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.

FIG. 1.

Each participant took part in two different interventions spaced ∼6–12 weeks apart. Starting with ingestion of a mixed meal, placebo (normal saline) or synthetic human GIP (20 ng · kg⁻¹ · min⁻¹) was administered intravenously for 3 h. At the same time, frequent blood samples were taken for 6 h to measure various factors known to be involved in glucose homeostasis. With the first bite, 1 g of acetaminophen was also given, and the rate of appearance of acetaminophen in plasma was taken as a measure of gastric emptying.

FIG. 2.

When compared with placebo, exogenous GIP infusion not only did not lower postprandial glucose but further worsened hyperglycemia during late postprandial period (120–360 min) in patients with type 2 diabetes. GIP infusion at a pharmacologic dose (20 ng · kg⁻¹ · min⁻¹) during a mixed meal is associated with a fivefold increase in plasma GIP levels (A), an early transient increase in plasma insulin (0–60 min) (B), a late postprandial elevation of plasma glucose (120–360 min) (C), a significant early postprandial increase in plasma glucagon (0–60 min) (D), and a significant decrease in late postprandial plasma GLP-1 levels (120–360 min) (E). GIP or placebo infusion was started a time 0 and continued for 180 min. A mixed meal was given at time 0. Data are presented as means ± SE. *Significant (P < 0.05) differences between GIP versus placebo at individual time points relative to baseline at t = 0. Blue circle, placebo; orange circle, GIP.

FIG. 3.

AUC_ALL (t = 0–360 min) for GIP (A-1), insulin (B-1), glucose (C-1), glucagon (D-1), and GLP-1 (E-1) during placebo (blue) and GIP infusion (orange). With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to area above and below baseline levels, respectively. The AUC for each curve, AUC_ALL (t = 0–360 min), was further divided into different time periods: AUC_0–60 (t = 0–60 min), AUC_60–120 (t = 60–120 min), AUC_120–220 (t = 120–220 min), and AUC_220–360 (t = 220–360 min) to better quantify the changes in response to placebo versus GIP infusion for GIP (A-2), insulin (B-2), glucose (C-2), glucagon (D-2), and GLP-1 (E-2). ***P < 0.001; **P < 0.01; *P < 0.05.

FIG. 4.

Acetaminophen level (A), used as a marker of gastric emptying, showed no difference between placebo (black solid line) and GIP infusion (gray dash line), as assessed by AUC of acetaminophen levels (B). ■, placebo; □, GIP.

FIG. 5.

GIP receptors are present on human and mouse islets. Immunofluorescent images show coexpression of insulin with GIPR and coexpression of glucagon with GIPR in human (A) and in mouse (B) islets. C: GIP receptors are present on αTC1 cells as shown on immunoflurescent images. Stimulation of αTC1 cells with GIP led to increased intracellular cAMP levels (D) and glucagon secretion (E) in a concentration-dependent manner. F: In αTC1 cells, GIP-mediated glucagon secretion was diminished in the presence of GIP (3–42), a GIP receptor antagonist. □, vehicle; ■, 1 μmol/l GIP. (A high-quality digital representation of this figure is available in the online issue.)