Pathophysiology Clinical Trial
Official title:
Ethnic Dependence of the Metabolic Defects in Prediabetic Individuals: Kuwaiti Arabs Versus Indians
Insulin resistance and beta cell dysfunction are the major core defects responsible for the
development of type 2 diabetes (T2DM). Although insulin resistance is the early metabolic
defect detected in subjects destined to develop T2DM, it is the beta cell failure which is
responsible for the development of hyperglycemia.
Longitudinal and cross-sectional studies have demonstrated that, initially, the compensatory
hyperinsulinemia is sufficient to offset the insulin resistance and maintain normal glucose
tolerance. However, when the beta cell fails to adequately compensate for the insulin
resistance, glucose homeostasis deteriorates. Initially, this is manifest as impaired glucose
tolerance (IGT) and later as overt diabetes. It follows that the level of beta cell failure
at which hyperglycemia becomes evident depends upon the prevailing level of insulin
resistance. A more severe insulin resistance results in development of overt hyperglycemia at
lower level of beta cell failure. The investigators previously have shown that the severity
of insulin resistance varies amongst different ethnic groups (Arabs versus Indians). Thus,
the level of beta cell failure at which overt hyperglycemia becomes evident amongst each
ethnic group also varies. Thus, individuals/ethnic groups with more severe insulin
resistance, overt hyperglycemia becomes evident at lower level of beta cell dysfunction.
Conversely, severe beta cell dysfunction is required for evert hyperglycemia to develop in
individuals/ethnicities with less severe insulin resistance.
In the present study, the investigators aim to quantitate beta cell function with the gold
standard technique (i.e. hyperglycemic clamp) in Arab and Indian non-diabetic individuals and
relate the level of beta cell function to the prevailing level of insulin resistance measured
as the glucose infusion rate divided by the mean plasma insulin concentration during the
clamp.
Insulin resistance and the accompanying hyperinsulinemia also lead to the development of
multiple metabolic abnormalities which are responsible, at least in part, for the excessive
risk of coronary heart disease in T2DM , non-alcoholic steatohepatitis (NASH), and impaired
diastolic left ventricular (LV) function. Thus, insulin resistance contributes, not only to
increased T2DM risk, but also to the morbidity and mortality associated with the disease.
Etiology of Insulin Resistance Insulin resistance is closely related to obesity. Multiple
mechanisms contribute to insulin resistance in obese individuals. Accumulation of fat in
insulin target tissues (i.e. ectopic fat), e.g. in myocytes and hepatocytes, plays a central
role in the pathogenesis of insulin resistance. When energy intake exceeds energy
expenditure, the energy excess is stored in subcutaneous adipocytes in the form of
triglycerides. However, under conditions of persistent positive energy balance, subcutaneous
fat stores become filled and the excess energy spills over into the circulation in the form
of FFA, leading to increased fat content in lean tissues, i.e. ectopic fat. Many studies have
documented the important role of ectopic fat content in the pathogenesis of insulin
resistance in obese individuals. The severity of insulin resistance in skeletal muscle and
liver strongly correlates with ectopic fat content in myocytes and hepatocytes, respectively.
Further, therapies that deplete ectopic fat, e.g. weight loss and pioglitazone, significantly
improve insulin sensitivity.
Fat spill over and the subsequent increase in ectopic fat content in lean tissues could
result from subcutaneous fat cells that are filled to capacity or the inability of the
subcutaneous fat stores to expand. Consistent with this hypothesis, several studies have
demonstrated increased fat cell size in subcutaneous fat in insulin resistant obese
individuals compared to insulin sensitive controls. Moreover, large fat cells have a higher
rate of lipolysis and decreased rate of FFA esterification compared to small fat cells,
suggesting decreased ability of large fat cells to further store fat in subcutaneous adipose
tissue in obese individuals. Of note, large fat cell size is a strong predictor of future
T2DM risk in non-diabetic individuals, independent of insulin resistance. Collectively, these
results have led to the hypothesis that inability of subcutaneous fat tissue to expand
results in fat spill over into muscle, liver, heart, etc and the subsequent development of
insulin resistance.
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