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


METHODS
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.
Sobngwi
Eugene
E
Department of Endocrinology and Diabetes, St. Louis Hospital, University of Paris VII School of Medicine, France.
Gautier
Jean-François
JF
Kevorkian
Jean-Philippe
JP
Villette
Jean-Marie
JM
Riveline
Jean-Pierre
JP
Zhang
Sumei
S
Vexiau
Patrick
P
Leal
Suzanne M
SM
Vaisse
Christian
C
Mauvais-Jarvis
Franck
F
D000354:Africa, Western / Q000208:ethnology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D016883:Diabetic Ketoacidosis / Q000453:epidemiology* / Q000235:genetics*; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012720:Severity of Illness Index
D005954:Glucosephosphate Dehydrogenase