetase, which catalyzes the conversion of succinyl-CoA to succinate in the TCA cycle.
IL-2 promotes XBP-1 mRNA transcription, while TCR ligation induces the splicing of XBP-1 mRNA. A recent report suggests GTPase of the immunity-associated protein 5 (Gimap5) mutation in BioBreeding diabetes-prone rat, a model for type 1 diabetes, leads to ER stress and thus induces spontaneous apoptosis of T cells.
Calcium signaling and calcium-calmodulin-dependent protein kinase II (CaMKII)As noted earlier, glucose-stimulated insulin secretion is a Ca2+-mediated process. ER stress regulates cytokine productionCytokine production is an important inflammatory process in response to insults of pathogens, mutated self-antigens or tissue damage. The increase of cytosolic calcium inside the beta-cell must be sensed and transduced in order to exert a secretory response.
ER stress is interconnected with the induction of inflammatory cytokines through multiple mechanisms including reactive oxygen species (ROS), NF?B and JNK (Figure 4). They are important mediators of inflammatory response., Oxidative stress, caused by the accumulation of ROS, was confirmed to be associated with ER stress (77). Besides being localized at the insulin secretory granules, CaMKII phosphorylates proteins involved in the secretory machinery, including synapsin I (Matsumoto, K. For example, the disulphide bond formation during the process of protein folding requires oxidizing condition (78). The PERK axis of UPR is able to activate antioxidant pathway by promoting ATF4 and nuclear factor-erythroid-derived 2-related factor 2 (NRF2) (79;80).
Therefore, deficiency of PERK markedly increases ROS accumulation in response to toxic chemicals (79;81). The IRE1 axis of UPR can activate NF?B, a key regulator in inflammation, by recruiting I?B kinase (82). As a result, loss of IRE1 reduces the activation of NF?B activation and production of TNF-? (82). In addition, the IRE1 axis can also activate JNK, and subsequently induce the expression of inflammatory genes by activating activator protein 1 (AP1) (83). Insulin release is then suggested to be modulated by CaMK II by mobilizing the secretory granules toward the cell membrane by MAP-2 phosphorylation and by potentially regulating the docking or priming mechanisms via VAMP and synapsin I protein phosphorylation.
ATF6, the third axis of UPR signaling, can also activate NF?B pathway and induce inflammatory response. Since CaM kinase II remains active after glucose stimulation, it is suggested as a mechanism of readily releasable pool replenishment. PERK promotes ATF4 and NRF2, which then suppress ROS production by activating antioxidant pathway. The G-protein coupled signaling pathways: PKA and PKCThe guanyl-nucleotide-binding (GTP) protein system or G-protein coupled system plays an important role on insulin secretion. XBP-1 induced by IRE1 can also induce the expression of various genes implicated inflammation. Furthermore, cleaved ATF6 can promote inflammation via activating NF?B.ER stress regulates the expression of cytokines, while cytokines in turn may also induce ER stress via pathways including inducible nitric oxide synthase (iNOS) and JNK. Suppression of JNK by its inhibitor SP600125 can protect? cells from IL-1?-induced apoptosis (85).
Inflammatory cytokines induce iNOS expression in ? cells and produce copious amount of nitric oxygen (86).Nitric oxygen is an important mediator of ?-cell death in type 1 diabetes.
Excessive nitric oxygencan induce DNA damage, which leads to ? cell apoptosis through p53 pathway or necrosis through poly (ADP-ribose) polymerase pathway (87). In addition, nitric oxygencan also deplete ER Ca2+ stores by activating Ca2+ channels or inhibiting Ca2+ pumps (88-90). ER stress in the autoimmune process of type 1 diabetesGiven the involvement of ER stress in both innate and adaptive immune systems, pathways of ER stress play a role in the autoimmune process of type 1 diabetes. For example, mice deficient in PERK, a molecule responsible for regulating UPR, are extremely susceptible to diabetes.
Although the exocrine and endocrine pancreas developed normally, the null mice display a progressive loss of ? mass and insulin insufficiency postnatally (93) (93). A severe defect of ? cell proliferation and differentiation was also found in PERK null mice, resulting in low pancreatic ? mass and proinsulin trafficking defects (94). Depending on the type of G? subunit present, these signals will activate or inhibit Adenylate Cyclase (G?s and G?i subunits respectively).
Consistent with those observations in mice, some infant-onset diabetic cases in humans are confirmed to be associated with the mutations in PERK. Similarly, disruption of UPR by mutating eIF2?, the downstream molecule of PERK signaling, enhances the sensitivity to ER stress-induced apoptosis and results in defective gluconeogenesis. Mice carrying a homozygous Ser51Ala mutation for eIF2? show multiple defects in pancreatic ? cells including the smaller core of insulin-secreting ? cells and attenuated insulin secretion (41).
When the Adenylate Cyclase is activated in the beta-cell, it converts ATP in cyclic AMP (cAMP), which in turn can activate the cAMP-dependent protein kinase (PKA) and the Rap guanine nucleotide exchange factor (GEF) 4 or Epac2.
PKA will phosphorylate several proteins, including L-type voltage-dependent calcium channels and proteins from the exocytotic machinery, increasing sustained insulin secretion (Ammala, C. The activation of IRE1 signaling is involved in the insulin biosynthesis induced by hyperglycemia. Transient exposure to high glucose enhances IRE1? phosphorylation without activation of XBP-1 and BiP dissociation. Epac2 has been shown to favor insulin secretion by increasing the size of the reserve pool and facilitating the recruitment of the granules to the plasma membrane (Shibasaki, T. IRE1? activation induced by transient exposure to high glucose induces insulin biosynthesis by up-regulating WFS1, a component involved in UPR and maintaining ER homeostasis (10;97). However, chronic exposure of ? cells to high glucose may cause activation of IRE1 but with a different downstream signaling, leading to the suppression of insulin biosynthesis (10).
The activation of ATF6 induced by ER stress also suppressed the expression of insulin by up-regulating orphan nuclear receptor small heterodimer partner (98).5. The involvement of ER stress in ? cell destructionIncreasing evidence suggests an important role of ER stress in autoimmune-mediated ? cell destruction (99;100). It was noted that ? cell loss is the direct causing factor for insufficient insulin secretion in type 1 diabetes patients.
Pancreatic ? cells have a very well-developed ER to fulfill their biological function for secreting insulin and other glycoproteins, causing the high sensitivity of ? cells to ER stress and the subsequent UPR.
The insulin gene itself has cAMP response elements in its promoter that modulate insulin transcription in response to this nucleotide (Melloul, D. As described earlier, all the three pathways of ER stress are important in the execution of ? cell function and involved in the autoimmune responses during the process of type 1 diabetes. Pro-inflammatory cytokines are believed as the major mediators contributing to ER stress in ? cell mediated by autoimmune response.
1979), while ligands that decrease adenylate cyclase activity affect insulin secretion in a negative way (Jones, P.M. Autoreactive immune cells infiltrated in pancreas produce pro-inflammatory cytokines, the primary causing factor for ? cell death in type 1 diabetes(101). Autoreactive macrophages and T-lymphocytes present in the pancreatic islets in the early stage of type 1 diabetes and secrete massive pro-inflammatory cytokines including IL-1?, IFN-? and TNF-?. Pro-inflammatory cytokines have been confirmed as strong inducers of ER stress in pancreatic ? cells. Hormones and neurotransmitters mostly act on insulin secretion by this pathway (see below).Phospholipase C (PLC) is the other effector protein regulated by G-protein coupled receptors in the beta-cell.
Insult of ? cells with IL-1? and IFN-? was reported to induce the expression of death protein 5, a protein involved in the cytokine-induced ER stress and ? cell death (102). PLC activation cleaves phosphoinositides into two second messengers, inositol 1,4,5-trisphosphate (IP3), involved in Ca2+ release from the endoplasmic reticulum, and diacylglycerol (DAG). Suppression of death protein 5 by siRNA provides protection for ? cells against pro-inflammatory cytokine-induced ER stress (102). In addition, stimulation of ? cells with IL-1? and IFN-? can decrease the expression of sarcoendoplasmic reticulum pump Ca2+ ATPase 2b, leading to subsequent depletion of Ca2+ in the ER (103). PKC phosphorylates the KATP channels and the voltage-dependent Ca2+ channels and mobilize the secretory vesicles (Doyle, M.E. It has been well demonstrated that altered ER Ca2+ concentration induces the accumulation of unfolded proteins in ER associated with the induction of UPR and ER stress in ? cells (104). Reactive oxygen species such as nitric oxygen produced during inflammation are believed to play a critical role in ER stress-induced ? cell death. Excessive nitric oxygen production during insulitis induces ? cell apoptosis in a CHOP-dependent manner (91).
Both nutrients and neurotransmitters may act through PKC activation, albeit by different mechanisms.
In addition to cytokine-induced ER stress, defective protein processing and trafficking are also a direct cause of ER stress in ? cell.
It has been proposed that nutrients may activate atypical isoforms of PKC (-?, -?, and –?) by a non-identified mechanism independent of DAG, while the typical isoforms (-?, -?, -?, and -?) of PKC (Protein Kinase C) are activated by DAG (Jones, P.M.
For instance, mis-folding of insulin in ? cells directly induces chronic ER stress as evidenced by the observations in Akita mice. The mutation of Ins2 gene in Akita mouse disrupts a disulfide bond between? and ? chain of proinsulin, leading to the mis-folding of the mutated insulin.
This mutation therefore induces chronic ER stress in ? cells and finally causes diabetes in Akita mouse (105). The inefficiency of protein trafficking from ER to Golgi apparatus also causes ER stress in ? cells (106).Hyperglycemia occurs only when ? cells fail to compensate the increased demand for insulin. Calcium increases the activity of calcium-dependent nitric oxide synthases, a key step in the synthesis of cGMP by soluble guanylyl cyclase(cGC). The increased insulin demandrequires the remaining functional ? cellsto increase insulin synthesis to compensate the decrease of ? mass. Calcium may also decrease cGMP synthesis by activating a calcium-dependent phosphodiesterase (PDE1).
The altered insulin synthesis causes ER stress in the ? cells of patients with type 1 diabetes.
On the other hand, protein kinase G (PKG), an enzyme activated by cGMP, may phoshporylate different targets and modulate intracellular calcium concentration, primarily closing KATP channels (Soria, B. In later case, this compensation is beneficial for control of blood glucose homeostasisin a short term.However, the long term alterations of insulin synthesis in the ? cells also induce ER stress which in turn exacerbates ? cell dysfunction and promotes disease progression. Collectively, there is convincing evidence that ER stress plays an essential role in ? cell destruction during the course of type 1 diabetes. Although several studies have pointed to a role of sGC and cGMP on insulin secretion (Laychock, S.G.
Mechanisms underlying ER stress-induced ? cell deathThe primary purpose of ER stress response is to compensate the damage caused by the disturbances of normal ER function. The mechanisms underlying ER stress induced cell death are not fully elucidated, due to the fact that multiple potential participants involved but little clarity on the dominant death effectors in a particular cellular context.
Generally, the process of cell death by ER stress can be illustrated in three phases: adaptation, alarm, and apoptosis (39). The adaptation response phase is to protect cells from damage induced by the disturbances of ER function and restore the homeostasis of ER.
As described earlier, UPR signaling involves three axes of responses: IRE1, PERK, and ATF6. These axes interact between each other and form a feedback regulatory mechanism to control the activity of UPR.
The accumulation of unfolded proteins in ER results in the engagement of ER resident chaperon BiP, and as a consequence, IRE1, PERK, and ATF6 are released from BiP. It has also been shown that PKG activity is necessary to increase ATP content in response to cGMP (Vilches-Flores, A. Therefore, over-expression of BiP can prevent cell death induced by oxidative stress, Ca2+ disturbances, and hypoxia (107).
Upon ER stress, the transcription of BiP is enhanced by ATF6p50, the cleaved form of ATF6 (108). Therefore, PERK deficiency results in an abnormally elevated protein synthesis in response to ER stress, and renders cells highly sensitive to ER stress-induced apoptosis (109). Consistently, as a downstream molecule of PERK, eIF2? is required for cell survival upon the insult of ER stress. A mutation at the phosphorylation site of eIF2? (Ser51Ala) abolishes the translational suppression in response to ER stress (41).
Nutrient modulation of insulin secretionBeta-cells may be considered fuel sensors, as they are continually monitoring and responding to nutrient concentration in the circulation in order to secrete insulin and therefore, regulate glucose homeostasis. Given that meals are composed by multiple nutrients, it is important to examine the interplay between glucose-sensing in the beta-cell and other dietary nutrients, such as amino acids, fatty acids and vitamins. Insulin secretion in response to fatty acidsWhile it would appear that free fatty acids do not stimulate insulin secretion in the absence of glucose, there is a substantial body of evidence that they are essential for glucose-stimulated insulin secretion (Salehi, A.
The transmembrane domain of ATF6 is cleaved in the Golgi apparatus and is then relocated into the nucleus, by which it regulates gene expression (51).During the alarm phase, many signal pathways are activated to alert the system. For instance, the cytoplasmic part of IRE1 can bind to TNF receptor-associated factor 2 (TRAF2), a key adaptor mediating TNF-induced innate immune response.
It has been proposed that, in the presence of glucose, fatty acid oxidation is inhibited, due to formation of malonyl-CoA by acetyl-CoA carboxylase. TRAF2 then activates NF?B pathway via activating IKK and activates the signaling for c-Jun N-terminal kinases (JNK) by apoptosis signal-regulating kinase 1 (Ask1). This permits the accumulation of long-chain acyl-CoA in the cytosol that then stimulate insulin secretion directly or through the formation of other lipid compounds such as diacylglycerol and various phospholipids (Nolan, C.J. It is reported that dominant negative TRAF2 suppresses the activation of JNK in response to ER stress (110). In addition, TRAF2 is also a critical component for E3 ubiquitin-protein ligase complex (111). E3 ubiquitin-protein ligase complex binds to Ubc13 and mediates the noncanonical ubiquitination of substrates, which is suggested to be required for the activation of JNK (112). Furthermore, IRE1 can also activate JNK signaling by interacting with c-Jun N-terminal inhibitory kinase (JIK) (113).Although the purpose of UPR is to maintain the homeostasis of ER, apoptosis could occur when the insult of ER stress exceeds the cellular regulatory capacity. Apoptosis is initiated by the activation of several proteases including caspase-12, caspase-4, caspase-2, and caspase-9. Studies in rodents suggest that caspase-12 is activated by IRE1 and is involved in ER stress-induced apoptosis. The effects of fatty acids on glucose-stimulated insulin secretion are directly correlated with chain length and the degree of unsaturation, where long-chain fatty acids (such as palmitate or linoleate) acutely improve insulin release, however, chronic increase of long-chain fatty acids reduce insulin release in response to glucose stimulation (Newsholme, P. Mice deficient for caspase-12 are resistant to ER stress-induced apoptosis, but remain susceptible to apoptosis induced by other stimuli (114). In response to ER stress, caspase-7 is translocated from the cytosol to the ER surface, and then activates procaspase-12 (115).
Insulin secretion in response to amino acidsIn addition to fatty acid involvement in glucose-stimulated insulin secretion, amino acids derived from dietary proteins and those released from intestinal epithelial cells, in combination with glucose; stimulate insulin secretion, in vivo.
Human caspase-4, the closest paralog of rodent caspase-12, can only be activated by ER stress-inducing reagents not by the other apoptotic reagents.
Amino acids individually are poor insulin secretagogues and a relatively small number of amino acids promote or synergistically enhance glucose stimulated insulin release from pancreatic beta-cells(Newsholme, P.
Knockdown of caspase-4 by siRNA reduces ER stress-induced apoptosis in neuroblastoma cells, suggesting the involvement of human caspase-4 in ER stress-induced cell death (116).
Inhibition of their activation either by inhibitors or siRNA reduces ER stress-induced apoptosis (117). Other than caspase proteins, Ask1 kinase and CHOP are also critical mediators for ER stress-induced cell death. Glutamine and alanine are quantitatively the most abundant amino acids in blood and extracellular fluids and therefore might be the most relevant to insulin secretion (Newsholme, P. The activation of JNK then induces apoptosis by inhibiting anti-apoptotic protein BCL-2 (118) and inducing pro-apoptotic protein Bim (119;120).
Deficiency of Ask1 suppresses ER stress-induced JNK activation and protects cells against ER stress-induced apoptosis (121).
CHOP, a transcription factor belonging to basic leucine zipper transcription factor family, can be activated by many inducers of UPR including ATF4, ATF6, and XBP-1. Alanine increase ATP production in islet beta-cells, an event that has potential to promote the K+ATP channel triggering pathway. Upon activation, CHOP induces cells undergoing apoptosis through suppressing anti-apoptotic protein BCL-2 (122-124).6. Alanine is also one of the electrogenic amino acids, being co-transported with Na+ so that its import depolarizes the plasma membrane and promotes Ca2+ influx, events that trigger insulin secretion (McClenaghan, N.H.
Conclusions and future directionsAlthough exogenous insulin therapy partly compensates the function of ? cells, it cannot regulate blood glucose as accurately as the action of endogenous insulin. As a result, long-term improperly control of blood glucose homeostasis predisposes patients with type 1 diabetes to the development of diverse complications such as diabetic retinopathy (125-127), nephropathy (128;129), neuropathy (130-132), foot ulcers (133-135), and cardiovascular diseases (136-138). Due to the long-term health consequences of diabetes, impact of insulin dependence on life quality, and increasing appearance in both young and old populations, understanding the pathophysiology of diabetes and finding a better way to treat diabetes has become a high priority. Although glutamine is rapidly transported and metabolized by islets, it does not promote insulin secretion by itself or enhance glucose-stimulated insulin secretion, but can elicit insulin release in the presence of leucine (Newsholme, P. Although the underlying mechanisms leading to type 1 diabetes have yet to be fully addressed, accumulating evidence suggests that ER stress plays a critical role in autoimmune-mediated ? cell destruction during the course of type 1 diabetes.
ER stress in ? cells can be triggered by either autoimmune responses against ?-cell self-antigens or the increase of compensated insulin synthesis.
During the course of type 1 diabetes, autoreactive immune cells secrete copious amount of inflammatory cytokines, leading to excessive production of nitric oxygenand ? cell destruction in an ER stress-dependent pathway. It is believed that this is because leucine activates glutamic dehydrogenase, which then increases the capacity of glutamine to contribute to anaplerosis via alpha-ketoglutarate (Newsholme, P. ER stress also regulates the functionality of immune cells with implications in autoimmune progression. The inadequate insulin secretion in patients with type 1 diabetes renders the residual ? cells for compensated insulin secretion to maintain blood glucose homeostasis.
2007a).Similarly as glucose-stimulated insulin release, leucine acts by generating ATP thought its metabolism, thus causing closure of ATP-sensitive potassium channels, membrane depolarization via opening of the L-voltage-dependent calcium channels, leading to calcium influx and increased cytoplasmic calcium concentrations.
This increase in insulin biosynthesis could overwhelm the folding capacity of ER, and exacerbate ? cell dysfunction by inducing ER stress in ? cells. Furthermore, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase, resulting in conversion of glutamate to 2-ketoglutarate, a compound that has been proposedto be a common mediator of glucose, amino acid, and organic acid insulin secretion (Odegaard, M.L. Although ER stress is a critical factor involved in the pathogenesis of type 1 diabetes, it should be kept in mind that the mechanisms underlying autoimmune-mediated ? cell destruction in type 1 diabetes are complex, and ER stress is unlikely the exclusive mechanism implicated in disease process. Despite recent significant progress in this area, there are still many questions yet to be addressed. Are there additional factors inducing ER stress in ? cells during type 1 diabetes development? Additionally, transamination of leucine to ?-ketoisocaproate and entry into TCA cycle via acetyl-CoA can contribute to ATP generation by increasing the oxidation rate of the amino acid and thus stimulation of insulin secretion.Other amino acids also stimulate insulin secretion by elevating cytosolic calcium concentration, although their mechanisms are achieved independently of ATP generation.
Can ER stress be served as a biomarker for ? cell destruction and autoimmune progression in the clinic setting? Positive charged amino acids such as arginine, lysine and histidine, elicit insulin secretion by beta-cell inward transport of positive charge, triggering depolarization of cytoplasm membrane, and influx of extracellular calcium (Newsholme, P.
Does blockade of ER stress in immune cells attenuate autoimmune progression and protect ? cells? Vitamin AVitamin A is found in the organism either as retinol, retinal or retinoic acid forms. Retinoic acid is the active form, and the majority of its effects involve the activation of ligand-dependent transcription factors from the superfamily of hormonal nuclear receptors. Two of these receptors are known: the retinoic acid receptors (RARs) and the rexinoid receptors (RXRs).
These can bind as heterodimers to specific DNA sequences named Retinoic Acid Response Elements, (RAREs) in the promoters of their target genes, or interact with other receptors such as Vitamin D receptors (VDRs), thyroid hormone receptors and PPARs (Peroxisome Proliferation Activating Receptors).
1987) and retinoic acid increases insulin secretion in cultured islets (Cabrera-Valladares, G. 1999), presumably by its stimulatory effect on pancreatic glucokinase expression and activity (Cabrera-Valladares, G. It can also be obtained from food in the form of ergocalcipherol (vitamin D2) or cholechalcipherol (vitamin D3). When UVB radiation is absorbed through the skin, 7-dehydrocholesterol reserves form the pre-vitamin D3, which is transformed into vitamin D3 (1,25(OH2)D3 ) in a further process, by the action of the 25(OH2)D3 hydroxylase (Holick, M.F. Vitamin D acts on Vitamin D receptors (VDRs), which are either in the nucleus or in the membrane, rendering two different mechanisms of action, genomic, and non-genomic (rapid response) (Norman, A.W.
It has been suggested that increases in cytosolic Ca2+, a non-genomic effect of vitamin D, can increase insulin secretion (Norman, A.W. Unrelated to this classic role, pharmacological concentrations of biotin regulate gene expression at both the transcriptional and the translational level (Rodriguez-Melendez, R. 2005), and have a wide repertoire of effects on systemic processes such as development (Watanabe, T.
We have found that biotin stimulates insulin and pancreatic glucokinase expression(Romero-Navarro, G.
1999), an enzyme that plays an important role in glucose homeostasis regulating insulin secretion in response to changes in blood glucose concentrations. Our group found that biotin concentrations of 10 to 1000 nM augmented glucokinase activity and mRNA abundance in cultured rat pancreatic islets (Romero-Navarro, G. A similar stimulatory effect on pancreatic glucokinase was observed in the insulinoma RIN 1046-38 cell line (Borboni, P.
1999) have revealed that glucose-stimulated insulin secretion increases in response to acute exposure to pharmacological doses of biotin in either primary cultured islets (Romero-Navarro, G.
In isolated pancreatic islets, using blockers and inhibitors of different signaling pathways, we have discovered that the induction of glucokinase mRNA and the increase on insulin secretion by biotin involves guanylate cyclase and PKG activation, which triggers ATP production (Vilches-Flores, A. 2009).Although the acute effect of biotin on in vitro insulin secretion has been well documented, further studies addressing the effect of this vitamin on in vivo models, resembling the actual doses and periods of treatment currently recommended for diabetes treatment, need to be done. Other modulatory signals of insulin secretion - hormones and neurotransmittersInsulin secretion in response to the plasmatic concentration of glucose can be increased or decreased by several hormones (including insulin itself) and neurotransmitters via activation of their membrane receptors on the beta-cells(Flat, P.R. The G protein receptors and adenylate cyclase pathway are responsible for mediating most of these effects. The adenylate cyclase pathway may be activated by some neurotransmitters, like acetylcholine, and hormones like GLP-1.
GLP-1 is also an important factor for insulin synthesis and secretion, having a trophic effect on the beta-cells as well (Baggio, L.L.
Other modulating pathways are activated in the beta-cells in response to oxidative stress caused by high glucose levels, like the JNK pathway, which ablates insulin synthesis and interferes with its action (Kaneto, H. Insulin and the beta-cell autocrine signaling Various studies have shown an autocrine role of insulin on beta-cell function and survival (Aikin, R. In this process, insulin binding to tyrosine-kinase receptors located in the beta-cell promotes the receptor’s autophosphorylation, catalyzing subsequent tyrosine phosphorylation of other proteins like IRS (IRS1 and IRS2).
Once phosphorylated, these proteins interact with signaling molecules, which results in a phosphorylation cascade where PI3K, PDK and Akt are sequentially activated. In human islets, insulin has a positive effect on insulin production at the transcriptional level, as well as on beta-cell proliferation (Persaud, S.J. Insulin secretion in response to glucagonGlucagon is considered the contrarregulatory hormone of insulin, as its systemic actions are contrary to the ones exerted by insulin.
Paradoxically, it has been shown that glucagon stimulates insulin secretion both in rats (Kawai, K. Glucagon induces a transient increase in plasma insulin up to 1 mg glucagon concentrations, and this increase is seen before glucose levels rise (Ahren, B. There is evidence that the positive effect of glucagon on insulin secretion is mediated by activation of glucagon receptors in the beta-cells (Kawai, K.
Effects of incretins on insulin secretion Incretins are hormones secreted in the postprandial state by the enteroendocrine cells in the gut. Two incretins have been described GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) (Brubaker, P.L. GLP-1 is released rapidly into the circulation after oral nutrient ingestion, and its secretion occurs in a biphasic pattern starting with an early (within10–15 min) phase that is followed by a longer (30 –60 min) second phase (Herrmann, C. Incretin-receptor activation leads to activation of adenylate cyclase and elevation of cAMP. Its actions include stimulation of glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to islet cells apoptosis (Brubaker, P.L. Both GIP and GLP-1 are cleaved and inactivated by the enzyme dipeptidyl peptidase 4 (DPP4).
The rapid degradation of GLP-1 by DPP4 has led to the development of degradation-resistant GLP-1–receptor agonists and dipeptidyl peptidase-4 inhibitors, in order to increase the incretin effects. Neurotransmitters in the regulation of insulin secretion Besides nutrients, neurohormonal signals such as autonomic innervation can markedly modulate glucose-stimulated insulin secretion.
Islets are thoroughly innervated by autonomic nerves, which contain an extensive variety of neuropeptide transmitters. Increased sympathetic activity affects insulin secretion in situations of stress, exercise and trauma.
Activation of parasympathetic nerves before and during feeding by the smell, taste and digestive tract, along with incretin hormones derived from the gut are responsible for enhancing insulin response to meals.Parasympathetic neurotransmitters that stimulate insulin secretion include acetylcholine, vasoactive intestinal polypeptide and gastrin-releasing polypeptide. Sympathetic neurotransmitters inhibit insulin release; these include norepinephrine, galanin and neuropeptide Y. The enteroinsular axis, mediated by incretin hormones, explains why the insulin response to an ingested nutrient load is greater than when the same load is given parenterally.
Gastrointestinal hormones such as gastric inhibitory peptide, glucagon-like peptide-1 (7-36) and cholecystokinin exert physiological relevant insulinotrophic effects (Flatt, P.R. In particular glucagon-like peptide-1 (7-36) has attracted attention by its potential role in the treatment of diabetes (see above). There are at least three potential sites were insulin can be modulated by hormones, peptides and neurotransmitters. Firstly, these may affect the ion channels that regulate membrane potential and calcium influx. Secondly, they may influence the mobilization of intracellular calcium stores, mainly the endoplasmic reticulum, and therefore cytosolic calcium concentration. Thirdly, they may modify the calcium sensibility of the contractile protein interactions that lead to the release of the insulin secretory granules (Flatt, P.R. The two better known targets of hormones, peptides and neurotransmitters within the beta-cell are related to adenylate cyclase and phospholipase C. Activation of adenylate cyclase produces cyclic adenosine monophosphate (cAMP), which inhibits calcium sequestration within intracellular stores.
Activation of cAMP-dependent protein kinase (PKA) results in phosphorylation of intracellular proteins that enhance calcium sensitization. PKA also promotes phosphorylation of voltage-dependent calcium channels thereby increasing calcium influx (Flatt, P.R. Phospholipase C activation cleaves phosphatidylinosistol in the membrane producing inositol-1,4,5 triphosphate wich in turn inhibits calcium sequestration into the endoplasmic reticulum, while the adjacent cleavage product, diacylglycerol activates protein kinase C. Similarly to the effects of adenylate cyclase signaling pathway, activation of phospholipase C alters insulin secretion by mechanisms related to calcium sensitivity and protein phosphorylation (Flatt, P.R. Beta-cell massBesides a correct beta-cell function, the organism’s beta-cell mass is also important for maintaining adequate insulin production and secretion.
Beta-cell mass is determined by cell number as well as cell size, and it increases progressively during fetal, neonatal and growth periods in the life of an organism, reaching a plateau during adulthood and decaying gradually with age (Ackermann, A.M. Diverse processes participate in increasing and maintaining the beta cell mass, such as neogenesis (newly forming of cells from precursors), proliferation (cell replication), beta-cell size increase (hypertrophy), and apoptosis (cell death) (Ackermann, A.M. 2008), the participation of neogenesis during post-natal and adult beta cell mass is limited (Dor, Y. 2000) the mainly responsible mechanisms for post-natal beta cell expansion (Ackermann, A.M. The organism is also capable of modifying beta-cell mass depending on its insulin requirements. In insulin resistance states, such as pregnancy and obesity, beta-cell mass is increased (Rhodes, C.J. Nevertheless, some of the factors regulating this process have been identified, such as growth factors (growth hormone, lactogens, insulin, insulin-like growth factors), incretins, cell cycle proteins, and transcription factors (PDX-1) (Ackermann, A.M.
Although many of the molecular regulators of postnatal beta-cell mass and beta-cell turnover have been identified in rodent models, it has been observed that human beta-cells’ ability to proliferate under the same signals is very restricted compared to rodent ones (Parnaud, G. Moreover, in humans, beta-cell proliferation has suggested to occur only until early adulthood, as proliferation studies in humans have shown that there is no beta-cell replication after the first 30 years of life (Perl, S.
Beta-cell failure and death in type 1 DMOvert hyperglycemia and therefore, the onset of type 1 diabetes occurs when 70-80% of the beta-cell mass is gone.
But the progressive loss of beta-cells is suggested to occur slowly over several years (Cnop, M.
This progressive damage may also account for a reduction of the first-phase insulin secretion seen in patients positive to islet cell antibodies but who had not developed hyperglycemia yet (Srikanta, S. Nevertheless, the rate of beta-cell destruction in type 1 diabetes patients is variable and so can be the first manifestations of the disease. While some patients, mainly children and teenagers, may present ketoacidosis as first sign of diabetes, others (usually adults) could show modest fasting hyperglycemia, which may not evolve to severe hyperglycemia nor ketoacidosis for several years due to remaining function of the beta-cell (ADA 2009). Regardless this variable nature, type 1 diabetes progression after the initiation of the autoimmune response may be divided in two different phases: insulitis and overt diabetes (Mathis, D.
Apoptosis of the beta-cell is present even in the initiation and, evidently, both in insulitis and diabetes.
These observations suggest that the beta-cell has a more important role in the pathophysiology of the disease than previously thought (Eizirik, D.L. It has been proposed that beta-cell death possibly participates in the initiation of the autoimmune response, particularly in autoantigen presentation (Filippi, C.M.
2000), may undergo physiological periods of apoptosis, particularly during the perinatal period. Moreover, viral infections or inflammatory cytokines may induce accumulation of misfolded proteins, causing ER stress, which can also lead to beta-cell apoptosis (Eizirik, D.L. When these T cells reencounter the islet-antigens, they are retained in the islet, triggering the inflammatory process or insulitis (Mathis, D. Beta-cells themselves are capable of producing chemokines and cytokines in response to inflammatory factors such as IL-1? and IFN? (Cardozo, A.K. 2003), a process mediated by activation of the transcription factors NF?? and STAT-1 (Cardozo, A.K. This cytokines, besides promoting beta-cell death, can contribute to the recruitment and activation immune cells (Eizirik, D.L.
Once insulitis is established, selective destruction of the beta-cells occur mainly by two proposed mechanisms: a recognition-linked mechanism and activation-linked mechanism. The former involves direct recognition of the beta-cell antigens by cytotoxic T-cells, while the latter is caused by exposure of soluble mediators secreted by T-cells that induce beta-cell death (Cnop, M.



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