Insulin binding to erythrocyte insulin receptors was studied in 10 women with gestational diabetes and compared with 10 matched, normal, pregnant women and 10 normal, non-pregnant controls, with no family history of diabetes. Pregnant women had higher mean fasting and post-glucose plasma immunoreactive insulin (IRI) compared to non-pregnant controls (p less than 0.001). Women with gestational diabetes had higher mean fasting and post-glucose plasma glucose levels and a lower mean specific binding of insulin when compared with the other two groups (p less than 0.001). The decreased insulin binding was significant only at lower insulin concentrations (0.2-2 ng/ml) when compared with those of normal pregnant women (p less than 0.01), suggesting decreased receptor affinity with no change in receptor number. In addition, an increased mean ED50 value for 50% inhibition of maximal binding and a lower mean average affinity constant Ke (empty site) obtained in gestational diabetes in comparison to the other two groups also suggested de decreased affinity of the receptor. The finding that pregnancy with normal glucose tolerance was not accompanied by changes in insulin binding against decreased insulin binding and affinity observed in gestational diabetes suggested a pathogenetic role for impaired insulin binding as one of the factors responsible for insulin resistance and hyperglycemia in gestational diabetes.
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The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought.
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