An observational study in Pathophysiology and Metabolic Glucose Disorders, sponsored by Dasman Diabetes Institute. Status unknown at 1 site in Kuwait. Open to participants aged 21 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-07-22.
Sponsored by Dasman Diabetes Institute · Observational
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.
257 studies on the registry are indexed under Glucose Metabolism Disorders; 40 are open to participants now.
This study's planned enrollment of 120 is above the median of 87 across 43 observational studies indexed under Glucose Metabolism Disorders.
Browse Glucose Metabolism Disorders studies →Dasman Diabetes Institute is the lead sponsor of 30 studies on the registry; 14 are open to participants now.
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Subjects from two ethnic groups will participate in the present study: (1) 60 Kuwaiti Arab subjects and (2) 60 subjects of Indian ethnicity. Each ethnic group will include 30 subjects with normal glucose tolerance (NGT), and 30 subjects with impaired glucose tolerance (IGT) according to the American Diabetes Association criteria.
Subjects in each ethnic group will be matched for age, sex, BMI and family history of type 2 diabetes.
Exclusion Criteria:
Subjects with
Insulin Resistance
Insulin Resistance measured as total glucose disposal TGD with the Insulin Clamp
Time frame: 15 months
Insulin Secretion
First phase and second phase insulin secretion measured with the hyperglycemic clamp
Time frame: 15 months
Beta Cell function
Beta cell function for the first phase and second phase measured as ∆C-Pep/(1/TGD)
Time frame: 15 months
Comparison of genetic markers
Genetic markers that correlate with the metabolic phenotype measured using GWAS
Time frame: 15 months
GLP1 Action
GLP1 Action measured as increase in C-peptide during the hyperglycemic clamp caused by exenatide infusion
Time frame: 15 months
This study is status unknown, as verified in Jul 2020. You cannot join it, but the record below documents what was studied.
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Dasman Diabetes Institute