The Enteroinsular Axis In Diabetes

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The importance of the enteroinsular axis in healthy individuals gave rise to the possibility that an incretin defect might be partially responsible for the metabolic abnormalities observed in type 2 diabetes. Several studies showed that the incretin effect (as studied by comparing isoglycemic oral and IV glucose loads) is reduced or abolished in these individuals [51]. Work in this area initially centered on the possibility of impaired GIP secretion, but early publications reached no consensus, as normal, increased, and decreased GIP secretion have all been reported in type 2 diabetes [52]. Some of these conflicting results could be attributed to the varying degrees of cross-reactivity that GIP assays displayed with biologically inactive forms of the hormone. A recent study has found normal or marginally impaired GIP secretion in diabetics drawn from a population with a wide spectrum of the disease [53]. However, similar studies with GLP 1 have shown a significant impairment of GLP 1 secretion in diabetes, which was related to impaired B cell function, regardless of whether the biologically-active intact hormone, or the metabolites of GLP 1, were measured [53]. Studies of identical twins, discordant for type 2 diabetes, have shown that GLP 1 responses are lower in the diabetic twin, and they are also normal in the first degree relatives of diabetic subjects [54]. This implies that the impaired GLP 1 secretion observed in diabetes is a consequence rather than a cause of the disease.

However, when the biological effects of IV infusions of GIP or GLP 1 in type 2 diabetic subjects was studied, the findings did not reflect the secretory defects of the two hormones in these individuals. While the insulinotropic effect of GLP 1 was similar to that of control subjects, the insulinotropic effect of GIP was almost lost in type 2 diabetes [55]. These findings point to a GIP receptor or postreceptor defect at pancreatic B cell level in type 2 diabetes. Defective expression of the GIP receptor has been observed in animals with genetically determined diabetes [56]. Polymorphisms in the coding region of the GIP-receptor gene have also been reported, but these have not been associated with either defective signaling or diabetes [57]. However, studies in healthy, first-degree relatives of diabetic patients showed a reduced insulinotropic effectiveness of GIP in comparison to healthy subjects without a family history of diabetes, suggesting that the GIP defect could possibly be a genetically determined, primary defect [58]. The mechanism of diminished GIP responsiveness in diabetics remains unclear. It appears to be severe, but confined to late-phase insulin secretion only, a finding that makes defective GIP-receptor expression an unlikely explanation [59]. Recent work with diabetic patients who do not conform to the classic obese type 2 pattern [60] has suggested that the defect is primarily a consequence rather than a cause of the diabetic state, although a genetic component cannot be ruled out.

The impairment of both the secretion of GLP 1 and the responsiveness of GIP in type 2 diabetes explains the findings of a severely diminished or absent incretin effect in these patients. It also has implications for the use of these hormones in the treatment of diabetes, as can be seen in the following section.

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