Ethnic Dependence of the Metabolic Defects in Prediabetic Individuals: Kuwaiti Arabs Versus Indians
试验速览
- 阶段
- 不适用
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Insulin Resistance
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 21 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •age 21-65 years
- •BMI=18-45 kg/m2
- •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.
- •Good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, lipid profile.
- •Stable body weight (± 3 lbs) over the preceding three months
- •Not participate in an excessively heavy exercise program.
排除标准
- •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
结局指标
主要结局
Insulin Resistance
时间窗: 15 months
Insulin Resistance measured as total glucose disposal TGD with the Insulin Clamp
Insulin Secretion
时间窗: 15 months
First phase and second phase insulin secretion measured with the hyperglycemic clamp
Beta Cell function
时间窗: 15 months
Beta cell function for the first phase and second phase measured as ∆C-Pep/(1/TGD)
Comparison of genetic markers
时间窗: 15 months
Genetic markers that correlate with the metabolic phenotype measured using GWAS
GLP1 Action
时间窗: 15 months
GLP1 Action measured as increase in C-peptide during the hyperglycemic clamp caused by exenatide infusion
次要结局
未报告次要终点
研究者
Dr. Ebaa Al Ozairi
Chief Medical Officer
Dasman Diabetes Institute