A3243G
mtDNA

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An A to G point mutation
at position 3243 on the
Mitochondrial DNA
causes MELAS and MIDD.

Mitochondrial Diabetes

A review of the paper by J. A. Maasen, 2002 - Mitochondrial Diabetes.

In his paper, J. A. Maasen, (May 2002) discusses over 30 scientific papers of research relating to Mitochondrial Diabetes.

In his introduction, he notes that :-

It has been known since 1992 that Mitochondria play an important part of Glucose homeostasis.
mtDNA is Maternally Inherited.
mtDNA exists in a harsh environment where it is susceptible to damage by oxidising agents, so it is not surprising that mtDNA shows a high mutation rate and that mutations accumulate with age.
The A3243G mtDNA mutation is associated with Diabetes and Deafness, a condition termed MIDD.

In relation to Mitochondrial Diabetes, he notes that :-

Clinical data does not provide evidence of peripheral Insulin Resistance, (such as is typical in Type II diabetes).
Carriers of A3243G generally do not have Islet Cell Antibodies, (such as is typical in Type I diabetes).
Most of the data suggests a change in the function of insulin secreting cells in the pancreas.

He describes the mechanism of insulin secretion by Pancreatic Beta Cells involves a number of steps :-

Pancreatic Beta Cells take up, (or absorb through the cell wall), Glucose by use of a Glucose Transporter GLUT2.
Once inside the cell, the Glucose is Phosphorylated to Glucose-6-Phosphate by the pancreatic beta cell specific enzyme called Glucokinase. This enzyme is rate limiting at physiological glucose levels and thereby determines the magnitude of the glycolytic flux.
The process of Oxidative Phosphorylation then continues as usual, with the glucose being converted to Pyruvate and imported into Mitochondria, which complete the conversion to Carbon Dioxide and Water - producing ATP.
The ATP which is produced increases the ratio of ATP to ADP inside the pancreatic beta cell. In turn this closes a specific Potassium channel.
This Potassium channel closure de-polarises the cell membrane which opens a voltage-gated Calcium channel.
The increased level of Calcium in the cell is a direct stimulator of Insulin secretion.
Furthermore, Calcium levels are a co-factor for rate limiting enzymes in the Krebs (or Citric Acid) cycle inside the Mitochondrion.

After discussing other findings relating to Mitochondrial Diabetes, he concludes that :-

"Thus mitochondrial diabetes involves primarily a defect in the glucose-induced insulin secretion by the pancreas".

He notes that most patients with the A3243G mutation :-

Develop Diabetes at the age of 35
The Diabetes is either Type I or Type II in nature - in similar proportions.
In Type II like patients, there is a trend to the rapid development of Insulin Dependency.
Most of the patients who develop diabetes have a low Body Mass Index.
An impaired hearing due to reduced detection of high tone frequencies is present in the majority of diabetic patients.
Both cardiomyopathy and neurological symptoms are present in A3243G carriers, at a higher frequency, than in the general population.
Some patients may develop Renal (kidney) insufficiency.

He notes that for patients with the A3243G mutation :-

Treatment for Diabetes is usually with Insulin, Sulphonylureas, or diet.
Metformin is contra-indicated (not recommended) because of it's published ability to induce lactic-acidosis and the vulnerability of individuals with impaired mitochondrial function for developing mitochondrial lactic-acidosis.
Treatment with CoQ10 (Suzuki et al 1998), and alpha-lipoic acid or thiamine seems from a theoretical viewpoint to have some benefit, however comprehensive clinical data showing a benefit is lacking.