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- Title
Intravenous GIP Worsens Postprandial Hyperglycemia in Humans with Type 2 Diabetes.
- Authors
Chia, Chee W.; Carlson, Olga; Melvin, Denise; Kim, Heeseung; Tagalicud, Arlene; Charles, Cornelia; Egan, Josephine M.
- Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from the enteroendocrine K-cells in response to food. Unlike the other incretin, glucagon-like peptide-1 (GLP-1), GIP is reported to have lost its insulinotropic effect and not have glucose-lowering properties in patients with type 2 diabetes mellitus (T2DM). We attempted to gain insight into the pathophysiology underlying the seeming lack of effects of GIP on glucose homeostasis in T2DM. We therefore administered synthetic human GIP (with a meal) to subjects who had T2DM, and then, for 6hr, took frequent blood samples to measure various factors known to be involved in glucose homeostasis. 22 insulin-naive subjects with T2DM (ages 52.6±9.3years; BMI 36.7±7.3kg/m²; HbA[sub 1c] 7.4±1.5%; fasting plasma glucose 155±46mg/dl; diabetes duration 4.3±4.2years; f/m ratio 13/9) that had been treated with diet alone, metformin and/or sulfonylurea were recruited. They stopped oral hypoglycemic medications for 5 days prior to testing and fasted for 8hr prior to 2 study visits, each visit separated by not less than 6 weeks. After 3 baseline blood draws, the subjects received continuous intravenous administration of either placebo (0.9%NaCl) or GIP (20ng/kg/min) for 180min starting with the first bite of a 550calorie mixed-meal, and 1g of acetaminophen to study gastric emptying. Frequent blood sampling took place over the subsequent 6hr (every 5min for the first 75min then every 15min until 180min and every 20min until 360min). Compared to placebo, GIP induced an increase in plasma insulin from 5-30min but a transient decrease in plasma glucose at the 10min time-point only (p<0.05). Intriguingly, and hitherto undescribed, GIP induced a later augmentation in glucagon secretion with a peak level at approximately 30min (p<0.05), a significant elevation in plasma glucose from 120-220min (p<0.05) and a decrease in GLP-I secretion at 135min that lasted for the remainder of the 6hr study period (p<0.05). Based on plasma acetaminophen levels, GIP did not affect gastric emptying and NEFAs were similar during both studies. In T2DM therefore, GIP, given at a pharmacological dose with a meal, still has an early, short-lived insulinotropic effect, resulting in a transient, clinically irrelevant plasma glucose drop. However, this was subsequently followed by increased plasma glucagon levels and worsening hyperglycemia. These findings make it unlikely that GIP or GIP receptor agonists will ever be useful as glucose-lowering agents.
- Publication
Diabetes, 2007, Vol 56, pA385
- ISSN
0012-1797
- Publication type
Academic Journal