Genes and the Metabolic Syndrome Monogenic Disorders

In addition to identifying genes for 'garden-variety' MetS, careful characterization of patients with rare monogenic disorders that recapitulate features of MetS have led to important insights that can be translated to the more common complex form. For instance, familial partial lipodystrophy (FPLD) syndromes are autosomal dominant disorders that occur with a frequency of perhaps 1:100 000 individuals in the general population.37-39 There are three distinct forms: FPLD1, FPLD2, and FPLD3, of which the latter two have been found to be due to mutations, respectively, in the LMNA gene, encoding nuclear lamin A/C and the PPAR-g gene, encoding peroxisome proliferator-g activated receptor (PPAR-g). Both FPLD2 and FPLD3 feature a loss of fat tissue in peripheral depots such as the extremities and gluteal region, with preservation of central and visceral fat stores. The infinite ratio of visceral to peripheral subcutaneous fat creates an extreme form of common visceral obesity, which leads to the development of several key features of the common MetS, including increased risk of atherosclerosis endpoints.44 FPLD2 (the LMNA form) implicates structural abnormalities of the nuclear envelope as a cause of insulin resistance, diabetes, and ultimately atherosclerosis. FPLD3 (the PPAR-g form) proved that inherited partial lipodystrophy was genetically heterogeneous, clarified the metabolic phenotype of PPAR-g-deficiency due to mutant PPARG, and confirmed the key role of PPAR-g in adipogenesis and metabolism. Comparison with FPLD2 indicated that FPLD3 was associated with less severe lipodystrophy and more severe insulin resistance,37 suggesting additional mechanisms underlying insulin resistance and metabolic changes beyond those attributed solely to adipose tissue redistribution. This suggests that intervening on the PPAR-g pathway could have multiple beneficial effects upon metabolic phenotypes and downstream complications. It is no coincidence that pharmacological agonists of PPAR-g have been shown to improve insulin resistance, lessen the intermediate metabolic disturbances, and likely reduce vascular endpoints.

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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