Free Fatty Acid-Mediated Impairment of Glucose-Stimulated Insulin Secretion in Nondiabetic Oji-Cree Individuals From the Sandy Lake Community of Ontario, Canada
A Population at Very High Risk for Developing Type 2 Diabetes
- André Carpentier1,
- Bernard Zinman2,
- Nathalie Leung2,
- Adria Giacca23,
- Anthony J.G. Hanley2,
- Stewart B. Harris4,
- Robert A. Hegele5 and
- Gary F. Lewis23
- 1Department of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada
- 2Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- 3Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- 4Thames Valley Family Practice Research Unit, University of Western Ontario, London, Ontario, Canada
- 5Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
Abstract
The Oji-Cree population of the Sandy Lake region of Ontario, Canada, has the third highest prevalence of type 2 diabetes in the world. Changes in their diet and physical activity over the past half-century, particularly the marked increase in consumption of dietary fats, are felt to be important factors accounting for this epidemic. The aim of the present study was to examine the β-cell response to a 48-h approximately twofold elevation of plasma free fatty acids (FFAs) (induced by Intralipid and heparin infusion) in members of the Sandy Lake Oji-Cree population (n = 12) and to compare the response to that in healthy age-matched nondiabetic Caucasian subjects (n = 16). The insulin secretion rate, insulin sensitivity index (SI), and disposition index (DI) (an index of insulin secretion that takes into account the ambient SI) were assessed in response to a 4-h graded intravenous glucose infusion followed by a 20 mmol/l 2-h hyperglycemic clamp. Total insulin secretory response to the graded glucose infusion did not change after a 48-h FFA elevation versus saline control in Caucasians and increased by ∼30% in Oji-Cree individuals (P = 0.04 for difference between the two groups). Infusion of heparin-Intralipid reduced SI by ∼40% in both groups (P = 0.002). Although DI was markedly reduced by heparin-Intralipid infusion in Caucasians (by ∼40%), it was reduced by only 15% in Oji-Cree individuals (P = 0.03 for difference of response between the two groups). However, SI and DI in the Oji-Cree individuals were already much lower than in Caucasians at baseline, in keeping with the very high risk of type 2 diabetes in this population. It is concluded that Oji-Cree individuals from a community at very high risk for developing type 2 diabetes are not more susceptible to the FFA-induced desensitization of glucose-stimulated insulin secretion than healthy non-Natives and, in fact, appear to be less susceptible. Whether this reflects an inherent resistance to lipotoxicity or an already-present lipotoxic effect in this population will require further study.
Footnotes
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Address correspondence and reprint requests to Dr. Gary Lewis, The Toronto General Hospital, 200 Elizabeth St., Room EN 11-229, Toronto, ON, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.
Received for publication 29 October 2002 and accepted in revised form 27 February 2003.
DI, disposition index; FFA, free fatty acid; Ginf, glucose infusion rate; GSIS, glucose-stimulated insulin secretion; HI, heparin-Intralipid; ISR, insulin secretion rate; SI, insulin sensitivity index.
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