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This version published online on May 24, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2545
A more recent version of this article appeared on August 1, 2005
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Submitted on December 27, 2004
Accepted on May 13, 2005

High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes

Eugene Sobngwi, Jean-François Gautier, Jean Philippe Kevorkian, Jean-Marie Villette, Jean-Pierre Riveline, Sumei Zhang, Patrick Vexiau, Suzanne M. Leal, Christian Vaisse, and Franck Mauvais-Jarvis*

Department of Endocrinology & Diabetes, Saint-Louis Hospital, University of Paris VII School of Medicine, and INSERM U 465, Paris, France 75010; Diabetes Center & Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, and Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030; Department of Internal Medicine B, Lariboisiere Hospital, Paris, France 75010; Department of Biochemistry, Saint-Louis Hospital, Paris, France 75010; Department of Diabetes and Metabolic Diseases, Sud Francilien Hospital, Corbeil-Essonnes, France 91100

* To whom correspondence should be addressed. E-mail: fmjarvis{at}bcm.edu.

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 auto-immune process.

Objective: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency suggesting that they exhibit a propensity to oxidative stress in {beta}-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress and G6PD deficiency (G6PDd), 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 the G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated c-peptide) in a cohort of hospitalized West Africans with KPD (n = 59), type 2 diabetes (T2DM, n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD (n = 100), T2DM (n = 59) and controls (n = 85).

Results: The prevalence of G6PDd was higher in KPD, than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, the 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 G6PDd in KPD without gene mutation.

Conclusions: This study suggests that 1) G6PDd alone is not causative of KPD, 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.
Key words: Ketosis-prone • genetics • oxidative stress • beta-cell failure • insulin deficiency




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