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

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 beta-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.

FIG. 1.

Prevalence of G6PD deficiency in KPD. A, REA in controls, T2DM, and KPD subjects. Results are expressed as the mean ± SE (percentage). *, By ANOVA: F = 7.80; P = 0.001. B, Prevalence of erythrocyte G6PD deficiency in controls, T2DM, and KPD subjects (percentage of the population). *, P = 0.005, KPD vs. T2DM; P = 0.006, KPD vs. controls. Relation between G6PD deficiency and insulin secretion in KPD. C, β-Cell insulin secretory reserve was assessed in a cohort of normoglycemic controls (n = 7), KPD patients (n = 34), and T2DM patients (n = 36) by measuring basal C peptide (0 min) and C peptide response after an iv glucagon injection (8 min). Data represent the mean ± SE. *, P < 0.01. D, Correlation between residual erythrocyte G6PD activity (percentage) and glucagon-stimulated incremental C peptide (nanograms per milliliter) in 34 patients with KPD. Spearman rank-order correlation coefficient: r_s = −0.33; P = 0.04.

FIG. 2.

Proposed mechanism for the predisposition to KPD.