PATHOPHYSIOLOGY AND TYPE II DIABETES

Pathophysiology and Type II Diabetes



Pathophysiology and Type II Diabetes

Abstract

Type 2 diabetes is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. ß-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal ß-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of ß-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. A marked reduction in ß-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in ß-cell apoptosis non-compensated by neogenesis.

Pathophysiology and Type II Diabetes

Table of Contents

Abstract2

Introduction4

Resistivity4

Deficiency4

Insulin therapy in recently diagnosed type 2 diabetes4

Conclusions4

References4

Introduction

Type 2 diabetes (T2DM), affecting more than 90% of all people with diabetes, is a complex metabolic disease, characterised by elevated plasma glucose levels . Fasting hyperglycaemia is caused by unrestrained basal hepatic glucose output, primarily a consequence of hepatic resistance to insulin action. Post-prandial hyperglycaemia, on the other hand, results from abnormal insulin secretion by ß-cells in response to a meal, impaired hepatic glucose production, and defective glucose uptake by peripheral insulin-sensitive tissues, particularly the skeletal muscle(Mahnberg, Ryden, Birkeland, Bootsma, Dickstein, Efendic & Waldenstrom, 2005). Chronic hyperglycaemia further impairs ß-cell secretory kinetics and tissue sensitivity to insulin, a phenomenon known as glucotoxicity . Thus, both impaired insulin action (insulin resistance) and dysfunctional insulin secretion (insulin deficiency) represent core elements in the pathogenesis of type 2 diabetes (Fig. 1). Although impairment of insulin secretion and defects in insulin action usually coexist in the same patient, phenotypic characterisation can help to identify subjects with (i) predominant insulin resistance with relative insulin deficiency, or (ii) predominant secretory defect with various degrees of insulin resistance, as stated in the ADA Clinical Practice Recommendations. The sequence with which these abnormalities develop in the single patient and their relative contribution to the overall diabetic phenotype remain unclear. Longitudinal studies in Pima Indians suggest that a defect in insulin action precedes the development of T2DM, and that the disease becomes evident only when insulin secretory dysfunction progresses. Moreover, various other studies have shown that ß-cell defects precede and predict overt T2DM, and that the ß-cell secretory function is already markedly reduced at the onset of diabetes.

Fig. 1. Pathogenesis of type 2 diabetes. The two major metabolic abnormalities, i.e. insulin resistance and insulin deficiency, contribute to hyperglycaemia and result from both genetic and environmental factors.

Treatment options for T2DM are quite diverse, including insulin sensitizers, a-glucosidase inhibitors, and ß-cell secretagogues(Bell, ...