GIP contributes to islet trihormonal abnormalities in type 2 diabetes

Abstract

Context: Research and clinical treatments on type 2 diabetes mainly focus on insulin deficiency with little attention paid to other islet hormones.

Objective: This study tested the hypothesis that glucose-dependent insulinotropic polypeptide (GIP) is involved in diabetes-associated multiislet hormone dysregulation.

Design: This paper included a case-control study involving 92 community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA): 23 with type 2 diabetes on glucose-lowering agents, 25 with newly diagnosed drug-naïve type 2 diabetes, 19 with prediabetes, and 25 with normal glucose tolerance; a separate intervention study with 13 non-BLSA volunteers with type 2 diabetes treated with diet alone, metformin, and/or metformin/sulfonylurea combination; a rodent study; and an in vitro cell line study.

Interventions: An oral glucose tolerance test was performed in the BLSA participants. For the intervention study, saline (0.9% NaCl) or synthetic human GIP (20 ng · kg(-1) · min(-1)) was administered to type 2 diabetes subjects for 180 minutes together with a meal, and plasma samples were obtained at predetermined intervals for 360 minutes. A bolus of GIP or placebo was given to C57BL/6 mice.

Main outcome measures: Plasma glucose, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and GIP were measured.

Results: After an oral glucose tolerance test, glucose, glucagon, PP, GLP-1, and GIP levels were significantly elevated in type 2 diabetes groups, compared with normal and prediabetes groups. GIP infusion in type 2 diabetes subjects was associated with significantly elevated PP levels compared with placebo. The GIP bolus given to C57BL/6 mice was followed by increased PP levels. GIP receptors were found in both human and mouse PP cells.

Conclusions: Up-regulation of GIP production may play an important role in multihormonal dysregulation in type 2 diabetes, most likely through interaction with GIP receptors on islets.

Trial registration: ClinicalTrials.gov NCT00233272 NCT00239707.

Figures

Figure 1.

The excursion profile of plasma glucose (A), insulin (B), glucagon (C),PP (D), GLP-1 (E), and GIP (F) after oral glucose ingestion in four groups of selected BLSA cohort (NGT, prediabetes, diabetes-new, and diabetes-med). Data are presented as means ± SE.

Figure 2.

When compared with placebo, exogenous GIP infusion at a pharmacological dose (20 ng·kg−1·min−1) during a mixed meal in 13 participants with type 2 diabetes is associated with the following: a 5-fold significant increase in plasma GIP levels (A); a significant late postprandial increase in plasma glucose levels (120–220 min) (C); no significant difference in insulin levels (E); a significant early postprandial increase in plasma glucagon (0–60 min) (G); and a significant increase in early postprandial (0–60 min) and late postprandial plasma PP levels (120–360 min) (I). GIP or placebo infusion was started a time 0 and continued for 180 minutes. A mixed meal was given at time 0. Data are presented as mean ± SE. Gray close circle, Placebo; black open circle, GIP. The AUC for GIP (B), glucose (D), insulin (F), glucagon (H), and PP (J) during placebo (gray) and GIP infusion (white) is shown. With fasting values (t = 0) serving as baseline levels, positive AUC and negative AUC corresponded to the area above and below the baseline levels, respectively. The AUC for each curve was divided into different time periods: AUC0–60 (t = 0–60 min), AUC60–120 (t = 60–120 min), AUC120–220 (t = 120–220 min), and AUC220–360 (t = 220–360 min) to better quantify the changes in the response to the placebo vs GIP infusion. ***, P < .001; **, P < .01; *, P < .05.

Figure 3.

Immunofluorescent images show that GIPRs are colocalized with PP-containing cells in both mouse islet (A) and human islet (B). Green, GIPR; red, PP; blue, nucleus (TO-PRO-3); yellow (with white arrow), colocalization of GIPR with PP. Fifteen minutes after a bolus of GIP was given, C57BL/6 mice had elevated levels of plasma glucagon (82 ± 4.5 pg/mL) (C) and plasma PP (148 ± 8.5 pg/mL) (E) in comparison with saline-injected C57BL/6 mice. White bar, control mice; black bar, mice given GIP bolus. No change in the plasma insulin levels were observed in either group (D).

Figure 4.

Schema of proposed integrated model representing the islet trihormonal abnormality hypothesis of type 2 diabetes. Upon ingestion of glucose, it is absorbed and simultaneously GIP is released into the circulation from which it interacts with α- (blue), β- (green), and PP cells (red). In type 2 diabetes, GIPRs on β-cells are not responsive to GIP and are therefore ineffective in enhancing insulin secretion response to glucose, even as plasma glucose level gets progressively higher. But GIPRs on α-cells are functional, and their activation causes increased glucagon secretion, unopposed by ineffective insulin secretion. This results in increased hepatic glucose output. GIPRs on PP cells are functional and their activation results in PP secretion. IR, insulin receptor.