Beta-cell Defects in Type 2 Diabetes and the Possibility of Treatment Options with GLP-1-based Therapies
Beta-cell Defects in Type 2 Diabetes and the Possibility of Treatment Options with GLP-1-based Therapies
US Endocrine Disease 2006 Issue 2
Published: October 2008
Published: October 2008
Type 2 Diabetes as a Progressive Disease
In type 2 diabetes, beta-cell dysfunction plays a major part not only in the pathogenesis of the disease, but also in disease progression over time. Under normal conditions, blood glucose concentrations are regulated within a very tight range. After a meal, insulin secretion from the beta cell is stimulated, whereas glucagon secretion from the alpha cells is suppressed. Insulin facilitates glucose uptake into the cells, whereas glucagon stimulates glucose production in the liver.
In the development of type 2 diabetes, environmental influences (most importantly diet and sedentary lifestyle) and genetic factors lead to the development of insulin resistance (i.e. reduced insulin sensitivity of the peripheral tissues, mainly the muscles, liver and adipose tissue) that only in the early stages can be compensated by hypersecretion of insulin from the beta cells.Already in pre-diabetes (impaired glucose tolerance (IGT)), the pattern of insulin secretion is disturbed and the rapid and accentuated first phase of insulin secretion observed in non-diabetic subjects after a sudden rise in plasma glucose is lost. This results in elevated blood glucose concentrations after a meal. With the further deterioration of insulin sensitivity, beta-cell function further worsens, leading to fasting hyperglycemia. Under chronic hyperglycemic conditions and persisting insulin resistance, insulin secretion further deteriorates. The concomitant lack of suppression of glucagon secretion from the alpha cells additionally contributes to high blood glucose concentrations due to increased glucose output from the liver. Finally, morphologically, a decrease in beta-cell mass due to increased cell death of beta cells and deposition of amyloid in the remaining beta cells can be found.1
Classical Treatment Options Do Not Influence the Natural Course of Type 2 Diabetes
With the classical treatment options of type 2 diabetes, a steady decline of beta-cell function is observed, since none of the current treatments is aimed at the amelioration of beta-cell deterioration.Therefore, none of these therapeutic options for type 2 diabetes is able to influence the natural course of the disease.
Sulfonylureas, which have been in use for half a century now, and chemically related metiglinides stimulate insulin release from remaining functional beta cells due to interference with the adenosine triphosphate (ATP)- dependent potassium channel on the cell membrane. Metformin and thiazolidinediones (TZDs) predominantly act on the peripheral tissues as insulin sensitizers . Alpha glucosidase inhibitors slow the resorption of monosaccharides from the intestinal tract. Exogenous insulin as well has no direct effect on betacell function and beta-cell mass.2
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