Metabolic Defects in Prediabetic Kuwaiti Arabs and Indians
Metabolic Defects in Prediabetic Kuwaiti Arabs and 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.
Inclusion Criteria:

 1. age 21-65 years

 2. BMI=18-45 kg/m2

 3. NGT (FPG<100 mg/dl and 2-hour PG <140 mg/dl) or IGT (FPG < 125 mg/dl, and 2-hour
 PG=140-199 mg/dl) according to the ADA criteria.

 4. Good general health as determined by physical exam, medical history, blood
 chemistries, CBC, TSH, T4, lipid profile.

 5. Stable body weight (± 3 lbs) over the preceding three months

 6. Not participate in an excessively heavy exercise program.

 Exclusion Criteria:

 Subjects with

 -  Haematocrit < 34.0

 -  Diabetes, Thyroid disorders, Cardiovascular Diseases, Cancer, Bronchial Asthma and any
 autoimmune disease.

 -  Subjects who receive medications which affect glucose tolerance, e.g. Steroids

 -  Subjects who participate in excessively heavy exercise programs, e.g. Athletes