β-Cell Dysfunction in Classic Transient Neonatal Diabetes Is Characterized by Impaired Insulin Response to Glucose but Normal Response to Glucagon

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Abstract
OBJECTIVE—To investigate β-cell function and the long-term health of four case subjects presenting with chromosome 6–associated transient neonatal diabetes (TND). RESEARCH DESIGN AND METHODS—Two unrelated case subjects presenting with paternal uniparental isodisomy of chromosome 6 (UPD6) and two siblings with a paternally inherited duplication of 6q24 were studied. Three case subjects presented with neonatal diabetes that recurred at 4–17 years, while diabetes was incidentally discovered in the other case subject at 14 years of age. β-Cell function was investigated after diabetes relapse by means of an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and glucagon tests. The quantitative insulin sensitivity check index (QUICKI) was calculated from fasting blood samples as an estimate of insulin sensitivity. RESULTS—β-Cell function was investigated at diabetes relapse in two case subjects: the insulin response to both an OGTT and IVGTT was low, whereas the basal levels of C-peptide were normal. No evidence of insulin resistance was found. Residual β-cell function was further explored by a glucagon test in all subjects at the age of 16–28 years and was found to be normal. Final height was within the normal percentiles, whereas one case, who had been poorly controlled since puberty, presented with diabetes-related microvascular complications. CONCLUSIONS—In patients with chromosome 6–associated TND, the β-cell is preserved and able to secrete insulin through the stimulatory G protein pathway while exhibiting a specific defect of insulin secretion after glucose stimulation. This form of diabetes can be managed with insulin or diet, although new therapeutic agents (glucagon-like synthetic analogs) may prove useful in the future. Lack of treatment leads to long-lasting hyperglycemia without the risk of ketoacidosis but associated with microangiopathy in adult life.