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Abnormal alpha cell hypoglycemic recognition in children with insulin dependent diabetes mellitus (IDDM)
R P Hoffman1, C Singer-Granick, A L Drash
1Department of Pediatrics, University of Pittsburgh.
Insights
Children with insulin-dependent diabetes mellitus (IDDM) show reduced glucagon release during hypoglycemia. This suggests a primary defect in pancreatic alpha cells
Area of Science:
- Pediatric Endocrinology
- Metabolic Disorders
- Diabetes Research
Background:
- Children with insulin-dependent diabetes mellitus (IDDM) exhibit impaired glucagon counterregulation during hypoglycemia.
- Understanding the mechanisms behind this diminished response is crucial for preventing severe hypoglycemic events in pediatric patients.
Purpose of the Study:
- To investigate the underlying mechanisms responsible for the blunted glucagon response to hypoglycemia in children and adolescents with IDDM.
- To differentiate between potential causes including hyperinsulinism, autonomic neuropathy, pan-islet cell dysfunction, and glucotoxicity.
Main Methods:
- Sixty children and adolescents with IDDM and a control group underwent testing of glucagon and pancreatic polypeptide responses to hypoglycemia induced by insulin bolus.
- Hormonal responses were assessed after both insulin withdrawal and a period of intensive insulin therapy.
- Arginine stimulation and mixed meal tolerance tests were also performed to evaluate other aspects of pancreatic islet cell function.
Main Results:
- Children with IDDM demonstrated significantly lower glucagon responses to hypoglycemia compared to controls.
- Glucagon response to arginine did not differ between groups and was significantly greater than the response to hypoglycemia in IDDM patients.
- Responses to hypoglycemia were consistent regardless of insulin withdrawal or intensive therapy, and pancreatic polypeptide responses did not differ significantly.
Conclusions:
- The diminished glucagon response to hypoglycemia in pediatric IDDM is not primarily due to hyperinsulinism suppression, autonomic neuropathy, or short-term glycemic control.
- Findings suggest a defect intrinsic to the pancreatic alpha cells, impairing their ability to recognize or respond to low glucose levels.
- This points towards a fundamental issue in counterregulatory hormone secretion in children with diabetes.
Abstract:
Children with IDDM have diminished glucagon responses to hypoglycemia. We evaluated possible mechanisms in 60 children and adolescents with IDDM (age 15.4 +/- 2.6 years, duration 7.8 +/- 3.5 years [mean +/- SD]) and without diabetic complications. These were: 1) suppression by hyperinsulinism, 2) autonomic neuropathy, 3) a pan-islet cell defect, and 4) a glucotoxic effect. Glucagon and pancreatic polypeptide responses to hypoglycemia (insulin bolus 0.15-0.75 U/kg) were studied after insulin withdrawal and 3 days of intensive insulin therapy. Responses to arginine and mixed meal were also studied. The control group consisted of children with non-growth hormone deficient short stature. IDDM children had lower glucagon responses to hypoglycemia than controls (p < 0.001), the response to arginine did not differ from controls, and was greater than the response to hypoglycemia (p < 0.001). Responses to hypoglycemia after insulin withdrawal and intensive therapy did not differ. Basal pancreatic polypeptide levels were lower in IDDM than in controls (p < 0.05) but responses to hypoglycemia did not differ between groups. Thus the diminished glucagon response to hypoglycemia reflects a defect in hypoglycemic recognition or response by the alpha cells.