Pathogenesis of type 2 diabetes -role of defects in insulin secretion and insulin sensitivity

University dissertation from Devjit Tripathy

Abstract: Type 2 diabetes is characterised by defects in insulin sensitivity, insulin secretion and increased endogenous glucose production. The relative contribution of each of these defects remains controversial. In order to characterise the metabolic defects in various stages of glucose tolerance, the insulin sensitivity and insulin secretion was measured in a large population based study in Finland and Sweden (Btonia study) The first aim was to evaluate surrogate markers of insulin sensitivity and insulin secretion in subjects with varying degree of glucose tolerance. The insulinogenic index provides a good surrogate estimate of the early insulin response to iv glucose. In contrast, the HOMA IR and indices from OGTT do not describe insulin sensitivity in the same way as glucose uptake measured during a clamp. The latter measures also suffer from the problem that insulin sensitivity is dependent upon the amount of insulin secreted. The second aim was therefore to validate a method for independent estimates of insulin sensitivity and insulin secretion during the same test; the so called Botnia clamp. The test fulfilled the expectations and provides a useful tool for metabolic studies. The results also underscore the importance of adjusting insulin secretion for insulin sensitivity. A third aim was to characterise the metabolic defects leading to type 2 diabetes. Our cross sectional data show that defects in muscle, liver, and islets occur in parallel and correlate with an increase in abdominal obesity and circulating FFA concentrations. They thus support the hypothesis that peripheral and hepatic insulin resistance as well as ?-cell dysfunction in type 2 diabetes could be caused by similar defects. They further demonstrate that these defects are influenced by variations in the calpain 10 gene. A fourth aim was to compare insulin secretion and insulin sensitivity in the prediabetic and diabetic state between subtypes of diabetes. We could demonstrate that carriers of MODY mutations are able to maintain normal glucose tolerance by up regulating insulin sensitivity. The last aim was to evaluate the impact of a family history of common type 2 diabetes and the particular phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives. The data underscore the importance to consider age at onset when selecting patients for genetic studies as the metabolic phenotype of the probands is shared by relatives of probands with early but not of late-onset diabetes. They further emphasize the value of stratifying for a phenotype characterised by abdominal obesity as this also shows a high degree of familiality. Taken together the results demonstrate a linear decrease in peripheral (muscle) glucose uptake, hepatic insulin sensitivity and ? cell function which precede onset of type 2 diabetes, and strongly correlate with an increase in abdominal obesity. They though emphasize the importance to consider changes in one variable when describing the change in the other.

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