Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes.

Abstract

OBJECTIVE:

Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

RESEARCH DESIGN AND METHODS:

Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

RESULTS:

Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse alpha-cells. In alphaTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS; GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.

• Authors: Chee W Chia, Olga D Carlson, Wook Kim, Yu-Kyong Shin, Cornelia P Charles, Hee Seung Kim, Denise L Melvin, Josephine M Egan
• Journal: Diabetes (Diabetes) Vol. 58 Issue 6 Pg. 1342-9 (Jun 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19276444 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Intracellular Signaling Peptides and Proteins
• Placebos
• Sulfonylurea Compounds
• TAX1BP3 protein, human
• Glucagon
• Metformin
• Cyclic AMP
• Glutaminase

Topics

• Area Under Curve
• Blood Glucose (metabolism)
• Cross-Over Studies
• Cyclic AMP (metabolism)
• Diabetes Mellitus, Type 2 (blood)
• Diet, Diabetic
• Glucagon (blood)
• Glutaminase (blood, pharmacology)
• Humans
• Hyperglycemia (blood, drug therapy, metabolism, prevention & control)
• Hypoglycemic Agents (therapeutic use)
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins (blood, pharmacology)
• Metformin (therapeutic use)
• Placebos
• Postprandial Period
• Sulfonylurea Compounds (therapeutic use)