Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by hyperglycaemia and insulin resistance, and affects nearly 5% of the general population. Inherited factors are important for its development, but the genes involved are unknown. We have identified a large pedigree in which NIDDM, in combination with a sensorineural hearing loss, is maternally inherited. The maternal inheritance and the observed decrease in mitochondrial enzyme activities of the respiratory chain indicate a genetic defect in the mitochondrial DNA. An A to G transition was identified at nucleotide 3,243, a conserved position in the mitochondrial gene for tRNA(Leu)(UUR). This mutation cosegregates with the disease in this family and is absent in controls, and indicates that a point mutation in mitochondrial DNA is a pathogenetic factor for NIDDM.

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 ␤-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 firstand 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 ␤-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. Diabetes 53 (Suppl. 1):S103-S109, 2004 D iabetes is a collection of diseases characterized by the presence of chronic hyperglycemia. Maintenance of normal glucose homeostasis involves the action of a glucose sensor in the pancreatic ␤-cell that detects an increase in blood glucose concentration and converts that into increased secretion of insulin. Increased circulating insulin concentrations suppress hepatic glucose output and stimulate glucose uptake by muscle and adipose tissue.Pathophysiological mechanisms leading to diabetes can involve an inappropriate secretion of insulin, insulin resistance of the liver, muscle and fat, or combined defects. The risk of an individual to develop diabetes involves a complex interaction between genetic and environmental factors. Gene variants that have been identified to contribute to the major forms of diabetes, such as autoimmune type 1 diabetes and metabolic syndrome-associated type 2 diabetes, are "low penetrance" variants that modulate the susceptibility of an individual to develop diabetes or that protect against the disease (1-3).A number of gene mutants have been identified in the past decade that represent high penetrance risk genes for diabetes. Carriers of these gene mutants have a nearly 100% chance to develop diabetes during their life span. These so-called monogenetic forms of diabetes com...

HFD induced a hypertrophy-like cardiac phenotype, characterised by a higher basal contractile force, an impaired recovery from increased workloads and decreased insulin-mediated protection against Ca2+ overload. Cardiac dysfunction was associated with myocardial insulin resistance and phospholamban hypophosphorylation. Our data suggest that myocardial insulin resistance, resulting from exposure to excessive alimentary fat, may contribute to the pathogenesis of diabetes-related heart disease.