| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Letters to the Editor |
1 Department of Medicine, Division of Nephrology, University Clinic, Würzburg, Germany
2 Department of Clinical Biochemistry, and Pathobiochemistry, University of Würzburg, Würzburg, Germany
aAddress correspondence to this author at: Division of Nephrology, Department of Medicine, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. Fax 49-931-201-36502; e-mail tom.lindner{at}mail.uni-wuerzburg.de.
To the Editor:
Mutations in the glucokinase gene lead to an impaired sensing of blood glucose by the pancreatic ß cell, causing an autosomal dominant form of type 2 diabetes, maturity-onset diabetes of the young type 2 (MODY2). Usually, MODY2 patients present with high fasting blood glucose (6–12 mmol/L) from an early age (1). This situation should significantly increase their risk for diabetic complications (2), but whereas other forms of diabetes typically lead to macrovascular complications, MODY2 patients rarely develop diabetes-related problems (3).
In a family with autosomal dominant diabetes, we identified a novel C
A substitution in the glucokinase gene at nucleotide position 695 [A232D (pancreatic isoform), A231D (liver isoform)] in all affected individuals (Fig. 1
). Codon 232 is highly conserved among nine different species. The mutation was not detected in 192 control chromosomes. Studied mutations around codon 232 (T228M and G261R) cause the lowest glucokinase activities of all mutations tested to date and suggest similar effects of A232D (4).
|
On the basis of our findings, we determined that individuals 0307 and 0309 were probably misdiagnosed with type 1 diabetes and individuals 0301 and 0304 with gestational diabetes. However, individual 0305 was an unaffected mutation carrier, which is not uncommon for MODY.
High hemoglobin A1c [HbA1c; reference interval, 4.3–6.1% by HPLC (Variant II; Bio-Rad)] should be associated with high triglycerides because it is an indicator of poor metabolic control (5). However, despite high HbA1c, affected individuals of our MODY2 family showed even lower fasting triglyceride concentrations (Fig. 1A
) than the unaffected family members (7 unaffected individuals, including 1 unaffected mutation carrier, vs 10 affected mutation carriers; individual 0206 received fenofibrate and was not considered); the mean (SD) values for affected vs unaffected family members were as follows: cholesterol, 5.71 (1.17) vs 5.62 (1.12) mmol/L; LDL-cholesterol, 3.44 (0.94) vs 3.30 (0.91) mmol/L; HDL-cholesterol, 1.85 (0.34) vs 1.58 (0.33) mmol/L. In another MODY2 family, Dresden-7 (V154fsdelTG; Fig. 1B
), we made the same observation (6). In both families, the difference for triglycerides was significant (P = 0.025, two-sided test; 7 unaffected and 13 affected individuals), but we had no homozygous mutation carrier and too few cases to make a general statement.
It is possible that glucokinase mutations lead to lower triglycerides, even within their reference interval (0.35–2.30 mmol/L). Glucokinase mutations impair glycolysis, which is responsible for delivering glyceraldehyde 3-phosphate as the later glycerol backbone of triglycerides (4). Transgenic mice overexpressing glucokinase develop hypertriglyceridemia in addition to other effects, indicating a direct link between glucokinase activity and triglyceride regulation (7). There is evidence that serum concentrations of triglycerides are directly correlated with rates of progression of coronary artery disease and other macrovascular complications (8)(9)(10). In the studied family, and in concordance with the much lower frequency of diabetic complications in known MODY2 families, only one individual (0205) had a macrovascular event (myocardial infarction).
In conclusion, impaired glucokinase activity could lead to particularly low triglycerides in the circulation. The contribution of triglycerides to the development of diabetic complications warrants further investigation.
Acknowledgments
T.H.L. was supported by the Deutsche Forschungsgemeinschaft (Li768/3-1/-3/, Li768/4-1/-2), and M.B. was supported by the Interdisziplinäres Zentrum für Klinische Forschung Würzburg IZKF-E9.
References
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
