Type 2 diabetes as an inflammatory disease pdf 2012,jan 8 12 36,sunweb gran canaria - How to DIY


Science, Technology and Medicine open access publisher.Publish, read and share novel research. Oggi e primo febbraio, e nell’emisfero nord oggi e il primo giorno del Mese Pinnerico del Gelone.
Generalmente si presentano nelle aree periferiche del corpo, perche sono le piu soggette ad avere un rallentamento della circolazione sanguigna con l’arrivo delle basse temperature.
I miei geloni di norma iniziano con un leggero formicolio dopo un’importante esposizione alle temperature fredde. Today is February 1st, and in the northern hemisphere today is the first day of the Official Pinneric Month of Chilblain.
I suffer from chilblains since I was a teenager: training every single day at the track and field arena brought me to catch chilblains on the hands, while feet were safe thanks to the training which kept them well warm.
According to Medterms, chilblain is “a cold injury which, while painful, causes little or no permanent impairment. Generally it appears in peripheral parts of the body like hands, feets, nose and ears as they suffer the slowdown of blood circulation more than other body areas. My chilblains generally start with a slight tingle after a huge exposition to cold temperatures. Enter your email address to subscribe to this blog and receive notifications of new posts by email. Subscribe to my ebooks mailing list and receive email updates about Chase's upcoming books, events and other newsworthy stuff!
Humans are natural hosts for many bacterial species that colonize the skin as normal flora. For most patients with impetigo, topical treatment is adequate, either with bacitracin (Polysporin) or mupirocin (Bactroban), applied twice daily for 7 to 10 days. Folliculitis is a superficial infection of the hair follicles characterized by erythematous, follicular-based papules and pustules. Topical treatment with clindamycin 1% or erythromycin 2%, applied two or three times a day to affected areas, coupled with an antibacterial wash or soap, is adequate for most patients with folliculitis. Infection begins with vesicles and bullae that progress to punched-out ulcerations with an adherent crust, which heals with scarring. Erysipelas is a superficial cutaneous infection of the skin involving dermal lymphatic vessels. Group A β-hemolytic streptococcus is the most common pathogen responsible for erysipelas, and S. Classically, erysipelas is a tender, well-defined, erythematous, indurated plaque on the face or legs (Fig. Diagnosis is by clinical presentation and confirmation by culture (if clinically indicated, ie., bullae or abscess formation). Necrotizing fasciitis is a rare infection of the subcutaneous tissues and fascia that eventually leads to necrosis. Infection begins with warm, tender, reddened skin and inflammation that rapidly extends horizontally and vertically. Necrotizing fasciitis is a surgical emergency requiring prompt surgical debridement, fasciotomy, and, occasionally, amputation of the affected extremity to prevent progression to myonecrosis.
Dermatophytosis implies infection with fungi, organisms with high affinity for keratinized tissue, such as the skin, nails, and hair. Tinea cruris (jock itch) occurs in the groin and on the upper, inner thighs and buttocks as scaling annular plaques (Fig. Tinea corporis (body), faciei (face), and manuum (hands) represent infections of different sites, each invariably with annular scaly plaques.
For most patients, topical treatment with terbinafine (Lamisil), clotrimazole (Lotrimin, Mycelex), or econazole (Spectazole) cream is adequate when applied twice daily for 6 to 8 weeks. Candidiasis refers to a diverse group of infections caused by Candida albicans or by other members of the genus Candida. Infection is common in immunocompromised patients, diabetics, the elderly, and patients receiving antibiotics.
Candidal intertrigo is a specific infection of the skin folds (axillae, groin), characterized by reddened plaques, often with satellite pustules (Fig. For candidal intertrigo and balanitis, topical antifungal agents such as clotrimazole, terbinafine, or econazole cream, applied twice daily for 6 to 8 weeks, is usually curative when coupled with aeration and compresses. Tinea versicolor is a common opportunistic superficial infection of the skin caused by the ubiquitous yeast Malassezia furfur.
Infection produces discrete and confluent, fine scaly, well-demarcated, hypopigmented or hyperpigmented plaques on the chest, back, arms, and neck (Fig. Selenium sulfide shampoo (2.5%) or ketoconazole shampoo is the mainstay of treatment, applied to the affected areas and the scalp daily for 3 to 5 days, then once a month thereafter.
Herpes simplex virus (HSV) infection is a painful, self-limited, often recurrent dermatitis, characterized by small grouped vesicles on an erythematous base. Disease follows implantation of the virus via direct contact at mucosal surfaces or on sites of abraded skin.
Primary infection occurs most often in children, exhibiting vesicles and erosions on reddened buccal mucosa, the palate, tongue, or lips (acute herpetic gingivostomatitis). Viral culture helps to confirm the diagnosis; direct fluorescent antibody (DFA) is a helpful but less-specific test. Acyclovir remains the treatment of choice for HSV infection; newer antivirals, such as famciclovir and valacyclovir, are also effective. Herpes zoster (shingles) is an acute, painful dermatomal dermatitis that affects approximately 10% to 20% of adults, often in the presence of immunosuppression. During the course of varicella, the virus travels from the skin and mucosal surfaces to the sensory ganglia, where it lies dormant for a patient's lifetime.
Herpes zoster is primarily a disease of adults and typically begins with pain and paresthesia in a dermatomal or bandlike pattern followed by grouped vesicles within the dermatome several days later (Fig.
Zoster deserves treatment, with rest, analgesics, compresses applied to affected areas, and antiviral therapy, if possible, within 24 to 72 hours of disease onset. HPV infection follows inoculation of the virus into the epidermis through direct contact, usually facilitated by a break in the skin. The common wart is the most common type: It is a hyperkeratotic, flesh-colored papule or plaque studded with small black dots (thrombosed capillaries) (Fig. The disease follows direct contact with the virus, which replicates in the cytoplasm of cells and induces hyperplasia.
Molluscum are smooth pink, or flesh-colored, dome-shaped, umbilicated papules with a central keratotic plug (Fig.
Treatment might not be necessary because the disease often resolves spontaneously in children. Impetigo is a superficial skin infection usually caused by Staphylococcus aureus and occasionally by Streptococcus pyogenes. Tinea versicolor is a common superficial infection of the skin caused by the ubiquitous yeast Malassezia furfur. Herpes simplex virus infection is a painful, self-limited, often recurrent dermatitis, characterized by small grouped vesicles on an erythematous base. On the short term insulin therapy might help to regulate blood sugars, but over the long haul insulin therapy is rather costly to our health as it is fattening, inflammatory and can worsen other chronic diseases like atherosclerosis and heart disease. This is not to say that insulin therapy should be avoided altogether, it is just a matter of appropriate use.
The problem we often see (based on ADA guidelines) is patients starting insulin therapy prematurely despite a functioning pancreas.
I cannot tell you how frequently I see overweight type 2 patients who are taking massive amounts of insulin to the tune of 150-250 units per day.
Teach patients how to eat low carb high fat (LCHF) foods, they lose weight and overnight insulin requirements are cut in half. I was under the impression that Insulin resistance is more closely related to a disfunction of the liver not just a lack of production by the beta cells, seeing as glucose can transverse cell membranes without insulin via glut-4. Hence the High Fasting blood sugar is not coming from a damning back of glucose into peripheral and fat tissue but rather from unregulated gluconeogenesis and glycolysis in the liver. So it may end up being in some instances that the Beta cells are fine, producing more then enough insulin, glucose is transversing fine into the peripheral tissue but the liver is resistant to insulin so it will not get the signal to inhibit actions when glucose levels are raised.
Early on insulin therapy will help to lower blood sugars via many pathways but insulin therapy does very little to alter blood glucagon levels and gluconeogenesis as diabetes worsens. There are blood tests that you can take to determine how much insulin your body is producing. If she is faithfully following a LCHF diet and not cheating in any way and still has such high blood sugar levels, there is a good chance that she is in the position that Dr. Celiac disease or gluten enteropathy is a chronic intestinal disease characterized by diarrhea, steatorrhea and malabsorption, generated by gluten intolerance. Celiac disease is a genetically determined condition that has a familial character, is 10 times more frequent in first degree relatives of people with celiac disease and 30 times more common in twins.
In celiac disease, exist in enterocytes a genetic deficiency of peptidases, which lead to sensitization of the enterocytes to alpha-gliadin, a component of gluten.
Prolonged contact of the enterocytes with undigested gliadin, will lead to a local immunologic conflict, through formation of immune complexes of gliadin and gliadin antibodies.
Interruption of eating gluten favors the restoring of chorionic epithelium, improving transit and malabsorption disorders, with the condition that the diagnosis should be put in the first 3 to 6 years after clinical onset of the disease. Celiac disease may be symptomatic or asymptomatic and may occur at any age, often without diarrhea or steatorrhea.
If it is celiac disease with onset in childhood, the child does not experience symptoms until the introduction of pasta in the diet.
In the adult form of celiac disease, gradually appear diarrhea, steatorrhea and malabsorption syndrome later. There are asymptomatic forms celiac disease that is manifested by iron deficiency anemia, short stature, hypocalcemia and dermatological diseases.
Intestinal biopsy association with positive serology for celiac disease is the gold standard in terms of the diagnosis of celiac disease. Anti endomisium antibodies are very sensitive, over 90% of cases of celiac disease, these antibodies are present.
Determination of antibodies in celiac disease is a useful test, especially in familial and population screenings, and in epidemiological studies, but the test that always confirm celiac disease is the intestinal biopsy.
In cases of celiac disease diagnosed and subjected to a gluten-free diet, the evolution is favorable, with disappearance of diarrhea, steatorrhea and malabsorption. Supervision of compliance with diet can be done by dosing anti gliadin antibodies, which after a few months to a year of proper diet will be normal, but will increase again in case of stopping the gluten-free diet.
Medications: When dose not appear a improvement of symptoms after eliminating gluten from the diet, because celiac disease is in an advanced stage, oral corticosteroids is recommended for a period of 4 to 8 weeks.
Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria.
Regulation of glucose-stimulated insulin secretion by nutrients, hormones and neurotransmitters. Leggendo pure quello anglofono, si aggiunge che i geloni appaiono sulla pelle rendendo quell’area rossa, gonfia, dolorosa e calda al tatto e pruriginosa. Il mio nuovo gelone e apparso ieri sera mentre portavo fuori il cane: anche se indossavo i guanti di pelle, ho avvertito questo formicolio e una sensazione spiacevole come se non mi sentissi piu le mani per il freddo. Si possono usare anche altri tipi di creme idratanti, o se preferite olio d’oliva, salvia o aloe (utilissima anche in caso di bruciature).
Evitate tutti quei tessuti che sono tecnici oppure sono sintetici, perche non isolano adeguatamente le mani dal freddo e possono creare delle condizioni di umidita favorevoli all’insorgenza dei geloni. Se dovesse succedere, praticate un massaggio per riportare la situazione circolatoria ad un livello ottimale. The current new chilblain came out while I was taking the dog for a walk yesterday evening: even though I was wearing leather gloves, I felt a tingle and a unpleasant sensation of not feeling my hands, as if they were frozen.
You can use any other moisturizer, or if you prefer olive oil, sage or aloe (it’s great even in case of burn). The fact is that if you catch them one time, there are several chances to catch them another time in the very same place you have had them. Don’t imitate me too in doing the stupid thing of putting my wet, frozen hands on the well-warm radiator. Avoid those made ??from synthetic fibers: they inadequately isolate from the cold and so create poor conditions of humidity.
Staphylococcus aureus and Streptococcus pyogenes are infrequent resident flora, but they account for a wide variety of bacterial pyodermas. The nonbullous type is more common and typically occurs on the face and extremities, initially with vesicles or pustules on reddened skin.
Furuncles are deeper infections of the hair follicle characterized by inflammatory nodules with pustular drainage, which can coalesce to form larger draining nodules (carbuncles). Systemic antistaphylococcal antibiotics are usually necessary for furuncles and carbuncles, especially when cellulitis or constitutional symptoms are present.2 Small furuncles can be treated with warm compresses three or four times a day for 15 to 20 minutes, but larger furuncles and carbuncles often warrant incision and drainage. Ecthyma is usually a consequence of neglected impetigo and often follows impetigo occluded by footwear or clothing. An oral antistaphylococcal antibiotic is the treatment of choice for cellulitis; parenteral therapy is warranted for patients with extensive disease or with systemic symptoms as well as for immunocompromised patients.
Necrotizing fasciitis commonly occurs on the extremities, abdomen, or perineum or at operative wounds (Fig.
Tinea unguium (onychomycosis) is fungal nail disease, characterized by thickened yellow nails and subungual debris (Fig.
These organisms typically infect the skin, nails, mucous membranes, and gastrointestinal tract, but they also cause systemic disease. The counterpart in men is balanitis, characterized by shiny reddish plaques on the glans penis, which can affect the scrotum. For thrush, the treatment is nystatin suspension or clotrimazole troches four to six times daily until symptoms resolve.
Purported risk factors include oral contraceptive use, heredity, systemic corticosteroid use, Cushing's disease, immunosuppression, hyperhidrosis, and malnutrition. Potassium hydroxide preparation exhibits short hyphae and spores with a spaghetti-and-meatballs appearance. Alternatively, a variety of topical antifungal agents, including terbinafine, clotrimazole, or econazole cream, applied twice daily for 6 to 8 weeks, constitute adequate treatment, especially for limited disease.11 Systemic therapy may be necessary for patients with extensive disease or frequent recurrences, or for whom topical agents have failed.
HSV type 2 infection is responsible for 20% to 50% of genital ulcerations in sexually active persons. After primary infection, the virus travels to the adjacent dorsal ganglia, where it remains dormant unless it is reactivated by psychological or physical stress, illness, trauma, menses, or sunlight. For recurrent infection (more than six episodes per year), suppressive treatment is warranted. Reactivation often follows immunosuppression, emotional stress, trauma, and irradiation or surgical manipulation of the spine, producing a dermatomal dermatitis. Anogenital warts are a sexually transmitted infection, and partners can transfer the virus with high efficiency.
Maceration of the skin is an important predisposing factor, as suggested by the increased incidence of plantar warts in swimmers. Most modalities are destructive: cryosurgery, electrodesiccation, curettage, and application of various topical products such as trichloroacetic acid, salicylic acid, topical 5-fluorouracil, podophyllin, and canthacur. Infection is common in children, especially those with atopic dermatitis, sexually active adults, and patients with human immunodeficiency virus (HIV) infection. Treatment is comparable to the modalities outlined for warts; cryosurgery and curettage are perhaps the easiest and most definitive approaches.
The American Diabetes Association (ADA) guidelines for years have pushed the use of insulin therapy in type 2 diabetic patients without much regard to endogenous (pancreatic) insulin production and more importantly proper diet. There is an absolute need for insulin, to the tune of 50-100 units or less per day depending on diet. The only way to reduce insulin requirement is to reduce the consumption of carbohydrates in the diet, period! Insulin resistance and type 2 diabetes are metabolic disorders caused by dietary carbohydrates and insulin overload. Insulin is not required for muscle and fat cells to access it, but it will enhance uptake at a certain level. In essence, the rate of disposal does not match the rate of production, producing high blood sugar, high ketone bodies, etc. Liver production of glucose significantly contributes to blood sugar but again the problem is insulin resistance and also glucagon production.
Metformin might help a little, but newer medications such as the GLP1 analogs (Byetta, Bydureon and Victoza), are insulin sensitizers and also work on the liver directly and also diminish glucagon production and the release of glucose from the liver.
I am certainly not a doctor but I am a Type 2 diabetic myself and your sister’s blood sugar is dangerously high.
Gerber writes about at the end of this article — she no longer produces enough endogenous insulin to exert any kind of control over her blood sugar levels and therefore must begin taking insulin through injections.
I read a lot of low carb blogs and I know that you’ve been asking this question about your sister on different blogs for a while now. Vernon which was an abject failure, but she might be open to seeing you if that were possible. Morphological element is the atrophy of jejunal mucosa and gluten-free diet leads to clinical and histological improvment of the disease.
These immune complexes are fixed on the intestinal mucosa, stimulates T-cell aggregation, leading in this way to the damage of mucosa with the loss of villi and proliferation of cryptic cells.
In cases of undiagnosed celiac disease will appear gradually malabsorption, which will lead in severe cases to death. IntroductionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin action, insulin secretion or both [1]. 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. E se state pensando che non c’e niente da fare come molti medici e siti web dicono, vi sbagliate. Asciugate accuratamente mani e piedi e copritele bene anche se dovete uscire fuori solo per qualche minuto.
Inoltre, rischiate anche di sviluppare una qualche predisposizione o forma di allergia, quindi fate attenzione. Questa storia del massaggio dovrebbe diventare una specie di abitudine per chi ha problemi coi geloni. And if you are thinking that there’s nothing to do according to some doctors and websites, you are wrong. Predisposing factors to infection include minor trauma, preexisting skin disease, poor hygiene, and, rarely, impaired host immunity. Impetigo commonly occurs on the face (especially around the nares) or extremities after trauma.


The vesicles or pustules eventually rupture to leave the characteristic honey-colored (yellow-brown) crust (Fig. Cellulitis is a warm, tender, erythematous, and edematous plaque with ill-defined borders that expands rapidly. Good hygiene, warm compresses three or four times a day for 15 to 20 minutes, and elevation of the affected limb help to expedite healing.
Thrush is oropharyngeal candidiasis, characterized by white nonadherent plaques on the tongue and buccal mucosa. HSV type 1 is usually associated with orofacial disease, and HSV type 2 is usually associated with genital infection. The Tzanck smear can be helpful in the rapid diagnosis of herpesviruses infections, but it is less sensitive than culture and DFA. Other types of warts include flat warts (verruca plana), plantar warts, and condyloma acuminatum (venereal warts). A quadrivalent HPV vaccine (Gardasil) has been available since 2006, and this represents the newest approach to preventing genital HPV infection and ultimately cervical cancer in women. Most patients have many papules, often in intertriginous sites, such as the axillae, popliteal fossae, and groin. In children, canthacur, applied topically then washed off 2 to 6 hours later, is well tolerated, and is very effective.
It does not matter if you are diabetic or not, insulin signals our fat cells to absorb food energy and make us fat.
On high carbohydrate standard American diets (SAD), patients and healthcare professionals have few medical options.
They all gained weight with the initiation of insulin therapy, especially the short acting varieties. Insulin injection therapy is not the answer and should only be reserved for type 1 and type 2 patients who no longer produce endogenous insulin. An Lc Diet may not necessarily fix that in all instances and may do more harm then good when seen from this perspective.
An HA1c of 10 means that her blood sugar averages 240 around the clock — more than two and a half times what it should be. Both you and she need to realize that there is no magic answer on the internet and sometimes diet alone won’t work. Her doctor of course wants to put her on insulin, but she is very reluctant and the idea concerns me greatly.
FAAFP is a board certified family physician and owner of South Suburban Family Medicine in Littleton, Colorado, where he is known as “Denver’s Diet Doctor”.
The condition is widespread in temperate climates and has a chronic evolution, with onset or exacerbation after consumption of wheat flour products.
The onset of diarrheal syndrome is often insidious,in childhood, but sometimes after age 20 to 30. Another cause of death is the development of lymphoid tumors, especially intestinal lymphoma. Diabetes has taken place as one of the most important diseases worldwide, reaching epidemic proportions.
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.
Occasionally, a pustule enlarges to form a tender, red nodule (furuncle) that becomes painful and fluctuant after several days. Often a continuum of folliculitis, furunculosis (furuncles), arises in hair-bearing areas as tender, erythematous, fluctuant nodules that rupture with purulent discharge (Fig.
Untreated staphylococcal or streptococcal impetigo can extend more deeply, penetrating the dermis, producing a shallow crusted ulcer.
Cellulitis is often accompanied by constitutional symptoms, regional lymphadenopathy, and occasionally bacteremia (Fig. Within 48 to 72 hours, affected skin becomes dusky, and bullae form, followed by necrosis and gangrene, often with crepitus. Kerion celsi is an inflammatory form of tinea capitis, characterized by boggy nodules, usually with hair loss and regional lymphadenopathy. Alterations in the host environment can lead to its proliferation and subsequent skin disease. Paronychia is an acute or chronic infection of the nail characterized by tender, edematous, and erythematous nail folds, often with purulent discharge (Fig. For paronychia, treatment consists of aeration and a topical antifungal agent such as terbinafine, clotrimazole, or econazole for 2 to 3 months; occasionally, oral antistaphylococcal antibiotics are needed, coupled with incision and drainage for secondary bacterial infection. Herpes labialis (fever blisters or cold sores) appears as grouped vesicles on red denuded skin, usually the vermilion border of the lip; infection represents reactivated HSV.
The rough surface of a wart can disrupt adjacent skin and enable inoculation of virus into adjacent sites, leading to the development and spread of new warts.
The immunomodulator imiquimod cream (Aldara) is a novel topical agent recently approved for treating condyloma acuminatum, and it might help with common warts as well, usually as adjunctive therapy.
The vaccine is safe and 100% effective and is recommended for girls and women ages 9 to 26 years.
The problem with type 2 patients is that insulin receptors become resistant to the insulin signal and the pancreas struggles to keep up with insulin demand. Unless her blood sugar is brought under control, she is at great risk of developing the debilitating complications of diabetes — amputation, kidney failure, heart disease, blindness. I suppose it’s possible that she might be able to try a drug such as metformin before trying insulin but she clearly needs to start working with a doctor to find a way to lower her blood sugar. She is very strict with her low-carb diet and is willing to go as strict as necessary and has continually tweaked her diet to make it higher in fat and lower in carbs. He has been providing personalized healthcare to the local community since 1993 and continues that tradition with an emphasis on longevity, wellness and prevention. Most often diarrhea occurs in 1 to 2 hours after a meal of pasta wheat, but other intolerances occur during celiac disease that are making difficult to diagnose it.
Other cancers which are favored by celiac disease are esophageal cancer and small intestine cancer. Completely cure of celiac disease (in pathology exam lesions can not be detect ) in 3 to 5 years of a gluten-free diet, but favorable clinical response can occur from 3 to 6 weeks after starting the diet.
Global estimates predict that the proportion of adult population with diabetes will increase 69% for the year 2030 [2].Hyperglycemia in the course of diabetes usually leads to the development of microvascular complications, and diabetic patients are more prone to accelerated atherosclerotic macrovascular disease. 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.
Antimicrobial therapy should be continued until inflammation has regressed or altered depending on culture results.
Ecthyma can evolve from a primary pyoderma, in a pre-existing dermatosis, or at the site of trauma. Left untreated, cellulitic skin can become bullous and necrotic, and an abscess or fasciitis, or both, can occur. Without prompt treatment, fever, systemic toxicity, organ failure, and shock can occur, often followed by death. Cheilitis resolves with aeration, application of a topical antifungal agent, and discontinuation of any aggravating factors.
Primary genital infection is an erosive dermatitis on the external genitalia that occurs about 7 to 10 days after exposure; intact vesicles are rare. When zoster involves the tip and side of the nose (cranial nerve V) nasociliary nerve involvement can occur (30%-40%). Sexual partners of patients with condyloma warrant examination, and women require gynecologic examination. Since she is still overweight (after 14 years on a low-carb diet), does that mean her pancreas is still producing insulin? Important elements are the clinical symptoms which are correlate with the consumption of wheat flour and symptom disappear at 2-3 weeks after their interruption.
These complications account for premature mortality and most of the social and economical burden in the long term of diabetes [3]. 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.
Computed tomography (CT) or magnetic resonance imaging (MRI) can help to delineate the extent of infection. Angular cheilitis is the presence of fissures and reddened scaly skin at the corner of the mouth, which often occurs in diabetics and in those who drool or chronically lick their lips (Fig.
A single 150-mg dose of fluconazole, coupled with aeration, is usually effective for vulvovaginitis.10 Treatment is summarized in Box 1. Most patients with zoster do well with only symptomatic treatment, but postherpetic neuralgia (continued dysthesias and pain after resolution of skin disease) is common in the elderly. Vernon didn’t seem to be able to understand that she had been on a low-carb diet for years and did not dig any deeper into hormonal or other issues. How can she find out if she is producing insulin and if she is one who really must take insulin to control her blood sugar? Increasing evidence suggests that oxidative stress plays a role in the pathogenesis of diabetes mellitus and its complications [4].
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.
Prodromal symptoms of pain, burning, or itching can precede herpes labialis and genital herpes infections. Hyperglycemia increases oxidative stress, which contributes to the impairment of the main processes that fail during diabetes, insulin action and insulin secretion.
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). In addition, antioxidant mechanisms are diminished in diabetic patients, which may further augment oxidative stress [5, 6]. 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.
I was such a believer that eating low-carb was the answer to preventing and even reversing Type II, but now I don’t know. 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. Oxidative stress At the beginning of life, the organisms obtained their energy (ATP) by anoxygenic photosinthesis, for which oxygen was toxic. 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. Most of the metabolic pathways were developed during this anaerobic stage of life, in which oxygen came later.
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. Cyanobacteria started producing oxygen from photosynthesis, which raised the atmospheric oxygen, and favored those organisms which have evolved into eukaryotic cells with mitochondria, able to use oxygen for a more efficient energy production [9].Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption. We also review how these mechanisms may be affected by the onset and progression of type 1 diabetes.
This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells [9]. Normal function of the beta-cell - glucose stimulated insulin secretionThe pancreas is an endocrine and exocrine gland. The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal.
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). Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA [10].
Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism [11]. Beta-cells are responsible for secreting insulin in response to rises in blood nutrient levels during the postprandial state. The process by which glucose promotes insulin secretion requires its sensing and metabolism by the beta-cell, a process called glucose-stimulated insulin secretion.
Insulin is secreted in a pulsatile and biphasic fashionGlucose-stimulated insulin secretion is biphasic and pulsatile (Stagner, J.I. The secretory pulses of beta-cells are associated with synchronous Ca2+ oscillations in response to glucose stimulus (Bergsten, P.
1994), and they have been suggested to be coupled to glycolysis oscillations of the beta cell (Kar, S. Shortly after glucose stimulus, a first burst of insulin secretion occurs, followed by a decrease in the rate of secretion. 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. 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). Glucose enters the cell by facilitated diffusion mediated by glucose transporters (GLUT2 in rodents, GLUT1 in humans). This enzyme plays a critical role in glucose-stimulated insulin secretion and is considered the glucosensor of the pancreatic beta cell. Due to its kinetic characteristics, glucokinase is a determining factor for glucose phosphorylation (Matschinsky, F.M. 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. These two events depolarize the membrane to a range that allows the opening of voltage-dependent T-type calcium (Ca2+) and sodium (Na+) channels.
Their activation triggers action potentials that increase in intracellular Ca2+ ([Ca2+]i) (Hiriart, M. 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. 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. 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. 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. A second or “slow” phase, characterized by an increasing rate of insulin secretion was sustained during the whole period of glucose infusion. 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. It was until the 1990s that evidence of mechanisms for glucose-stimulated insulin secretion independent of ionic action (i.e. 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.
Biphasic insulin secretion has been explained by the existence of different pools of insulin-containing granules inside the beta cell (Aizawa, T.
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. 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. 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. 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”. 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. 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. 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.
Some of these factors include PDX-1, HNF4?, MAFA, FOXA2 and NeuroD1 (Lazo-de-la-Vega-Monroy, M.L.
PDX-1 is one of the most important transcription factors regulating the insulin gene transcription. Many of the target genes for pdx1 are crucial for glucose-induced insulin secretion, such as glucose transporter glut2 (Ahlgren, U. PDX1 plays a role in the maintenance and proliferation of beta-cells as well (Holland, A.M.
Itsoverexpression in diabetic mice (Irs2 knockouts) participates in beta-cell mass recovery and helps ameliorate glucose tolerance (Kushner, J.A.
PDX1 decrease has also been associated with apoptosis and reduced expression of the anti-apoptotic genes BclXL and Bcl-2 (Johnson, J.D. 2006), defects in post-translational processing of insulin, inhibition of GLP-1 receptor expression (Wang, H. 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.
Some of these metabolic coupling factors participate in mitochondrial shuttles, involving NADPH, pyruvate, malate, citrate, isocitrate, acyl-CoAs, and glutamate (Jitrapakdee, S.


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. 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. There is even evidence of an uncommon subform of diabetes, mitochondrial diabetes, where mutations in mitochondrial DNA causepancreatic beta-cell dysfunction (Maechler, P.
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. 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. Moreover, several studies have correlated pyruvate carboxylation with insulin secretion (Han, J.
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. Isocitrate, for example, is converted to ?-ketoglutarate by the NADP-dependent isocitrate dehydrogenase, rendering NADPH.
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.
Calcium signaling and calcium-calmodulin-dependent protein kinase II (CaMKII)As noted earlier, glucose-stimulated insulin secretion is a Ca2+-mediated process. The increase of cytosolic calcium inside the beta-cell must be sensed and transduced in order to exert a secretory response.
Besides being localized at the insulin secretory granules, CaMKII phosphorylates proteins involved in the secretory machinery, including synapsin I (Matsumoto, K. 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.
Since CaM kinase II remains active after glucose stimulation, it is suggested as a mechanism of readily releasable pool replenishment.
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. Depending on the type of G? subunit present, these signals will activate or inhibit Adenylate Cyclase (G?s and G?i subunits respectively). 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. 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. The insulin gene itself has cAMP response elements in its promoter that modulate insulin transcription in response to this nucleotide (Melloul, D. 1979), while ligands that decrease adenylate cyclase activity affect insulin secretion in a negative way (Jones, P.M. 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. 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).
PKC phosphorylates the KATP channels and the voltage-dependent Ca2+ channels and mobilize the secretory vesicles (Doyle, M.E. Both nutrients and neurotransmitters may act through PKC activation, albeit by different mechanisms. 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. Calcium increases the activity of calcium-dependent nitric oxide synthases, a key step in the synthesis of cGMP by soluble guanylyl cyclase(cGC).
Calcium may also decrease cGMP synthesis by activating a calcium-dependent phosphodiesterase (PDE1). 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. Although several studies have pointed to a role of sGC and cGMP on insulin secretion (Laychock, S.G. It has also been shown that PKG activity is necessary to increase ATP content in response to cGMP (Vilches-Flores, A. 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. 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. 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.
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. 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. 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. 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. Alanine increase ATP production in islet beta-cells, an event that has potential to promote the K+ATP channel triggering pathway.
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.
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.
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. 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. 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. 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. 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.
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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