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Summary This review sought to collect and interpret the evidence base on home telehealth in managing type 2 diabetes. Summary The ideal for which home telehealth interventions appear to strive is a care delivery system that allows for specialist consultation and ensures high continuity of care while minimizing physician time commitment.  This is most frequently accomplished through heavy involvement of nurses. Science, Technology and Medicine open access publisher.Publish, read and share novel research. The Role of the Kidney in Glucose HomeostasisMaria Mota1, Eugen Mota2 and Ilie-Robert Dinu2[1] Department of Diabetes, Nutrition, Metabolic Diseases, University of Medicine and Pharmacy Craiova, Romania[2] Department of Nephrology, University of Medicine and Pharmacy Craiova, Romania1. Anemia of Chronic Kidney Disease — A Modifiable Risk Factor in a Growing High Cardiovascular Risk PopulationNadine Montemarano1, Jennifer Guttman1 and Samy I. Based on reference 3 Beutler et al.Multiple risk factors increase the risk of developing anemia. National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Andrew S. National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.
Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States : Results From the National Health and Nutrition Examination Survey, 1999 -2000. Writing Group Members for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart Disease and Stroke Statistics—2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R. The mandible is the lower jaw and articulates with the skull at the coronoid process and the mandibular condyle. The pyloric sphincter valve is found between the stomach and the duodenum of the small intestine. Generic Starlix is a medication used for lowering blood sugar in those patients who are suffering from type 2 diabetes. Store Nateglinide pills in an air-tight container and at room temperature, either at 59-86 degrees F or at 15-30 degrees C.
Similarly, if a person takes probenecid, NSAIDs, blood thinner, sulfa drugs, oral diabetes medications, etc. If a person has taken more dosage than prescribed, he is likely to experience symptoms of severe hypoglycemia like extreme weakness, trouble in speaking, stomach pain, seizure, blurred vision, etc.
Della Reese: Staying Strong with Diabetes - Diabetic recipes, free diabetes magazine & more! It turns out that, in addition to having an impressive resume, Della is part of a segment of the population most at risk for diabetes. In addition, African and Hispanic-Americans experience higher rates of many diabetes-related complications, including heart disease, blindness, kidney failure and even amputation. For Della, dealing with the disease and managing it has meant not only taking in as much information about it as possible, but also tackling on diabetes head-on with an aggressive diet, exercise, and medication plan. Della also has created her own diabetes management team—a step she feels is too important to overlook. When you register, we will send you timely reminders about upcoming Twitter chats via email. Constance Brown-Riggs, MSEd, RD, CDE, CDN—an award-winning RD, certified diabetes educator, and past national spokesperson for the Academy of Nutrition and Dietetics, is the author of The African American Guide to Living Well With Diabetes, which received the Favorably Reviewed designation from the American Association of Diabetes Educators, and Eating Soulfully and Healthfully with Diabetes. Lauren Harris-Pincus, MS, RDN is a nutrition communications specialist, registered dietitian in private practice, social media consultant, speaker, spokesperson and corporate consultant. Maureen Sullivan – RN, CDE has worked for many years as a Registered Nurse, most of them in emergency and trauma services. An essay outline is a good way to organize your thoughts on the chosen topic and the research material you have gathered on it.
A good writer should be familiar with the common logical errors in writing, such as slippery slopes, appeals to ignorance, hasty generalizations, non-sequiturs, etc.
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Body: This is the main portion of the essay and it is used to discuss the topic in great detail.
Next, a section that is strictly providing background to the topic can be used, but is is optional and not necessary in all cases. The conclusion is just a summary of the essay, and confirmation of what was said in the introduction. If you don’t have a good template or outline structure, there are plenty of good options available all over the internet, so look there!
The body can obviously be a tough part of an essay to write because so much information goes into it, and there are different things that have to be focused on throughout it. Similarly, there are specific rules for the other formats, which need to be strictly adhered to. An essay template is a guide that ensures your approach is correct and that you do not deviate from the main purpose. We looked at 3 areas: Patients: How is home telehealth used in care management for people with type 2 diabetes?  Do patients like it?  How clinically effective is it? A mobile health intervention for inner city patients with poorly controlled diabetes: Proof-of-concept of the TExT-MED Program. Effect of nephrectomy on glucose needs for maintaining euglycemia in hepatectomized rabbits (Adapted from [6])2.2. Glucose filtration and reabsorption in the proximal tubule of the kidney (adapted from [28])Table 1.
IntroductionIt is only in recent years that the attention was drawn on the important role of the kidney in glucose homeostasis. Role of the Kidney in Normal Glucose Homeostasis and in the Hyperglycaemia of Diabetes Mellitus: Therapeutic Implications. The Relationship of Kidney Function to the Glucose Utilization of the Extraabdominal Tissues.
Renal Glucose Production Compensates for the Liver During the Anhepatic Phase of Liver Transplantation. Effects of Glucagon on Renal and Hepatic Glutamine Gluconeogenesis in Normal Postabsorptive Humans. Sustained Liver Glucose Release in Response to Adrenaline Can Improve Hypoglycaemic Episodes in Rats under Food Restriction Subjected to Acute Exercise. Relative Importance of Liver, Kidney, and Substrates in Epinephrine Induced Increased Gluconeogenesis in Humans.
Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-dependent Glucosuria in Healthy Subjects.
Na+-D-glucose Cotransporter SGLT1 is Pivotal for Intestinal Glucose Absorption and Glucose-dependent Incretin Secretion. Molecular Characterization of Vibrio Parahaemolyticus vSGLT:a Model for Sodium-coupled Sugar Cotransporters.
The Role of Kidney in Glucose Homeostasis - SGLT2 Inhibitors, a New Approach in Diabetes Treatment.
Abnormal Renal, Hepatic, and Muscle Glucose Metabolism following Glucose Ingestion in Type 2 Diabetes.
Maximum Tubular Reabsorption Capacity for Glucose and Renal Hemodynamcis During Rapid Hypertonic Glucose Infusion in Normal and Diabetic Subjects.
Glucose Transporters in Human Renal Proximal Tubular Cells Isolated from the Urine of Patients with Non-Insulin-Dependent Diabetes. Interactions in Vivo Between Oxidation of Non-Esterified Fatty Acids and Gluconeogenesis in the Newborn Rat. Correction of Hyperglycemia with Phlorizin Normalizes Tissue Sensitivity to Insulin in Diabetic Rats.
Aglycone Exploration of C-arylglucoside Inhibitors of Renal Sodium-dependent Glucose Transporter SGLT2. Among multiple factors, individuals with CVD, DM and CKD, HTN(HTN) and of African American race are at significantly high risk than the general population [4,5,6].
The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?
Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health Nutrition Examination Survey(NHANES)1999-2004.
Cardiovascular disease associated with anemia in diabetic patients with chronic kidney disease. Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. Bethesda, MD, The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006. The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal dis- ease.
Abnormal membrane fluidity and acetylcholinesterase activity in erythrocytes from insulin-dependent diabetic patients. Membrane lipid alteration and Na-pumping activity in erythrocytes from IDDM and NIDDM subjects. Changes in fluidity and composition of erythrocyte membranes and in composition of plasma lipids in type I diabetes. In vitro effects of high glucose concentrations on membrane protein oxidation, G- actin and deformability of human erythrocytes. Transferrinuria in type 2 diabetic patients with early nephropathy and tubulointerstitial injury. Left ventricular mass index increase in early renal disease: impact of decline in haemoglobin. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Ethnic Disparities in Cardiovascular Risk Factors and Coronary Disease Prevalence among Individuals with Chronic Kidney Disease: Findings from the Third National Health and Nutrition Examination Survey.
Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: A pooled analysis of community-based studies. Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. TREAT Investigators: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. Predictors of fatal and nonfatal cardiovascular events in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia: an analysis of the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin-alfa) Therapy (TREAT).
USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Reducing the burden of cardiovascular calcification in patients with chronic kidney disease. New insights into the pathophysiology of diabetic nephropathy: from hemodynamics to molecular pathology. Case for intrarenal hypertension in initiation and progression of diabetic and other glomerulopathies. The FDA approved medication stimulates the cells in pancreas for making more insulin, thereby helps in lowering blood sugar level. Some of the less serious side-effects that are not troublesome in nature are diarrhea, nausea, back pain, joint pain, flu symptoms, etc.
Therefore, it is important to tell doctors about all prescription, non-prescription, herbal and dietary supplements which a person is taking. Her vocal ability quickly attracted the attention of gospel great Mahalia Jackson, who hired Della as a back-up singer. While family history, obesity and inactivity all can play a role in the onset of diabetes, certain ethnic groups are at increased risk for the disease.
She is a Certified Emergency Nurse, Certified Diabetes Educator, and the former manager of a hospital stroke program.
Rebecca and her team of six Registered Dietitians have counseled thousands of clients struggling with diabetes for over twenty-five years. On the other hand, there is nothing wrong with getting help from a good consultant on the correct outline format.
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This is where arguments are made and streghtened with information the supports the message that’s trying to be made. After the first sentence, the topic should be discussed, as well as a preview of what is yet to come in the essay. Here is an easy to way to keep the body on track, and help keep thoughouts focused and alligned. An essay template is the product of what ideas you have in your mind about developing the essay.
Nevertheless, along with the liver, the kidney has an important role in ensuring the energy needs during fasting periods.
IntroductionDiabetes Mellitus (DM) has become a modern day epidemic, affecting millions of people around the globe. Generic Starlix should be taken together with exercise and diet to treat non-insulin dependent diabetes. The generic Starlix is a short-acting drug which is used for lowering blood sugar levels after meals. The drug also shows some serious side-effects like jaundice, seizure, allergic reactions, difficulty in breathing, etc.
In case, a person skips any meals, then it is advised to skip the dosage of Nateglinide pill.
All and all it can be said that do not start new medication along with generic Starlix without consultation with doctor. After collapsing on the set with a terrible headache, the music and TV star was rushed to the hospital, where she learned that she shared a disease with 18.2 million other Americans.
This early introduction to the world of gospel entertainment set the stage for Della’s own music legacy that has now spanned five decades and includes multiple Grammy Award nominations.
More than 5 million African-Americans and Hispanic-Americans in the United States today live with diabetes. And, she is an enthusiastic consumer of information, reading everything possible to help her learn more about the disease and how best to manage it. Lauren strongly believes that we should “Think Healthy, not Skinny”, and “EveryBODY is unique, your diet should be too”.
Maureen’s wealth of knowledge, passion for nursing and education, and ability to engage people makes her an excellent teacher and a captivating lecturer.
They work closely with each other along with internists, endocrinologists, therapists, and families.
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You simply place an order with the writing instructions you have been given, and before you know it, your essay or term paper, completely finished and unique, will be completed and sent back to you. It has grown parallel to the rising epidemic of obesity, leading to increased cardiovascular disease (CVD) morbidity and mortality. Postulated mechanisms of anemia in CKD, CVD and DMCKD, CVD and DM are intricately interconnected with one another. The drug is used when diet and exercise alone are unable to control the blood sugar levels. It is important to seek medical attention as soon as person experiences these kinds of side-effects.
Furthermore, if a person has taken the pill but not taken his meal within the time span of 30 minutes, then he is recommended to eat something as soon as possible.
In addition to her acting and singing achievements, Della is an ordained minister with an active congregation in Los Angeles, where she works to inspire young people to pursue their dreams. These groups are almost twice as likely to develop type 2 diabetes than the rest of the population. Lauren was co-host of the Family Food Experts Kitchen radio show, available for listening on iHeart Radio and iTunes.
She is a leading authority on inflammation and its role in weight loss, preventing disease and optimizing health. Below you can find a sample essay outline structure to get a better idea on how to organize your own outline.
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Over 65% of our first-time customers come back with repeat orders for our excellent academic compositions. An essay template is important not only in writing the essay, but also in the research process. Having a glomerular filtration rate of 180 liters per day, it filters approximately 180 grams of glucose per day, bringing its contribution in maintaining normal fasting plasma glucose (FPG) levels [2]. Chez une personne resistante a l’insuline donc diabetique, cette cle dysfonctionne soit en assurant moins bien cette mission soit en le l’assurant plus du tout. Currently, DM is the most common cause of chronic kidney disease (CKD) and subsequent end stage renal disease (ESRD) requiring renal replacement therapy. You should also go through the essay template to learn more about essay structure ones your outline is done. When you order a paper on our website, an outline is just one of the free add-ons that are included. It is a way to organize thoughts and warn you of any mistakes you may encounter while researching and writing. The reabsorption of glucose is ensured by the sodium-glucose cotransporter (SGLT) 2, responsible for the reabsorption of 90% of glucose, and SGLT1, that reabsorbs the remaining glucose [3].Despite the large amount of data regarding the implication of the kidneys in glucose homeostasis, this organ is often overlooked as a key player in glucose metabolism. Although statistics indicate a leveling off in the incidence of ESRD among diabetics, these statistics do not hold true for some of the most vulnerable populations such as minority populations.CVD is the primary cause of death in people with DM who also possess traditional risk factors such as hypertension (HTN), obesity (particularly central obesity), dyslipidemia (decreased HDL, and elevated triglycerides), increased age, sedentary lifestyle and smoking. According to the Center for Disease Control (CDC), more than 35% of people aged 20 years or older with DM have CKD and more than 20% of people aged 20 years or older with HTN have CKD [9]. Other extras are free formatting, free unlimited revisions, free reference page, free title page and a free plagiarism report.


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But the awareness of the renal mechanisms of glucose control is likely to increase due to the development of new types of glucose-lowering drugs that target this metabolic pathway [4].2.
Nontraditional risk factors for CVD include increased inflammation, stimulation of the renin-angiotensin-aldosterone system (RAAS), increased fibrinogen, increased platelet activator inhibitor factor -1 (PAI-1) among others. Regardless of the level of estimated glomerular filtration rate (e-GFR), anemia is both more frequent and more severe in diabetics compared to non-diabetic patients [10]. Il arrive que le diabete se declare a l’occasion de la grossesse on parle alors de diabete gestationnel.
Diabetic kidney disease (DKD) is a well established cause of CVD and currently, it is considered a cardiovascular equivalent.
Diabetes types 1 and 2, are the leading cause of CKD in the western world, accounting for approximately 30-40% of cases.
Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Just put the code FPE15OFF in the order form to get the discount, and request your free add-ons. Early non-human studiesThe first researchers in this field, Bergman and Drury brought the first clues about the involvement of the kidney in glucose homeostasis in 1938 [5]. Put together a healthcare team, including your Costco pharmacist, and make the commitment to take control!
They used the glucose clamp technique in order to maintain euglycemia in two groups of rabbits – one functionally hepatectomized and another one functionally hepatectomized and nephrectomized. The exact cause of increased CVD risk in CKD is likely multifactorial but is largely unknown. A number of mechanisms contribute to the development of anemia in diabetics with CKD such as decreased red blood cell (RBC) life span, iron deficiency, nutritional folate deficiency, occult blood loss, systemic inflammation and what appears to be the most dominant causal factor, erythropoietin deficiency [11]. In the group of hepatectomized and nephrectomized rabbits, the amount of glucose requested in order to maintain euglycemia was very high compared to the one required by the other group [6] (Figure 1).
Anemia has been shown to increase cardiovascular risk in this vulnerable population and prior studies have demonstrated that treatment of anemia reduces this risk and improves quality of life [5]. Renal anemia is associated with a reduction in the number of RBCs and with an increase in oxidative stress to RBCs [23].
On the other hand, recent trials have shown an increased risk of CVD in those with higher hemoglobin values being treated with ESA [56]. He also determined the arteriorenal venous glucose concentrations in the hepatectomized rats.
It is unclear whether the ESA in large doses confers this harm or whether the correction of anemia to high hemoglobin levels is responsible.
While this phenomenon has been recognized for over 50 years, the mechanism is not completely understood [12]. He found that the glucose levels in renal vein exceeded the arterial levels when the animals became hypoglycemic proving that, under these conditions, the kidneys can release glucose into the circulation [7].In 1950, Drury et al. These uncertainties explain why many clinicians prefer transfusion therapy over the use of ESA.
Some studies show that the decrease in RBC half life is partially caused by the uremic environment present in CKD patients. Several questions remain unanswered including the mechanisms by which anemia confers increased cardiovascular risk in CKD and dialysis patients. His experiment indicated that the kidney represents the source of the glucose produced endogenously and released into the circulation after hepatectomy [8].In other experiments, Teng proved that the renal cortex of the animal models with diabetes released glucose at a very high rate, but treatment of these animals with insulin could reverse this effect.
Another important issue surrounded by controversy is the degree to which anemia should be corrected with erythropoietic stimulating agents (ESA).
Studies have also shown that the RBCs in diabetics have multiple metabolic and functional abnormalities [17,18].
A few years later, in 1960, Landau was able to prove, having a similar model, that gluconeogenesis from pyruvate was increased by the diabetic kidney [6].In several experiments, Krebs tried to characterize the substrates that the kidney uses for gluconeogenesis [9], the efficiency of the renal gluconeogenesis in several species [10], and some aspects of the regulation of renal gluconeogenesis [11]. Ces dernieres ont pour role de synthetiser cette hormone qui est essentielle a l'utilisation du glucose sanguin par l'organisme comme source d’energie. In this chapter, we discuss the relationship between DM and CKD and the associated CVD risk factors, highlighting the pathophysiologic mechanisms that link anemia and CVD. We also explore the therapeutic rationale behind the current guidelines provided by the National Kidney Foundation for the management of anemia. En effet, normalement notre organisme dispose de moyens de defense pour lutter contre ce qui lui est etranger, mais ici ces moyens de defense se retournent contre l’organisme lui-meme en attaquant les cellules qui fabriquent l’insuline. These guidelines are constantly updated as new randomized controlled trials continuue to emerge. According to Manodori et al, as a result of these changes, RBC life span in diabetic patients is decreased compared to nondiabetic patients with similar degrees of renal impairment [22]. They tried to measure the differences of glucose concentrations between arterial and renal venous blood. By not taking into consideration that the kidney is able to produce and consume glucose in the same time, the fact that many researchers found little or no differences between arterial and venous glucose values led to the conclusion that the kidneys are not able to release glucose [6].In the mid 1960s, Aber et al. Les recherches scientifiques en faveur d’un traitement s'effectuent principalement vers la comprehension des mecanismes detruisant les cellules responsables de la production d'insuline.
Transferrin is a protein that captures iron that has been absorbed from the GI tract and that has been released from macrophages and delivers it to maturing RBCs. Les chercheurs pensent qu'une predisposition genetique et certains facteurs lies a l'environnement contribuent au developpement du diabete de type 1. Newer research differentiates anemia cutoffs based on both race and age in addition to sex. On sait notamment que certains virus et certaines toxines peuvent declencher une telle reaction chez les personnes ayant des predispositions genetiques. Table 1 lists proposed lower limits of normal for hemoglobin concentration based on Scripps-Kaiser data for the 5th percentiles and the NHANES data published in 2006 [2].
As uremia leads to platelet dysfunction, CKD patients are at increased risk for bleeding and iron loss [24]. Hemodialysis patients are at particular risk because of the chance for blood loss during dialysis [25]. These data led to the current textbook idea that the liver is the only source of glucose, in general, except after prolonged fasting or under acidosis.On the other hand, in subjects that undergo liver transplantation, it may still be observed after removal of the liver, endogenous glucose production [14].
Diabetics with nephropathy are at an added risk for iron loss by urinary excretion as their proteinuria progresses [26]. Shortly after the removal of the liver, the production of endogenous glucose decreased only by 50% (Joseph et al.) [14]. Ils doivent, en complement suivre un regime alimentaire approprie ainsi qu’un programme d'exercices physiques d’entretien. Systemic Inflammation is one of the leading features of diabetics with CKD that appears to contribute to anemia.
Recent research using isotopic measurements have indicated that the kidney can release significant quantities of glucose in postabsorptive normal volunteers.3. This inflammatory response is secondary to a variety of factors including elevated levels of inflammatory cytokines, volume overload and oxidative stress.
The involvement of kidneys in glucose homeostasisThe plasma glucose concentration is determined by the amount of glucose synthesized, and the one removed from the circulation and metabolized. Increased level of cytokines impair bone marrow function and significantly alter iron metabolism. This concentration must be maintained within a relatively narrow range despite the wide daily fluctuations in glucose ingestion and glucose demands in various tissues [4]. Les traitements etant quotidiens (souvent plusieurs fois par jour), le patient doit apprendre a s'administrer lui-meme ses injections. Erythropoietin (EPO) is a glycoprotein growth factor that is produced by the peritubular interstitial fibroblasts of the renal cortex and outer medulla [27]. Other substrates such as free fatty acids (FFAs), glycerol, lactate and ketone bodies have greater daily fluctuations.
The release of EPO is regulated by a complex feedback mechanism at the level of the kidney.
This can be explained by the need of the body to protect himself against hyper- and hypoglycaemia. Hyperglycaemia is associated with both chronic effects (such as nephropathy, retinopathy, neuropathy and premature atherosclerosis) and also acute complications (including diabetic ketoacidosis and hyperosmolar hyperglycaemic state that are associated with higher morbidity and mortality). Hypoglycaemia is also harmful because it can cause neurological events (including coma, seizures), cardiac arrhythmias and death [4].The regulation of endogenous production of glucose is determined by hormonal and neural factors [15]. In the acute phase, glucoregulatory mechanisms involve insulin, glucagon and catecholamines and they can effect changes in plasma glucose levels in a matter of minutes. Insulin is able to suppress glucose release in both the kidney and liver by direct enzyme activation ? deactivation and by reducing the availability of gluconeogenic substrates. In this group, EPO deficiency is regarded as functional as it stems from a failure to increase EPO levels in response to a falling hemoglobin level, even though the absolute value of EPO may be within normal limits. Glucagon has no effect on the kidneys, but it stimulates glycogenolysis and gluconeogenesis in the liver [16].
L'objectif est de s'assurer, a tout moment, que la glycemie est aussi proche que possible de la normale. EPO deficiency appears to contribute largely to the development of anemia in patients with diabetic nephropathy and CKD [28, 29]. On a recemment demontre que l'insulinotherapie intensive avait pour effet de diminuer sensiblement l'incidence et la gravite des complications associees au diabete de type 1. Multiple explanations have been postulated to account for the EPO deficiency in this patient population including microvascular damage, chronic hypoxia, oxidative stress, and autonomic neuropathy. Damage to the tubulointerstitial cells has been observed in the early stages of diabetic nephropathy resulting in impairment of the signaling cascade that triggers transcription and release of EPO [29].
Renal gluconeogenesisFrom the point of view of glucose utilization, the kidney is considered as 2 separate organs; the renal medulla is characterized mainly by glucose utilization and the renal cortex is responsible for glucose release. Unregulated activation of the Renin-Angiotensin-Aldosterone System (RAAS) in diabetics may also contribute to impaired erythropoietin release. The separation of these activities represents the consequence of differences in the distribution of numerous enzymes along the nephron. En raison des risques, la transplantation du pancreas est reservee aux cas ou le diabete ne peut etre controle par les injections d'insuline ou en cas de complications graves. Similarly, experimental models have illustrated that autonomic dysfunction, as seen in diabetics who tend to develop splanchnic nerve dysfunction, have impaired production of EPO [30]. The cells in the renal medulla can use only glucose for their needs (like the brain) and they have enzymes capable of glucose-phosphorylation and glycolysis. Moins couteuse et moins risquee, la transplantation des ilots de Langerhans est encore au stade experimental.
They can therefore phosphorylate important amounts of glucose and accumulate glycogen but, because these cells do not have glucose-6-phosphatase or any other gluconeogenic enzymes, they are unable to release glucose into the bloodstream. Il existe aussi une piste de recherche a travers la reactivation des ilots par des nano particules qui elle aussi est au stade experimental. Moreover, the cells in the renal cortex have gluconeogenic enzymes and they can produce and release glucose into the circulation. Many of the same risk factors that contribute to DM, CKD and CVD, both independently and synergistically. Almost 50% of this is the result of glycogenolysis from the liver stocks and the other half is produced by liver and kidney gluconeogenesis.
Some of the traditional risk factors include obesity, hypertension, dyslipidemia and smoking. The renal cortex (like the liver) contains gluconeogenic enzymes and it can synthesize glucose-6-phosphate from precursors (lactate, glutamine, glycerol and alanine). Les cellules sont moins sensibles a l’action d’une concentration d’insuline donnee, on dit qu’elle developpent une insulino-resistance qui explique le maintien d’une hyperglycemie chronique, meme avec une secretion d’insuline parfois superieure a la normale. Among the non traditional risk factors are anemia, chronic systemic inflammation, oxidative stress, hyperparathyroidism, hyperhomocysteinemia, endothelial dysfunction and prothrombin states [34]. Because it contains glucose-6-phosphatase, it is able to release glucose into the blood stream [18] and the human liver and kidneys are the only organs that can perform gluconeogenesis. Le diabete de type 2, ne resultant pas d’une disparition de la secretion d’insuline et dit non insulino-dependant.
Diabetic kidney disease, also known as diabetic nephropathy, is one of the major complications of type 2 diabetes. Therefore, after an overnight fast, the liver produces 75–80% of glucose released into the circulation and the remaining 20–25% is derived from the kidneys [4].Several studies have indicated that human kidneys and liver provide approximately the same amounts of glucose through gluconeogenesis in postabsorptive period. La tres grande majorite des personnes atteintes de diabete presentent ce type de diabete (90 % des cas).
If the duration of fasting is increased, the glycogen stores are depleted and gluconeogenesis produces all the glucose released into circulation.An important aspect is that kidney and liver use different gluconeogenic precursors and several hormones have different effects on their release of glucose. Depuis quelques annees, on remarque que ce diabete apparait plus tot et chez certaines populations a risque. The increased intracellular glucose leads to increased production of glucose intermediaries cycling through multiple metabolic pathways.
Lactate represents the predominant gluconeogenic precursor in both organs, but regarding the aminoacids, the kidney prefers to use glutamine, whereas the liver preferentially uses alanine [19].
This leads to the production of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-beta (TGF-beta), GTP-binding proteins, and the formation of reactive oxygen species (ROS) [64]. Insulin can suppress glucose release in both organs with almost comparable efficacy [20], whereas glucagon stimulates hepatic glucose release only [21]. Nous savons que les peuples autochtones, les latino-americains, les asiatiques et les populations d'origine africaine , semblent developper la maladie plus que les autres. Catecholamines normally have a direct effect only on renal glucose release [22], but their effect on both hepatic and renal glucose release may be indirect by increasing the quantity of gluconeogenic substrates available and by suppressing insulin secretion. Une predisposition genetique, une surcharge ponderale de base associees a une insuffisance d’activite physique contribuent a l'apparition d'un diabete de type 2. In addition to these metabolic events, there is also a hemodynamic component to diabetic kidney disease.
Other hormones, such as growth hormone, cortisol and thyroid hormones can stimulate hepatic glucose release over a great period of time [15].
Les etudes complementaires tendent a demontrer qu’une alimentation trop abondante et trop riche en graisse pourrait aussi etre un facteur de risque. Hyperglycemia impairs glomerular circulation, mainly dilation of the afferent arteriole, which subsequently leads to increased glomerular capillary pressure [67, 68]. Their effects on the kidneys regarding glucose release in humans are not completely deciphered.In the postprandial state the situation changes significantly. The culmination of these hyperglycemia induced metabolic and hemodynamic derangements sets off a cascade of aberrant cell growth, angiogenesis, extracellular matrix abnormalities, hyalinization of arterioles, proteinuria, and hyperfiltration, ultimately resulting in diabetic kidney injury [64]. Type 2 diabetes is the most common cause of CKD among the US adult population and both DM and CKD can cause anemia. After glucose ingestion, plasma glucose levels reach the peak in 60–90 minutes and they return to post-absorptive levels in almost 3–4 h.
The decreased oxygen carrying capacity associated with anemia may aggravate myocardial hypoxia, increase cardiac output, cause volume overload, increase heart rate, stimulate the RAAS, and can lead to left ventricular hypertrophy (LVH).
The plasma insulin increases four times and the plasma glucagon levels decrease by 50% [15]. En apportant des corrections importantes aux habitudes de vie de la population et en augmentant les regles d’hygiene de vie (dietetique et pratique sportive), il est possible de retarder l'apparition de la maladie et d'en diminuer l'impact dans la population generale.
The damage caused as a result produces myocyte loss, progressive fibrosis, coronary heart disease (CHD) and heart failure [32,33]. Type 2 diabetes increases the risk of CHD events by at least by two- to three fold compared with non-diabetics [31]. There is also a reduction in hepatic gluconeogenesis by 82% and glucose molecules generated through hepatic gluconeogenesis are also directed into hepatic glycogen, not only released in the circulation.Renal gluconeogenesis can increase by approximately twofold and it can represent ~60% of endogenous glucose production in the postprandial state [24]. This mechanism is believed to facilitate the repletion of glycogen stocks in the liver.A new concept of hepatorenal glucose reciprocity emerged from the differences observed in regulation and interchange between renal and hepatic glucose release [24].
This concept refers to the facts that a pathological or physiological reduction in glucose release by kidney or liver determines a compensatory increase in glucose release of the other one (liver or kidney) in order to avoid hypoglycaemia. EpidemiologyGiven the constant influx of immigrants to the western world, addressing the medical issues facing minorities holds critical relevance.
C'est-a-dire se faire tester 2 heures apres une ingestion de 75 g de glucose dilues dans de l’eau. Approximately one third of American population currently identifies as minority, including Hispanics, African Americans, Asians, and Native Americans [35].
GlycogenolysisGlycogenolysis is the breakdown of glycogen to glucose-6-phosphate and a hydrolysis reaction (using glucose-6-phosphatase) in order to free glucose.
Between 2010 and 2050, this population is expected to grow geometrically, most markedly in the Asian and Hispanic American populations, which are both anticipated to double during this period [36].
So, the cleavage of hepatic glycogen releases glucose, while the cleavage of glycogen from other sources can release only lactate.
Ethnic differences in CKDESRD is much more common among ethnic minorities with rates per million as high as 925 among blacks, 501 among Hispanics, and 465 among Native Americans compared with 276 among NHWs. ESRD as caused by HTN, the second leading cause, is also much more common in minorities with a nearly 11 times greater prevalence among blacks than whites [48].
Glucose reabsorptionApart from the important role in gluconeogenesis and the role of renal cortex in glucose uptake, the kidneys contribute to glucose homeostasis by filtering and reabsorbing glucose. On top of that, in patients with ESRD, the prevalence of HTN is greater in both Hispanic and NHBs compared with NHWs. In normal conditions, the kidneys can reabsorb as much glucose as possible, the result being a virtually glucose free urine.
Approximately 180 grams of glucose are filtered by the glomeruli from plasma, daily but all of this quantity is reabsorbed through glucose transporters that are present in cell membranes located in the proximal tubules [24].These glucose transporters have a limited capacity of reabsorption. Levels of C-reactive protein (CRP) and white blood cells are highest among blacks in this population, suggesting a role for inflammation in disease progression [49]. Elevated levels of CRP are associated with the development of Type 2 diabetes [50], an increased risk for coronary events [51] and symptomatic PAD [52] and may help to explain the increased prevalence of CKD in the black population.CKD puts patients at greater risk for MI, stroke and death, with approximately 6 million Americans suffering from both CVD and CKD.
According to NHANES, the prevalence of CVD is 63 percent in those with CKD stages 3–5, compared with 5.8 percent in those without kidney disease [48]. Toutefois, il faut preciser que dans la moitie des cas, le diabete gestationnel apparait en l’absence de facteur de risque. The risk for these cardiovascular endpoints is even higher among African Americans with CKD. When the blood glucose is very high and the TmG is reached, the transporters cannot reabsorb all the glucose and glucosuria occurs (Figure 2). Nevertheless, there can be slight differences between the nephrons and the inaccurate nature of biological systems may potentially lead to the development of glucosuria when blood glucose is below TmG. Glucosuria may occur at lower plasma glucose levels in certain conditions of hyperfiltration (eg. L'enfant risque d'etre plus gros et plus fragile que la normale au risque de compliquer l’accouchement et de developper lui-meme, ulterieurement,  un diabete (Le bebe ne nait pas diabetique, cependant il peut heriter d’un patrimoine diabetique (diabete de type 2)). Ethnic differences in diabetic CKDDM is significantly more prevalent among Non Hispanic Blacks (NHB) than among non-Hispanic whites (NHW). Because of the increased risk of Type 2 diabetes among blacks and among other ethnic minorities [38], the number of Americans with DM is expected to triple from 20 million [37] to more than 60 million over the next forty years [39]. Adapted from [26]In a given day, the kidneys can produce, via gluconeogenesis, 15–55g glucose and it can metabolize 25–35g glucose. Regarding the glucose metabolic pathways, it is obvious that renal reabsorption represents the main mechanism by which the kidney is involved in glucose homeostasis.


Among those aged 30–39, the rate of ESRD in diabetics has risen by 69 percent between 2000 and 2010 whereas it has dropped by one percent in age matched whites.
Si, malgre ces changements, la glycemie ne parvient pas a etre stabilisee, les medecins recourront a l'utilisation d'insuline injectable car l’emploi d’antidiabetiques oraux est contre-indique lors d’une grossesse. Similarly, Native Americans in this age group have seen an increase of ESRD by 30.1 percent during this period. Renal glucose transportersGlucose is a polar compound with positive and negative charged areas; therefore it is soluble in water. La plupart des femmes atteintes de diabete gestationnel et qui suivent le protocole prescrit par leur medecin donnent naissance a des bebes en bonne sante.
This contrasts with rates of ESRD in diabetics older than sixty where ESRD has dropped more dramatically among ethnic minorities than among whites. Its transport into and across cells is dependent on two specialized carrier protein families: the GLUTs (facilitated glucose transporters) and the SGLTs (sodium-coupled glucose cotransporters).
These transporters are responsible for glucose passage and reabsorption in several tissue types, including the proximal renal tubule, blood-brain barrier, small intestine [27].
Par consequent, il est necessaire de realiser un test de depistage (dit test O ‘Sullivan) des le debut de chaque grossesse et quel qu’est ete le deroulement des grossesses anterieures.
Ethnic differences in CKD as one of diabetic CVD complicationsDM is also linked with a greatly increased risk of CVD.
GLUTs are responsible for the passive transport of glucose across cell membranes, in order to equilibrate its concentrations across a membrane. The rise in prevalence of both coronary heart disease (CHD) and peripheral arterial disease (PAD) ranges between double and quadruple the risk of the general population [40].
The risk of PAD increases by 28 percent with each one percent increase in glycosylated hemoglobin, a marker for blood glucose levels [41].Furthermore, NHBs are at significantly greater risk of both PAD and CVD than NHWs [39].
Based on the third National Health and Nutrition Examination Survey (NHANES III), 5 million US adults above age 40 have PAD. Of the family of GLUT proteins expressed in the kidneys, GLUT2 is the major transporter and it releases into circulation the glucose reabsorbed by SGLTs in the proximal tubular cells [28].The renal glucose transport was investigated by analyzing the gene mutations within SGLT family. These can lead to several inherited diseases presenting renal glucosuria that include familial renal glucosuria (FRG) and glucose-galactose malabsorption (GGM). FRG represents an autosomal recessive or autosomal dominant disorder caused by several SGLT2 mutations.
According to the NAACP, NHB males have a 30 percent greater chance of dying from heart disease than NHW males [44].The development and the worsening of CKD as a complication of diabetic CVD is the result of a number of interacting pathways.
Its main characteristic is persistent glucosuria without hyperglycemia or renal tubular dysfunction.
These include enhanced levels of oxidative stress, inflammation, endothelial dysfunction, and RAAS activation [48].
Most of the patients with FRG do not have any clinical manifestations; this is why FRG is not commonly described as a “disease” but as a condition known as benign glucosuria.
In addition, hypertriglyceridemia, associated with CVD, promotes lipid accumulation in renal cells and consequent dysfunction [49]. Nevertheless, there is a severe form of FRG, known as type O, where mutations of the SGLT2 gene lead to a complete lack of renal tubular glucose reabsorption.
Furthermore, vascular calcification in CVD is commonplace among the renal vessels, fostering CKD progression [63]. Thus, ethnic minorities are more likely to develop these conditions both independently and as part of cardiorenal syndrome. Part of the racial discrepancy in CKD, diabetic CKD and the associated complications may be explained by an increase in metabolic risk factors among minorities.
Based on a three-year, cross-sectional sample of 15,826 patients with Type 2 diabetes, both Hispanics and NHBs were found to have higher body mass index, HbA1c, and LDL values in comparison with NHWs. They appear in the first few days of life and determine glucose and galactose malabsorption. The consequences are severe; diarrhea and subsequent dehydration may become fatal unless a special diet (glucose- and galactose-free) is initiated.
Moreover, ethnic minorities are both less physically active and have worse dietary behaviors compared to NHWs [46].
Some patients with GGM may present glucosuria but it is typically mild, and some other subjects have no sign of urinary glucose excretion. Minorities are also less likely to have health insurance coverage or to have a regular doctor [44].
As a result of the lower levels of glycemic control and the higher prevalence of both vascular disease and metabolic risk factors, rates of mortality from DM are persistently higher among NHBs than among NHWs [47].
The mutations involving the GLUT family are associated with more severe consequences, because these transporters are more widespread throughout the major organ systems.
The difference in the prevalence of cardiovascular disease in those with DM and CKD among different ethnicities is striking. SGLT2 and SGLT1 are located mainly in the renal system, but GLUT2 is present almost everywhere in the organism, having an important role in glucose homeostasis through its involvement in intestinal glucose uptake, renal reabsorption of glucose, and hepatic uptake and release of glucose [24].Direct in vivo experiments of Vallon et al.
As health disparities continue to grow, a closer investigation into the root of these ethnic differences will help clinicians to create a more targeted approach.3.
Therapeutic rationale Anemia is a risk factor for cardiovascular morbidity and mortality that is reversible [54]. There are currently two Food and Drug Administration (FDA) approved ESAs in the United States, Epoetin alfa (Epogen, Procrit) and Darbepoetin alfa (Aranesp).
According to the Kidney Foundation Guidelines, all patients with CKD should be screened at least annually for anemia with a set of labs that include a complete blood count (CBC), a hemoglobin concentration (MCHC), iron studies, folate and Vitamin B12. Its secondary structure consists of 14-transmembrane helices (TM1–TM13) with both the NH2 and COOH termini facing the extracellular side of the plasma membrane [32].
Patients found to be iron deficient need to be started on iron supplementation, especially hemodialysis patients who may lose up to 3-5g of iron per year. The kidney in diabetes mellitusAll the metabolic pathways regarding the involvement of the kidney in glucose homeostasis are modified in subjects with diabetes mellitus.
Subjects with type 2 diabetes mellitus (T2DM) have an increased renal release of glucose into the circulation in the fasting state [34]. The kidney can increase its glucose production with 300% compared with the liver that can increase gluconeogenesis only by 30%. Gluconeogenesis, in the kidney, could explain this glucose increase, in the fasting state [34].In postprandial state, renal glucose release is greater increased in subjects with T2DM than in people without glucose metabolism abnormalities [35].
During this three year study complete correction of anemia did not affect the likelihood of a first cardiac death. The result was determined by a higher endogenous glucose release because the general appearance of ingested glucose was only 7 g greater in the subjects with DM. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) trial in 2009 is randomized, double blind placebo controlled trial that was conducted to evaluate whether increasing the hemoglobin level with the use of darbepoetin would lower the rate of death, cardiovascular events or end stage renal disease in patients with type 2 diabetes and CKD. Almost 40% of the increased endogenous glucose release was caused by increased renal glucose release [35].
This fact was determined mainly by impaired suppression of endogenous glucose release and secondary by reduced initial splanchnic sequestration of ingested glucose. Darbepoetin did not reduce the primary endpoints of death, cardiovascular events or ESRD in patients with DM and CKD.
This is determined by the increased glucose reabsorbtion in subjects with diabetes mellitus.
Therefore, the Tm for glucose is increased and glucosuria may occur at higher than normal blood glucose levels. Several studies indicated that the Tm increased from near 350 mg ? min in subjects with normal glucose tolerance to approximately 420 mg?min in subjects with diabetes mellitus [36].As an evolutionary process, the kidney was able to develop a system in order to reabsorb all of the filtered glucose in order to conserve energy especially at a time when energy intake was reduced. Therefore, this may be considered as an adaptive response as the SGLT2 transport increases in response to hyperglycaemia. Their findings brought to light several important ways to improve CVD risk stratification [57]. But, in subjects with diabetes this adaptive response is considered maladaptive, and glycosuria occurs only at very high plasma glucose levels.
A 2012 update to the National Kidney Foundation clinical practice guidelines for DM and CKD was recently published to address new evidence that has emerged since the release of the 2007 guidelines. Thus, instead of allowing the kidneys to excrete excess of glucose, SGLT2 transporters help maintain a higher plasma glucose concentrations [1].Human and animal studies of renal cells have demonstrated enhanced expression of SGLT2 transporters [37]. Factors like hyperglycaemia, albumin and angiotensin II have been reported to increase the expression of SGLT2 in T2DM [37].It has also been demonstrated that acidosis increases renal gluconeogenesis and impairs hepatic gluconeogenesis [38].
Therefore one can speculate that the kidney represents an important factor that accelerates gluconeogenesis in diabetic ketoacidosis. If the anemia is addressed in its early stages, the risk of complications can be significantly reduced, especially those related to cardiovascular morbidity and mortality among the diabetic population. Moreover, the exaggerated increase in renal glucose release can be the result of the insufficient suppression of endogenous glucose release postprandial in diabetic patients [39]. In addition, appropriate and timely treatment can improve the quality of life for these patients.
It is important that physicians screen patients who are at risk for developing anemia as per accepted guidelines. A major part of the high renal glucose release found in subjects with diabetes may be determined by increased renal glycogenolysis [6].5. This is especially important given that based on data collected from 1998-2008, NHANES found that the prevalence of DKD has steadily been increasing. Diabetic nephropathyDiabetes represents the most common single cause of end-stage renal disease (ESRD) in the United States and Europe.
The latest United States Renal Data System (USRDS) reported a 30 percent increase in the incidence of ESRD in diabetics in the United States between 1992 and 2008 [59, 60]. There can be several factors responsible for this, including an increased prevalence of T2DM, longer life spans among patients with diabetes, and better recognition of kidney disease [40].
These figures indicate that anemia as caused by CKD in diabetics is an ongoing and ever-increasing problem in which all of the risk factors involved need to be addressed as part of regular preventative health measures. Comparing with subjects with type 1 diabetes mellitus, only a smaller fraction of those with T2DM develop ESRD, but due to the increased prevalence of T2DM, these individuals represent more than a half of those with diabetes on dialysis. The detection of albumin in the urine increases the risk of progression to persistent albuminuria, progressive decline in glomerular filtration rate (GFR), increased blood pressure and cardiovascular morbid-mortality. The risk of developing CVD is significantly increased in diabetics with CKD compared with non-diabetics with CKD.
But because T2DM may be present for many years before diagnosis, a higher proportion of individuals with T2DM have microalbuminuria and overt nephropathy shortly after diagnosis. It is known that without treatment, 20-40% of patients with T2DM and microalbuminuria progress to overt nephropathy. Nevertheless, after 20 years from the onset of nephropathy, only 20% will have progressed to ESRD [40]. The explanation comes from the greater risk among subjects with diabetes and chronic kidney disease of dying from cardiovascular disease than progressing to ESRD.Several clinical trials indicate that the onset and development of diabetic nephropathy may be significantly influenced by numerous interventions including tight glucose control and also use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
This is the reason why annual screening for microalbuminuria is critical since it can lead to early diagnosis of nephropathy.
In the ADVANCE trial, after almost 5 years, subjects that were on intensive glycemic control had a 10% relative reduction in the combined outcome of major macrovascular and microvascular events.
This was happening mainly because of a 21% relative reduction in the risk of developing nephropathy. The intensive glucose control is also important because it is associated with a 9% reduction in new onset microalbuminuria [41]. Results of this study are of great importance since renal impairment is strongly associated with future risk of major vascular events, and death in patients with diabetes. Nevertheless, the role of modified renal glucose reabsorption in the progression of diabetic nephropathy is not elucidated [4].6. SGLT2 inhibitorsSGLT2 is highly specific for (several authors consider that it is found only in) the proximal tubules of the kidney, as compared to SGLT1 or GLUT2, therefore it is a preferred target for more specific renal pharmacologic interventions.
Thus, the idea of interfering with the activity of the SGLT2 has gained much attention [2].Inhibition of SGLT2 transporter ‘resets’ the reabsorption system by lowering the threshold for glycosuria, resulting the correction of the hyperglycemia [1]. Reduction of the blood glucose level can improve insulin resistance in muscle by increasing insulin signaling, GLUT4 and glycogen synthase activity [1].The history of SGLT2 inhibitors starts in 1835 when phlorizin was found in the root bark of apple tree [42]. Many years after, it was found to be a non-specific SGLT1 and SGLT2 and it could increase glucosuria and reduce blood glucose levels and normalize insulin sensitivity in a pancreatectomized animal model of T2DM [43]. Being non-selective and inhibiting SLGT1 at the intestinal brush border, it can cause serious problems regarding the absorption of dietary glucose.
Inhibition of SGLT1 can result in glucose–galactose malabsorption and cause diarrhea, events that occur naturally in SGLT1 deficiency [44]. Moreover, in the intestine, phlorizin is poorly absorbed and is rapidly hydrolyzed to phloretin, a substance that blocks GLUT1, leading to disturbance in glucose uptake in several tissues [45]. Highly-specific inhibitors of SGLT2 have subsequently been developed in order to overcome some of these shortcomings.Ellsworth et al [46] discovered a group of C-aryl glycosides that includes dapagliflozin [47] and canagliflozin [48]. They are resistant to degradation produced by ?-glucosidase enzymes in the gastrointestinal tract. Moreover, dapagliflozin has a very high sensitivity for SGLT2 compared to SGLT1, blocking renal glucose reabsorption by almost 40–50%. Clinical trials evaluating the treatment with dapagliflozin, either as monotherapy or in association with metformin or with insulin in subjects with T2DM have demonstrated its efficacy in reducing glucose and HbA1c levels [3]. Pharmacokinetics and bioavailability of dapagliflozin are not influenced by a high-fat meal and there are no reports regarding any interactions with several other drugs used in the treatment of T2DM [3].Human trials analyzing canagliflozin are more limited than for dapagliflozin. Some of them, such as ipraglifozin and empagliflozin, are being tested in phase III trials and are promising very good results while other compounds have disappointed in clinical trials due to possible side effects (sergliflozin) or to susceptibility to hydrolysis by ?-glucosidase enzymes (sergliflozin and remogliflozin) [3].As already mentioned, patients diagnosed with FRG often gave higher urinary glucose excretion of almost 120 g per day. It remains unclear why treatment with SGLT2 inhibitors cannot achieve the same levels of glycosuria even when the maximal doses are used. Moreover, SGLT2-null mice can only reabsorb up to a third of the filtered glucose [29], but subjects taking dapagliflozin reabsorb ~50% at the highest doses.
One possible explanation may be that SGLT1 has a greater role in the kidney than it was previously imagined [50]. There are some theories that include antisense nucleotide technology to knock out SGLT2 in order to achieve a higher degree of blockade of glucose reabsorption than SGLT2 inhibition.
Preliminary data in human subjects with T2DM with moderate or severe renal impairment indicate that SGLT2 inhibition determines proportionally less glycosuria than in subjects with preserved renal function [51]. These findings confirm that a low GFR in subjects with T2DM is accompanied by a comparable loss of tubular absorptive capacity that represents the anticipated consequence of nephron loss [3].The approach of lowering hyperglycaemia in T2DM by blocking glucose reabsorption has many attractions. One of them is represented by the activity of SGLT2 inhibitors that is not dependent on pancreatic ?-cell function, which deteriorates over time.
Other drugs such as the insulin secretagogues [glinides, sulphonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists] and insulin sensitizers (thiazolidinediones and metformin) depend on insulin secretion. The insulin independence of their action indicates that the risk of hypoglycaemia is very low [6].As a consequence, the liver can react to the induced glycosuria by increasing glucose release.
The relative small decrease in plasma glucose but also insulin concentrations after massive glycosuria may stimulate endogenous glucose release. Moreover, glucose output is usually not decreased enough to attain and maintain normal glucose values in patients with T2DM treated with SGLT2 inhibitors [52]. Adaptation of glucose metabolism to massive glycosuria needs further investigation.Osmotic diuresis accompanies glycosuria. It is usually detected an increase in urine output with acute SGLT2 inhibition; while chronic administration of SGLT2 inhibitors is accompanied by an excess urine volume of 200–600 ml per day. As a consequence, haematocrit increases are noted but they are moderate and clinical signs of volume depletion, such as tachycardia and orthostatic hypotension, are rarely met [52].SGLT2 inhibitors determine glucose and sodium reabsorption blocking and natriuresis also occurs. Changes in serum sodium concentration are not frequent with chronic SGLT2 inhibition because at the nephron level, reduced sodium reabsorption in the proximal segment determines the increase of sodium delivery to the juxtaglomerular apparatus, and the inhibition of the renin-angiotensin-aldosterone system (RAAS) occurs. In experimental diabetic rats fed a high-salt diet [53], SGLT2 inhibition could prevent blood pressure increase.
This effect may be countered by an activation of the RAAS if volume depletion appears as a consequence of excessive diuresis.
SGLT2 inhibition in patients with T2DM also determines the reduction of blood pressure levels (by 2–5 mmHg) [52].
Because most of the individuals with T2DM also present high blood pressure, this effect is of great importance in clinical practice.Several phase III clinical trials of dapagliflozin reported the decrease of serum uric acid concentrations [54]. Sodium and urate are handled together in several physiological circumstances, and also in response to several drugs such as diuretics and antihypertensives. Therefore, the excretion of urate determined by SGLT2 inhibitors is explained by this mechanism. At first, this weight loss is predominantly due to fluid depletion, but soon after that appears the loss of subcutaneous and visceral depots of adipose tissue. Nevertheless, body weight loss remains constant after several months of treatment [3].Clinically, the most frequent and undesired effect of SGLT2 inhibitors is represented by high incidence of genitourinary infections.
These infections were observed more frequent in women than in men taking SGLT2 inhibitors and tend to occur in susceptible subjects; these include postmenopausal women, history of urinary tract infections or poor hygiene. Interestingly, studies with dapagliflozin in addition to metformin reported a not significant difference in incidence of genitourinary infections between individuals in the placebo and treatment groups [56], while in subjects receiving dapagliflozin in addition to insulin, the difference was significant [57].
This might explain a possibly increased risk of this adverse effect in patients with advanced T2DM (when immune function may be defective) [3].The incidence of genitourinary infections tends to decrease in time, with long-term treatment, when the adaptation to the treatment is installed or exclusion of susceptible individuals over time appears. The increased PTH might indicate a mild form of secondary hyperparathyroidism but the available studies so far offer very few data regarding the long-term effects of SGLT2 inhibitors on bone metabolism, making room for other clinical studies on this important issue.There have been reports regarding several cases of bladder cancer and breast cancer, in subjects with T2DM receiving treatment with dapagliflozin [58].
Trials with large numbers of patients with different SGLT2 inhibitors are required to assess any associated increased risks of breast or bladder cancer [3].Theoretical safety and tolerability concerns also include impairment in renal function [54].
Although, until now, there are no data indicating that the SLGT2 inhibitors would determine or be responsible for deterioration of renal function, the few clinical studies investigating these drugs have relatively short duration (6-12 months).
Moreover, several authors are speculating that SGLT2 inhibitors may play an important role in preventing diabetic nephropathy. First, improved glycaemic control decreases the risk of diabetic nephropathy and other diabetic complications [40].
Second, by increasing the quantity of sodium in the juxtaglomerular apparatus, the use of SGLT2 inhibitors may determine a protective effect on the kidney, independently of glucose decreased.In T2DM, the high quantity of glucose and sodium absorbed in the proximal tubule reduces the quantity of sodium to be delivered to the juxtaglomerular apparatus. Thus, the glomerulo-tubular feedback reflex is activated; this leads to high renal plasma flow, increased intra-glomerular pressure and elevated GFR. All these processes can induce normal salt delivery to the juxtaglomerular apparatus; however this can result in increased intra-glomerular pressure.
All these alterations in renal hemodynamic lead to renal hypertrophy and eventually the result is represented by diabetic nephropathy [59]. SGLT2 inhibitors may prevent diabetic nephropathy by inhibiting the glomerulo-tubular feedback reflex and, therefore increasing sodium delivery to the distal nephron [1]. New clinical trials are expected to evaluate the efficacy and safety of SGLT2 inhibitors.The pathogenesis of type 2 diabetes combines numerous defects in many tissues. Therefore, there is no single antidiabetic drug that can compensate all the metabolic disturbances, and a good treatment for diabetes will require the use of multiple drugs in combination.
Having a unique pharmacokinetic and a special mechanism of action, the SGLT2 inhibitors can be used not only as monotherapy [61] but also in combination with currently available antidiabetic agents [62,63].7. ConclusionsAlthough not traditionally discussed, the kidneys play a very important role in maintaining glucose homeostasis by gluconeogenesis and glucose reabsorption, the latter being mediated by active (SGLT) and passive (GLUT) transporters.
Only recently, excessive renal glucose reabsorption was taken into consideration regarding its importance in the physiopathology of T2DM. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, bringing their contribution to chronic hyperglycemia. Knowing the kidneys’ role in glucose homeostasis and the effect of glucose dysregulation on the kidneys is very important for the optimal management of T2DM and prevention of associated renal complications.



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Comments

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    That Gary Taubes asserts that's low fat.

    07.03.2015

  2. Akulka

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    07.03.2015

  3. ZUZU

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  4. rash_gi

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  5. RIHANNA

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    07.03.2015