Lessons from other monogenic syndromes

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Apart from MODY, T2D-like diabetes is a component of many other monogenic syndromes. These include transient neonatal diabetes mellitus, attributed to biallelic expression of an imprinted gene on chromosome 6q24 (Gardner et al., 2000); and permanent neonatal diabetes mellitus, in some cases due to homozygous mutations in GCK (Njolstad et al., 2001). Recent work has demonstrated that many cases of both transient and permanent neonatal diabetes mellitus are caused by mutations in the KCNJ11 gene which encodes one component of the pancreatic beta-cell's KATP channel, closure of which is a key event in glucose-stimulated insulin secretion (Gloyn et al., 2004; 2005). Whilst the mutated channels have lost the capacity to respond to endogenously generated adenosine triphosphate (ATP), they typically retain the ability to close in response to exogenous drugs. Many patients with neonatal diabetes have been able to dispense with lifelong insulin therapy and to achieve better, more convenient control on sulphonylureas (Zung et al., 2004).

Diabetes can also result, in rare instances, from mutations in the genes encoding both insulin (leading to familial hyperproinsulinemia) and the insulin receptor (Rabson-Mendelhall syndrome). A wide range of uncommon multisystem syndromes have a prominent diabetic phenotype including Wolfram's; Alstrom's; and thiamine-responsive megaloblastic anemia (respectively attributed to mutations in WFS1, ALMS1 and SLC19A2) (Inoue et al., 1998; Diaz et al., 1999; Collin et al., 2002). Although rare, these diverse conditions illustrate the wide spectrum of molecular abnormalities (involving primary defects in a number of different tissues and systems) which can result in T2D. One of the most instructive of these syndromes (although not strictly a monogenic condition) is that associated with a mutation at position 3243 in the mitochondrial genome, within the gene encoding the non-nuclear form of tRNA (leucine). Depending on the tissue load of the abnormal mitochondrial sequence in any given individual, this mutation can result in either MELAS (a neurological syndrome characterized by Myalgic Encephalopathy, Lactic Acidosis and Stroke-like episodes) or Maternally-Inherited Diabetes and Deafness (MIDD) (Kadowaki et al., 1994). The molecular mechanism here is thought to be one of disrupted mitochondrial metabolism, resulting in reduced oxidative phosphorylation, and ATP depletion. In the beta-cell this compromises glucose-stimulated insulin secretion.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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