Abnormalities of Insulin Secretion and β‐Cell Defects in Type 2 Diabetes

Keypoints • Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder caused by a combination of genetic and environmental factors which adversely affect β cell function and tissue insulin sensitivity. • About 10% of patients with phenotypic T2DM actually have a late onset form of autoimmune diabetes while up to another 5% have autosomal dominantly inherited forms such as maturity onset diabetes of the young and mitochondrial diabetes. The remaining 85% of patients have “ garden variety ” T2DM which is a polygenic disorder. • The preponderance of available information indicate that genetic factors primarily affect β cell function whereas acquired factors (obesity, physical inactivity, glucose and lipid toxicity) are mainly responsible for the insulin resistance seen in this condition. Impaired β cell function can be detected in genetically predisposed individuals (i.e. the monozygotic twin or fi rst degree relative of someone who has T2DM) at a time when they have normal glucose tolerance and normal tissue insulin sensitivity. • T2DM develops because of a progressive deterioration in β cell function coupled with the addition of acquired insulin resistance for which the β cell cannot compensate. At time of diagnosis, β cell function is already reduced about 50% and most of the defects demonstrable in people with T2DM are already present in individuals with impaired glucose tolerance and those genetically predisposed to develop T2DM. • Commonly found insulin secretion abnormalities include: absent fi rst phase and diminished second phase release. Responses to ingestion of mixed meals and to non glucose stimuli are reduced with a decrease in maximal secretory capacity. The secretory pulses, both rapid and ultradian, are smaller and less regular. The ratio of proinsulin to insulin release is also elevated. • Normally there is a curvilinear hyperbolic relationship between β cell function and tissue insulin sensitivity so that as tissue insulin sensitivity decreases (as in obesity and pregnancy), β cell function increases in a compensatory fashion to maintain normal glucose tolerance. Prospective longitudinal studies have shown that people who have impaired glucose tolerance and progress to T2DM fall off this curve because of an inability of the β cell to compensate for insulin resistance. • Acquired factors also adversely affect β cell function and contribute to the development of T2DM. These include adverse effects of hyperglycemia and increased plasma free fatty acids, respectively termed glucotoxicity and lipotoxicity, alterations in incretins (GLP 1, GIP) and malnutrition in utero and in early life which may affect programing of the β cell with respect to glucose sensing, apoptosis, regeneration and the ability to compensate for insulin resistance. Endoplasmic reticulum stress induced apoptosis and the effect interleukin 1 β has on β cell function and life cycle are recently receiving more attention for their role in the pathogenesis of T2DM. • A pathologic feature present in 90% of patients with T2DM is the abnormal extracellular deposits of islet amyloid. It is composed of insoluble fi brils formed from the protein islet amyloid polypeptide (IAPP). Other histologic changes include a 30 – 50% decrease in islet mass and an alteration in the relative proportion of the islet cell population. • The IAPP and its amyloid deposits have not been clearly found to be cytotoxic to β cell and recent evidence from animal studies suggests that the formation of intracellular smaller IAPP oligomers is possibly the cytotoxic form associated with increased β cell apoptosis.