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High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes

Departments of Endocrinology and Diabetes (E.S., J.-F.G., P.V., F.M.-J.) and Biochemistry (J.-M.V.), St. Louis Hospital, University of Paris VII School of Medicine, and Institut National de la Santé et de la Recherche Médicale, Unité 465 (E.S., J.-F.G., P.V., F.M.-J.), 75010 Paris, France; Diabetes Center and Department of Medicine, University of California San Francisco (S.Z., C.V., F.M.-J.), San Francisco, California 94143; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine (F.M.-J.), and Department of Molecular and Human Genetics (S.M.L.), Baylor College of Medicine, Houston, Texas 77030; Department of Internal Medicine B, Lariboisiere Hospital (J.-P.K.), 75010 Paris, France; and Department of Diabetes and Metabolic Diseases, Sud Francilien Hospital (J.-P.R.), 91100 Corbeil-Essonnes, France

Address all correspondence and requests for reprints to: Dr. Franck Mauvais-Jarvis, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCMA 700B, Houston, Texas 77030. E-mail: fmjarvis{at}bcm.edu.

Abstract

Context: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process.

Objective: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in ß-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD.

Design: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85).

Results: The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation.

Conclusions: This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

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