Metabolic Defects in Prediabetic Kuwaiti Arabs and Indians

NCT04268862 | Unknown

• 1 other identifier: RA HM-2019-003
• Study Type: observational
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pathophysiology; Metabolic Glucose Disorders

Keywords

Beta cell function; Insulin Resistance; Arabs; Asian Indians

Outcome Measures

Primary Outcomes (5)

• Insulin Resistance

  Insulin Resistance measured as total glucose disposal TGD with the Insulin Clamp

  15 months

• Insulin Secretion

  First phase and second phase insulin secretion measured with the hyperglycemic clamp

  15 months

• Beta Cell function

  Beta cell function for the first phase and second phase measured as ∆C-Pep/(1/TGD)

  15 months

• Comparison of genetic markers

  Genetic markers that correlate with the metabolic phenotype measured using GWAS

  15 months

• GLP1 Action

  GLP1 Action measured as increase in C-peptide during the hyperglycemic clamp caused by exenatide infusion

  15 months

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Dasman Diabetes Institute: lead

Study Sites (1)

Dasman Diabetes Institute

Kuwait City, 15462, Kuwait

RECRUITING

Related Publications (15)

• Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95. doi: 10.2337/db09-9028. No abstract available.

  PMID: 19336687 BACKGROUND

• Abdul-Ghani MA, DeFronzo RA. Pathophysiology of prediabetes. Curr Diab Rep. 2009 Jun;9(3):193-9. doi: 10.1007/s11892-009-0032-7.

  PMID: 19490820 BACKGROUND

• DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010 Jul;53(7):1270-87. doi: 10.1007/s00125-010-1684-1. Epub 2010 Apr 2.

  PMID: 20361178 BACKGROUND

• Clarke GD, Solis-Herrera C, Molina-Wilkins M, Martinez S, Merovci A, Cersosimo E, Chilton RJ, Iozzo P, Gastaldelli A, Abdul-Ghani M, DeFronzo RA. Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes. Diabetes Care. 2017 Nov;40(11):1530-1536. doi: 10.2337/dc17-0078. Epub 2017 Aug 28.

  PMID: 28847910 BACKGROUND

• Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279. doi: 10.1155/2010/476279. Epub 2010 Apr 26.

  PMID: 20445742 BACKGROUND

• Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ, Smith SR. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab. 2011 Jun;96(6):1654-63. doi: 10.1210/jc.2011-0585.

  PMID: 21602457 BACKGROUND

• Lettner A, Roden M. Ectopic fat and insulin resistance. Curr Diab Rep. 2008 Jun;8(3):185-91. doi: 10.1007/s11892-008-0032-z.

  PMID: 18625114 BACKGROUND

• Sabag A, Way KL, Keating SE, Sultana RN, O'Connor HT, Baker MK, Chuter VH, George J, Johnson NA. Exercise and ectopic fat in type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2017 Jun;43(3):195-210. doi: 10.1016/j.diabet.2016.12.006. Epub 2017 Feb 2.

  PMID: 28162956 BACKGROUND

• Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T, Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and 'hyperleptinaemia'. Diabetologia. 2007 Mar;50(3):625-33. doi: 10.1007/s00125-006-0572-1. Epub 2007 Jan 10.

  PMID: 17216279 BACKGROUND

• Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000 Dec;43(12):1498-506. doi: 10.1007/s001250051560.

  PMID: 11151758 BACKGROUND

• McLaughlin T, Craig C, Liu LF, Perelman D, Allister C, Spielman D, Cushman SW. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans. Diabetes. 2016 May;65(5):1245-54. doi: 10.2337/db15-1213. Epub 2016 Feb 16.

  PMID: 26884438 BACKGROUND

• Badoud F, Perreault M, Zulyniak MA, Mutch DM. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J. 2015 Mar;29(3):748-58. doi: 10.1096/fj.14-263913. Epub 2014 Nov 19.

  PMID: 25411437 BACKGROUND

• Arner P, Engfeldt P, Ostman J. Relationship between lipolysis, cyclic AMP, and fat-cell size in human adipose tissue during fasting and in diabetes mellitus. Metabolism. 1979 Mar;28(3):198-209. doi: 10.1016/0026-0495(79)90065-9.

  PMID: 216883 BACKGROUND

• Scherer PE. The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture. Diabetes. 2016 Jun;65(6):1452-61. doi: 10.2337/db16-0339.

  PMID: 27222389 BACKGROUND

• Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab. 2004 Feb;89(2):463-78. doi: 10.1210/jc.2003-030723. No abstract available.

  PMID: 14764748 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Insulin and C-peptide will be measured in plasma samples

MeSH Terms

Conditions

Glucose Metabolism Disorders; Insulin Resistance

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperinsulinism

Study Officials

• Ebaa AlOzairi, MD, PhD

  Dasman Diabetes Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ebaa AlOzairi, Md, PhD

CONTACT

+965 22242999; ebaa.alozairi@dasmaninstitute.org

Smitha Abraham

CONTACT

+965 22260005; smitha.abraham@dasmaninstitute.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Medical Officer

Study Record Dates

• First Submitted: October 20, 2019
• First Posted: February 13, 2020
• Study Start: March 1, 2020
• Primary Completion: July 15, 2021
• Study Completion: December 31, 2021
• Last Updated: July 22, 2020

Record last verified: 2020-07

Locations

KU (1)