Cross-Sectional and Longitudinal Studies of Pre-Diabetes in the Pima Indians

Study Overview
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Brief Summary
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Insulin resistance and a defect in early insulin secretion are risk factors for the development of type 2 diabetes mellitus. A recent longitudinal analysis which tracked the development of diabetes demonstrated that both insulin action and early insulin secretion deteriorate as individuals progress from normal to impaired glucose tolerance and then to diabetes. These results suggest that both inherent (apparent in normal glucose tolerant subjects who progress to diabetes and likely to have a genetic basis) and acquired (evident as individuals progress from NGT to IGT to diabetes and possibly environmental in origin) defects in insulin action and secretion contribute to the pathogenesis of type 2 diabetes. To identify the genetic and environmental determinants of diabetes we are continuing to determine: (1) if there are genes that segregate with metabolic risk factors for diabetes which might therefore be genetic markers for type 2 diabetes and (2) the mechanisms mediating genetic and environmental determinants of insulin resistance and impaired insulin secretion. <TAB> Volunteers for this study will be admitted to the clinical research ward where they will undergo several tests to determine body composition, oral and intravenous glucose tolerance and in vivo insulin action. In addition, in selected subjects, adipose and/or skeletal muscle tissue will be obtained by percutaneous biopsy for in vitro studies of gene expression and insulin action in these tissues. A transformed lymphocyte cell line will be established for each subject as a permanent source of DNA for genetic studies. Genetic markers for type 2 diabetes and insulin resistance will be sought by typing each individual at positional and functional candidate loci in the hopes of finding an association between these loci and obesity, insulin secretion, insulin resistance and/or type 2 diabetes.

Detailed Description
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Insulin resistance and a defect in early insulin secretion are risk factors for the development of type 2 diabetes mellitus. A recent longitudinal analysis which tracked the development of diabetes demonstrated that both insulin action and early insulin secretion deteriorate as individuals progress from normal to impaired glucose tolerance and then to diabetes. These results suggest that both inherent (apparent in normal glucose tolerant subjects who progress to diabetes and likely to have a genetic basis) and acquired (evident as individuals progress from NGT to IGT to diabetes and possibly environmental in origin) defects in insulin action and secretion contribute to the pathogenesis of type 2 diabetes. To identify the genetic and environmental determinants of diabetes we are continuing to determine: (1) if there are genes that segregate with metabolic risk factors for diabetes which might therefore be genetic markers for type 2 diabetes and (2) the mechanisms mediating genetic and environmental determinants of insulin resistance and impaired insulin secretion. <TAB> Volunteers for this study will be admitted to the clinical research ward where they will undergo several tests to determine body composition, oral and intravenous glucose tolerance and in vivo insulin action. In addition, in selected subjects, adipose and/or skeletal muscle tissue will be obtained by percutaneous biopsy for in vitro studies of gene expression and insulin action in these tissues. A transformed lymphocyte cell line will be established for each subject as a permanent source of DNA for genetic studies. Genetic markers for type 2 diabetes and insulin resistance will be sought by typing each individual at positional and functional candidate loci in the hopes of finding an association between these loci and obesity, insulin secretion, insulin resistance and/or type 2 diabetes.

Official Title
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Cross-Sectional and Longitudinal Studies of 'Pre-Diabetes'

Conditions
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Weight Gain, Overweight, Insulin Resistance, Obesity, Diabetes Mellitus, Type 2

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects from all racial and ethnic backgrounds will be invited to participate if they are: Ages: 18-55 years old (up to 2200 participants) Gender: male or female EXCLUSION CRITERIA: Subjects will be excluded who are: Taking medication for a chronic illness. Have any acute or chronic diseases or conditions not specifically mentioned that in the opinion of the provider may interfere with the study or decrease safety for participation will be considered exclusionary. Women who currently pregnant or breastfeeding. Positive for drug and/or nicotine use. All medications and alcohol consumption are to be stopped for two weeks prior to admission. A urine drug-screening test for drugs such as narcotics, marijuana, and barbiturates will be performed on everyone to exclude from the study people whose urine show active or recent drug use. A positive drug test could confound the results of the study in an unpredictable manner. The results of this test will become a part of the patient s medical records and may be released if requested (please see page 6 of the consent for details regarding medical records release).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult volunteers<br>Volunteers aged 18-55 who are healthy as determined by medical history, physical examination, and laboratory tests | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose tolerance via oral glucose tolerance test (OGTT) | Measured via OGTT after ingestion of 75 grams of glucose over 2 minutes | Baseline, and after 180 minutes on day 4 | 
| Glucose tolerance via intravenous glucose tolerance test (IVGTT) | Measured via IVGTT after administration of a glucose bolus (25 g as a 50% solution injected over 3 minutes) | Baseline and after 10 minutes on day 5 | 
| Basal endogenous glucose production | Assessed using deuterium (D-6,6 2H) glucose as a tracer, infused as a 10 mL bolus followed by 0.150 mL/min for a total of 350 minutes | Baseline, and after 100 minutes on day 10 | 
| 24-hour metabolic rate | Assessed from the rates of caloric expenditure and substrate utilization while in the human respiratory chamber for 24 hours | Baseline and after 23.5 hours on day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin Sensitivity, Insulin Secretion, Glucose Tolerance, Adipose Tissue, Preadipocytes, Natural History