Mechanisms regulating insulin response to intragastric glucose in lean and non-diabetic obese subjects

Background/Objectives

The changes
in blood glucose concentrations that result from an oral glucose challenge are
dependent on the rate of gastric emptying, the rate of glucose absorption and
the rate of insulin-driven metabolism that include the incretins,
glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1
(GLP-1). The rate of insulin-driven metabolism is clearly altered in obese
subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma
insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone
secretions in obese subjects and healthy controls during increasing glucose
loads.

Subjects/Methods

The study
was conducted as a randomized, double-blind, parallel-group trial in a hospital research
unit. A total of
12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6
men and 6 women) participants took part in the study. Subjects received
intragastric loads of 10 g, 25 g and 75 g glucose
dissolved in 300 ml tap
water.

Results

Main
outcome measures were plasma GLP-1
and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance
(P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin
disposal (P < 0.001); iii) trend
for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon
levels (P < 0.001) in obese
subjects.

Conclusions

It seems
that, rather than changes in incretin secretion, fasting hyperglucagonemia and
consequent hyperglycemia play a role in reduced disposal of insulin,
contributing to hyperinsulinemia and insulin resistance.