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Metabolic Defects in Prediabetic Kuwaiti Arabs and Indians

19 juli 2020 bijgewerkt door: Dr. Ebaa Al Ozairi, Dasman Diabetes Institute

Ethnic Dependence of the Metabolic Defects in Prediabetic Individuals: Kuwaiti Arabs Versus Indians

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.

Studie Overzicht

Toestand

Onbekend

Conditie

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Inschrijving (Verwacht)

120

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

Koeweit
- - Kuwait, Koeweit, 15462
    - Werving
    - Dasman Diabetes Institute

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

21 jaar tot 65 jaar (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Geslachten die in aanmerking komen voor studie

Allemaal

Bemonsteringsmethode

Kanssteekproef

Studie Bevolking

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.

Beschrijving

Inclusion Criteria:

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.

Exclusion Criteria:

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat	Maatregel Beschrijving	Tijdsspanne
Insulin Resistance Tijdsspanne: 15 months	Insulin Resistance measured as total glucose disposal TGD with the Insulin Clamp	15 months
Insulin Secretion Tijdsspanne: 15 months	First phase and second phase insulin secretion measured with the hyperglycemic clamp	15 months
Beta Cell function Tijdsspanne: 15 months	Beta cell function for the first phase and second phase measured as ∆C-Pep/(1/TGD)	15 months
Comparison of genetic markers Tijdsspanne: 15 months	Genetic markers that correlate with the metabolic phenotype measured using GWAS	15 months
GLP1 Action Tijdsspanne: 15 months	GLP1 Action measured as increase in C-peptide during the hyperglycemic clamp caused by exenatide infusion	15 months

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Dasman Diabetes Institute

Onderzoekers

Hoofdonderzoeker: Ebaa AlOzairi, MD, PhD, Dasman Diabetes Institute

Publicaties en nuttige links

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Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

1 maart 2020

Primaire voltooiing (Verwacht)

15 juli 2021

Studie voltooiing (Verwacht)

31 december 2021

Studieregistratiedata

Eerst ingediend

20 oktober 2019

Eerst ingediend dat voldeed aan de QC-criteria

11 februari 2020

Eerst geplaatst (Werkelijk)

13 februari 2020

Updates van studierecords

Laatste update geplaatst (Werkelijk)

22 juli 2020

Laatste update ingediend die voldeed aan QC-criteria

19 juli 2020

Laatst geverifieerd

1 juli 2020

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

RA HM-2019-003

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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