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Differential sensitivity to beta-cell secretagogues in "early," type I diabetes mellitus
Insights
Children with early type 1 diabetes mellitus show a significant loss of insulin secretion. Beta-cells lose responsiveness to glucose and other secretagogues, indicating a functional defect before complete cell destruction.
Area of Science:
- Endocrinology
- Immunology
- Metabolic Disorders
Background:
- Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of pancreatic beta cells.
- Understanding the early functional status of remaining beta cells is crucial for T1DM management and research.
- This study investigates beta-cell responsiveness in children with early-stage or remitted T1DM.
Observation:
- Four children (ages 10-12) with early T1DM or in remission were studied.
- One child was an anti-islet antibody-positive twin, two had impaired glucose tolerance and elevated T-cells, and one was in remission post-immunotherapy.
- Insulin release was assessed using various beta-cell secretagogues.
Findings:
- A negligible first-phase insulin increment was observed after intravenous glucose in all subjects.
- Responses to intravenous glucagon, tolbutamide, arginine, and oral glucose were significantly reduced (10-43% of normal controls).
- A consistent rank order of responsiveness was noted: arginine > glucagon > oral glucose > tolbutamide > glucose.
Implications:
- These findings reveal a functional beta-cell defect in early T1DM, characterized by a complete loss of glucose-stimulated insulin secretion and partial loss to other stimuli.
- This defect precedes complete beta-cell destruction and may explain the progressive decline in insulin release observed in T1DM.
- The results highlight the importance of assessing beta-cell function beyond glucose stimulation in T1DM research.
Abstract:
The insulin secretory response to various beta-cell secretagogues was studied in four children (ages 11, 11, 12, and 10 yr) in "early" stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of Ia-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0-10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine greater than i.v. glucagon greater than oral glucose greater than i.v. tolbutamide greater than i.v. glucose. These studies indicate that a "functional" beta-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete beta-cell destruction. This alteration in beta-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings to type I diabetic subjects.