ß-cell failure in type 2 diabetes mellitus Introduction Obesity is becoming a worldwide problem. In America for instance, more than 60 percent of the habitants are overweight or suffering from obesity. Obesity is an important risk factor for cardiovascular diseases, stroke, and high cholesterol. Another severe disease that has a high correlation with obesity is diabetes mellitus type 2 (D2M). Between 60 and 80 percent of cases of D2M appear to be related to obesity.(4) Research has predicted that the incidence of diabetes in 2025 will reach to 300 million patients worldwide.(9) In recent years, there has been much interest in the ß-cell of the pancreas as the cause of D2M (figure 1). The ß-cell produces the hormone insulin and insulin plays a central role in the metabolism of glucose. It has become very clear now that dysfunction of the ß-cell is the main trigger for the development of D2M. It is therefore important to search what ails the beta-cell in D2M patients en investigate new approaches to restore the beta-cell function. The glucose metabolism All human cells need energy for their maintenance, growth and repair processes. The primary fuel molecule for these cells is glucose. The principal organ of glucose homeostasis is the liver, which absorbs and stores glucose in the post-absorptive state and releases it into the circulation between meals to match the rate of glucose utilization by peripheral tissues. It is insulin that efficiently integrates body fuel metabolism both during periods of fasting and during feeding by binding to the insulin receptors on the cells. In the postprandial phase (phase after a meal) the insulin level is high (figure 2) and suppresses the glucose production from the liver and stimulates the entry of glucose into the peripheral tissues, such as fat and muscle tissues. During the fasting state insulin levels in the blood will decrease, which leads to mobilization of lipids from adipose tissue and mobilization of amino acids from body protein stores, so that they can function as substrate for the hepatic gluconeogenesis (production of new glucose). Hereby the glucose concentration in the blood will stay constant which is very important for the cells to maintain their functions. Thus, insulin plays a very important role in the metabolism of glucose.(1) Pathogenesis of diabetes "Individuals with underlying genetic and/or acquired predispositions to insulin resistance and beta-cell dysfunction begin with a normal glucose tolerance, but they can develop impaired glucose tolerance as their beta-cell function decreases (because of over nutrition and lack of physical activity)" (Islet ß-cell failure in type 2 diabetes, page 2). In this stage, their blood glucose concentration has risen above the normal level, but they have not established D2M yet. These individuals are pre-diabetics.(9) Pre-diabetics are insulin resistant like patients with obesity and/or D2M.(6) This means that there is an increased demand for insulin, because the insulin receptor on the cells need more insulin to bind to get activated and to achieve the same reaction as in non-diabetic individuals. The fact that pre-diabetics have not established D2M yet is because of the compensation of the ß-cells of the pancreas. The ß-cells grow in mass and compensate for this loss of sensitivity by producing and secreting more insulin into the blood. This way the insulin receptor can still be activated and glucose will be taken up by the cells. However, at a certain point the compensation fails, because the ß-cells start to dysfunction. This leads to a poor amount of secreted insulin and high concentrations of glucose in the blood, resulting in D2M.(9) Thus D2M only develops in individuals that are unable to sustain the ß-cell compensation. "It is believed that substantial ß-cell failure occurs at an early stage during the disease progression (prior to diagnosis), after which decline accelerates precipitously.", (Targeting Beta-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus, page 1). Progressive ß-cell failure in D2M is determined by both genetic and acquired factors. In combination, these factors produce ß-cell mass and function incapable of responding adequately to increased demand.(6) Treatment of DM2 Patients suffering from D2M will always be advised to follow a diabetes-diet and to do exercises regularly. If a high blood glucose remains, then patients will start with oral anti-diabetic agents, such as metformin (improves insulin sensitivity). However, most of these patients have to move on to insulin injections or sulfonylureases. The latter works on the ß-cells in the pancreas and stimulates them to secrete more insulin. Animal studies and in vitro studies have suggested that the ß-cell mass and/or function are modifiable parameters, especially in earlier stages of the disease.(6) "The shorter the period of exposing the ß-cells to glucose, the more likely that ß-cells will recover.", (Beta-cell adaptation and decompensation during the progression of diabetes, page 3). There is also clinical evidence that is suggestive for this phenomenon: The Finnish Diabetes Prevention Study and the US Diabetes Prevention Program, both showed a 58% reduction in diabetes incidence among individuals with IGT (impaired glucose tolerance) treated with diet and exercise for 3 years.(3) This means that dieting and exercising are efficient in preventing ß-cell dysfunction and D2M. Unfortunately, in some cases, the doctor decides too soon to give the patient pharmacological therapy and does not stimulate the patients enough to carry on with dieting and exercising. It is, as naturopathic doctor Barker pointed out, "They think that patients are not going to follow the diet, so they give the patient medications. Unfortunately, the medications have side-effects." One of the well-established pharmacological therapies is treatment with thiazolidinediones. Thiazolidinediones have been shown in animal studies to prevent the loss of net ß-cell death and, in clinical trials appear to improve ß-cell function in patients with D2M.(2,11) A new target for therapy is the DPP-IV inhibitor. DPP-IV is an enzyme that breaks down GLP-1 (a gut hormone that is important for the secretion of insulin). Several clinical trials have shown that the DPP-IV inhibitors improve both postprandial and fasting ß-cell function in patients with D2M for up to 24 weeks.(7) Conclusion In short, individuals with underlying genetic and/or acquired predispositions to both insulin resistance and ß-cell dysfunction can develop diabetes mellitus type 2 and only when they are unable to sustain the ß-cell compensatory response. Fortunately, research on this topic develops fast and studies have shown that there are possibilities to restore or prevent the dysfunction of the ß-cell. There are many pharmacological therapies which can help to restore the ß-cell function, but diet and exercising remain important for the treatment of diabetes mellitus type 2. References 1. W.F. Boron and E.L. Boulpaep, 2009, Medical physiology, Philadelphia 2. A. Gastaldeli e.a., Thiazolidinediones improve beta-cell function in type 2 diabetic patients, March 2007, American Journal of Physiology 3. C.E. Gleason e.a., Determinants of glucose toxicity and its reversibility in the pancreatic islet beta-cell line, HIT-T15, November 2000, American Journal of Physiology 4. M. Kasuga, Insulin resistance and pancreatic B-cell failure, July 2006, The Journal of Clinical Investigation 5. J.L. Leahy, Pathogenesis of type 2 diabetes mellitus, May 2005, Arch Med Res 6. J.L. Leahy, Targeting Beta-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus, Journal of Clinical Endocrinology & Metabolism 7. A. Mari e.a., Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes, August 2005, The Journal of clinical endocrinology and metabolism 8. T. Mazzone e.a., Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial., December 2006, JAMA 9. M. Prentki; C.J. Nolan, Islet beta-cell failure in type 2 diabetes, July 2006, The Journal of Clinical Investigation 10. G.M. Reaven, Role of insulin resistance in human disease, 1988, Diabetes 11. G.C Weir. e.a., Beta-cell adaptation and decompensation during the progression of diabetes, Februari 2001, Diabetes 12. P. Zimmet e.a., Global and societal implications of the diabetes epidemic, Nature 2001