Abnormalities of glucagon secretion and action in diabetes
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page106-107
2025-10-22
87
The potent effects of glucagon to promote fasting hepatic glucose production can be amplified in the setting of diabetes, where insulin secretion is impaired and insufficient for normal opposition of glucagon effects. The secretion of both principal islet hormones, insulin and glucagon, is abnormal in people with diabetes. Plasma glucagon levels tend to be substantially elevated in suboptimally managed diabetes with severe insulin deficiency or ketoacidosis. In a classic study using somatostatin to inhibit α- cell secretion, individuals with type 1 diabetes had substantial improvements in hyperglycaemia and ketogenesis when plasma glucagon was reduced. Among groups with type 2 diabetes, some individuals will have modest fasting hyperglucagonaemia even without metabolic decompensation, and clinical studies suggest that this increase is sufficient to contribute to the elevated hepatic glucose production in individuals with diabetes. Moreover, in a group of individuals with type 2 diabetes who had suppression of islet hormone secretion by somatostatin, there was a significant reduction of basal hepatic glucose production, and this effect was enhanced when insulin was given at basal levels. Together these findings exemplify the basis for concluding that glucagon action contributes to pathogenic elevations of fasting glucose in at least a subset of those with type 2 diabetes.
Similar to the β cell in individuals with diabetes, the α cell has abnormal sensitivity to glucose and is less suppressed during hyper glycaemia. As a result, plasma glucagon levels after mixed- nutrient meals are generally higher with type 2 diabetes. In contrast, glucagon responses to hypoglycaemia are also reduced. The mechanism for this is not clear, but the functional result suggests another form of α- cell glucose insensitivity. There is emerging evidence that α- cell dysfunction in diabetes has a genetic origin. Specifically, a common polymorphism in the KCNJ11 gene, which encodes the KIR6.2 component of the KATP channel, predisposes individuals to type 2 diabetes and is related to blunted glucose- induced suppression of glucagon.
In addition to the effects of hyperglucagonaemia on fasting glucose levels, abnormal α- cell regulation also contributes to glucose intolerance. Following meals, glucagon levels remain abnormally elevated in individuals with diabetes, rather than undergoing the abrupt post- prandial decline typical of individuals without diabetes. In normal physiological regulation, the post- prandial suppression of glucagon is a key factor in shifting hepatic metabolism from glucose production to glucose clearance, and failure to make this shift disrupts normal glycaemic regulation after meals. For example, individuals without diabetes have significantly greater glycaemic excursions after a test meal when glucagon levels are maintained at fasting concentrations compared to when they are allowed to follow the normal post- prandial decline. Similar results can also be demonstrated in individuals with type 2 diabetes. Thus, failure to suppress fasting glucagon levels after a meal contributes to glucose intolerance, and this effect is magnified in the setting of diabetes where insulin secretion and action are reduced.
الاكثر قراءة في الغدة البنكرياسية
اخر الاخبار
اخبار العتبة العباسية المقدسة
