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


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.
Chia
Chee W
CW
National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.
Carlson
Olga D
OD
Kim
Wook
W
Shin
Yu-Kyong
YK
Charles
Cornelia P
CP
Kim
Hee Seung
HS
Melvin
Denise L
DL
Egan
Josephine M
JM
D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D003927:Diet, Diabetic; D005934:Glucagon / Q000097:blood; D005972:Glutaminase / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood / Q000494:pharmacology*; D008687:Metformin / Q000627:therapeutic use; D010919:Placebos; D019518:Postprandial Period; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D010919:Placebos; D013453:Sulfonylurea Compounds; C421249:TAX1BP3 protein, human; D005934:Glucagon; D008687:Metformin; D000242:Cyclic AMP; D005972:Glutaminase