Mody
. Department of Molecular Cell Biology,
Mutations in mitochondrial DNA (mtDNA) associate with
various disease states. A few mtDNA mutations
strongly associate with diabetes, with the most common mutation being the
A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR)
gene. This article describes clinical characteristics of mitochondrial diabetes
and its molecular diagnosis. Furthermore, it outlines recent developments in
the pathophysiological and molecular mechanisms
leading to a diabetic state. A gradual development of pancreatic beta-cell
dysfunction upon aging, rather than insulin resistance, is the main mechanism
in developing glucose intolerance. Carriers of the A3243G mutation show during
a hyperglycemic clamp at 10 mmol/l glucose a marked
reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G
mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in
maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes
does show a pronounced age-dependent deterioration of pancreatic function
indicating involvement of additional processes. Furthermore, one would expect
that all mtDNA mutations that affect ATP synthesis
lead to diabetes. This is in contrast to clinical observations. The origin of
the age-dependent deterioration of pancreatic function in carriers of the
A3243G mutation and the contribution of ATP and other mitochondrion-derived
factors such as reactive oxygen species to the development of diabetes is
discussed.
PMID: 14749274 [PubMed - as supplied by publisher]
Maturity-onset
diabetes of the young (MODY) resulting from mutations in the glucokinase (GCK) gene accounts for approximately 20% of
MODY in the