Insulin Secretory Defects in Pima Indians at High Risk for NIDDM
Condition: NIDDM
MeSH terms: Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      The Pima Indians have the highest reported prevalence of NIDDM of any population in the
      world. Within this population, it is possible to identify subgroups of individuals at a
      particularly high risk for NIDDM. This project examines whether defects in insulin secretion
      contribute to the higher risk of NIDDM in these subgroups and whether they progress over the
      course of the disease.

      Healthy Pima men and women at high risk for NIDDM including individuals in the following 3
      groups will be recruited: 1)persons whose mothers and/or father developed diabetes at an
      early age (< 35 y); 2) persons whose mothers were diabetic during pregnancy; and 3) persons
      whose birthweight was < 2500 g. These individuals, as well as subjects with none of the above
      risk factors and a group of non-Pima controls, will be admitted to the NIH Clinical Research
      Unit at Phoenix Indian Medical Center for the following series of studies. Body composition
      will be determined by DXA scanning and by measuring the amount os visceral abdominal fat
      using MRI. A 75-g oral glucose tolerance test and a 25-g intravenous glucose tolerance test
      will be performed. Insulin action will be measured with a hyperinsulinemic-euglycemic glucose
      clamp (insulin infusion: 40mU/m(2) min and insulin secretory responses to glucose will be
      measured during a 5-step hyperglycemic glucose clamp immediately thereafter. Pima subjects
      will be followed longitudinally after discharge from the unit and oral glucose tolerance
      tests will be performed every three months. Individuals who transition from normal to
      impaired glucose tolerance or impaired glucose tolerance to diabetic will be invited back to
      the Clinical Research Center for repeat testing.

      By comparing insulin secretion-glucose dose-response curves, it may be possible to discern
      subtle defects in insulin secretion predisposing certain individuals to NIDDM. In addition,
      comparison of the responses in the offspring of diabetic pregnancies with those in the
      offspring of mothers who subsequently became diabetic may allow us to separate defects due to
      genetic causes from those due to the intrauterine environment. Finally, studying subjects as
      they progress from normal glucose tolerance to diabetes will test whether the defects in
      insulin secretion are progressive and contribute to the development of NIDDM.
    

Detailed description: 
      The Pima Indians have the highest reported prevalence of NIDDM of any population in the
      world. Within this population, it is possible to identify subgroups of individuals at a
      particularly high risk for NIDDM. This project examines whether defects in insulin secretion
      contribute to the higher risk of NIDDM in these subgroups and whether they progress over the
      course of the disease.

      Healthy Pima men and women at high risk for NIDDM, including individuals in the following 4
      groups, will be recruited: 1) persons whose mother and/or father developed diabetes at an
      early age (less than 35 y); 2) persons whose mothers were diabetic during pregnancy; 3)
      persons whose birth-weight was less than 2500 g; and 4) persons with enlarged abdominal fat
      cells (greater than 1.08 microgram lipid/cell). These individuals, as well as subjects with
      none of the above risk factors and a group of non-Pima controls, will be admitted to the NIH
      Clinical Research Unit at Phoenix Indian Medical Center for the following series of studies.
      Body composition will be determined by DXA scanning and by measuring the amount of fat in the
      abdomen and thigh using MRI. Fat cell size will be determined by image scanning of randomly
      chosen photographs of the isolated fat cells. Skeletal muscle tissue will be obtained by
      percutaneous biopsy for histochemical determination of the fat content of muscle cells. A
      75-g oral glucose tolerance test and a 25-g intravenous glucose tolerance test will be
      performed. Insulin action will be measured with a hyperinsulinemic-euglycemic glucose clamp
      (insulin infusion: 40mU/m(2) min) and insulin secretory responses to glucose will be measured
      during a 5-step hyperglycemic glucose clamp immediately thereafter. Pima subjects will be
      followed longitudinally after discharge from the unit and oral glucose tolerance tests will
      be performed every three months. Individuals who transition from normal to impaired glucose
      tolerance or impaired glucose tolerance to diabetic will be invited back to the Clinical
      Research Center for repeat testing.

      By comparing insulin secretion-glucose dose-response curves, it may be possible to discern
      subtle defects in insulin secretion predisposing certain individuals to NIDDM. In addition,
      comparison of the responses in the offspring of diabetic pregnancies with those in the
      offspring of mothers who subsequently became diabetic may allow us to separate defects due to
      genetic causes from those due to the intrauterine environment. Finally, studying subjects as
      they progress from normal glucose tolerance to diabetes will test whether the defects in
      insulin secretion are progressive and contribute to the development of NIDDM.
    

Keywords: Insulin Resistance; Body Composition; Kinetic Modeling