The Pathophysiology of Diabetes Involves a Defective Amplification of the Late-Phase Insulin Response to Glucose by Glucose-Dependent Insulinotropic Polypeptide—Regardless of Etiology and Phenotype

Oct 15, 2003The Journal of clinical endocrinology and metabolism

Diabetes involves a weak late insulin boost from a gut hormone after glucose, regardless of type or cause

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Abstract

In five distinct groups of diabetic patients, the late-phase plasma insulin response to glucose was attenuated by glucose-dependent insulinotropic polypeptide (GIP) but preserved by glucagon-like peptide-1 (GLP-1).

The early-phase plasma insulin response (0-20 min) was enhanced by both GIP and GLP-1 compared to glucose alone in all patient groups.
The late-phase plasma insulin response (20-120 min) to GIP was consistently lower than that to GLP-1 across all groups.
Higher glucose infusion rates were needed during the late-phase GLP-1 stimulation compared to GIP stimulation.
The diminished GIP response in the late phase is associated with diabetes mellitus and may characterize most forms of diabetes.

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The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.

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The Pathophysiology of Diabetes Involves a Defective Amplification of the Late-Phase Insulin Response to Glucose by Glucose-Dependent Insulinotropic Polypeptide—Regardless of Etiology and Phenotype

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