Peripheral insulin resistance is a well-known component of Type 2 diabetes, but it clearly is not enough, as clinical experience and work with many transgenic mice reveal . However, a compelling molecular link to diabetes emerges from the finding in mice that inhibition of the IRS2 branch of the insulin/IGF signaling system impairs the capacity of the pancreatic P-cells to compensate for insulin resistance [21,56]. Not only do IRS2-/- mice develop peripheral insulin resistance, but they also eventually fail to sustain compensatory insulin secretion . The convergence of peripheral and islet defects around the IRS2 branch of the insulin/ IGF signaling pathway reveals a common pathway to diabetes.
In mice, IRS1 and IRS2 contribute to peripheral insulin response, and there is no reason to suspect different roles for these proteins in people [27,56,92]. IRS1 exerts its greatest effect on metabolism by regulating insulin signals in muscle and adipose tissue, whereas it plays a lesser role in mediating the effects of insulin on liver metabolism [56,93-97]. But, IRS1 -/- mice never become diabetic because they develop lifelong compensatory hyperinsulinemia. The amount of functional P-cell mass increases throughout the life of IRS1-/-mice, and the P-cells continue to detect changes in the serum glucose levels [93,98]. By contrast, IRS2-/- mice display dysregulated lipolysis, peripheral glucose uptake, and hepatic gluconeogenesis and ultimately develop diabetes due to P-cell failure . Although IRS2-/- mice are nearly normal at birth and up to weaning, IRS2-/- mice develop hyperinsulinemia as young adults; males die at 12 weeks of age and females by 30 weeks of age . As the disease progresses, pancreatic islet size invariably decreases and P-cell function fails .
groins PDX1 HNF1« HNF4<x
fgfr2 -> [i-cell Growth GCK
Figure 6 A potential pathway linking IRS2 signaling to the expression and function of the homeodomain transcription factor PDX1. The diagram shows the relation between the MODY genes, especially PDX1, and the IRS2 branch of the insulin signaling pathway . Drugs that promote IRS2 signaling are expected to promote PDX1 function in P-cells which will support glucose tolerance and cure diabetes.
The progressive loss of P-cell function and the onset of diabetes in Irs2-/- mice might be associated with decreased expression in pancreatic islets of the homeodomain transcription factor PDX1 (also called IDX1 and IPF1) . PDX1 is critical for the development of the pancreas in mice and people, and pancreas agenesis occurs upon the complete disruption of PDX1 [102,103]. Moreover, PDX1 is required in adult humans and mice to promote normal glucose sensing and insulin secretion [104,105]. Genetic defects in the PDX1 gene occur in about 5% of people with Type 2 diabetes. Inactivating mutations are associated with autosomal early-onset diabetes (MODY), whereas missense mutations predispose humans to late-onset Type 2 diabetes [106,107]. The functional association between IRS2 signaling and Pdx1 expression observed in mice creates a molecular link between Type 2 diabetes and the less frequent and less severe autosomal forms of diabetes (MODY) . Dysregulation of PDX1 by genetic or functional mechanisms might be one of the common links between early-onset (MODY) and ordinary Type 2 diabetes (Fig. 6). This hypothesis is supported by the finding that transgenic expression of PDX1 postpones P-cell failure and reduces by years the progression of diabetes in IRS2-/- mice . If insulin resistance in people includes an IRS2 component, then reduced PDX1 function might eventually impair P-cell function as noted in people with MODY, and drugs that promote the IRS2^Pdx1 pathway might provide new strategies to promote P-cell growth and function in both Type 1 and Type 2 diabetes.
Was this article helpful?
All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.