Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes: Systematic review and meta-analysis of clinical studies

OBJECTIVE

To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests.

RESEARCH DESIGN AND METHODS

Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied.

RESULTS

Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n = 363) exhibited no significant differences (P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min⁻¹), and time-corrected incremental area under the curve (iAUC × min⁻¹) in comparison with nondiabetic control subjects (n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min⁻¹ to be reduced and showed tAUC and tAUC × min⁻¹ to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min⁻¹), BMI (tAUC, iAUC, and iAUC × min⁻¹), and HbA_1c (iAUC and iAUC × min⁻¹) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA_1c on GIP responses and showed a positive influence of BMI on GIP responses.

CONCLUSIONS

Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA_1c are associated with reduced GIP secretion.Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino-acid hormone secreted by intestinal K cells, located predominantly in the proximal small intestine (duodenum and proximal jejunum), in response to luminal presence of nutrients (carbohydrate, protein, and fat) (1). After secretion, the two N-terminal amino acids of GIP are cleaved-off by the enzyme dipeptidyl peptidase 4 (DPP-4), and the hormone is then inactivated. DPP-4 is present in the intestinal and renal brush border membranes, in hepatocytes, in capillary endothelium, and it is also found in a soluble form in plasma. As a consequence of the ubiquity of DPP-4, only a small amount of the intestinally secreted GIP circulates in the systemic circulation as intact hormone (2). Intact 42-amino-acid peptide GIP [GIP (1–42)] is a potent stimulator of glucose-dependent insulin secretion in healthy humans (3,4). In contrast, in patients with type 2 diabetes the insulinotropic effect of GIP is severely impaired (5), presumably as a consequence of the diabetic state (6). Besides the renowned insulinotropic effect of GIP, the hormone also exerts glucagonotropic and adipogenic effects (7,8). Therefore, GIP could play a crucial role in determining some of the key pathophysiologic characteristics of the type 2 diabetic phenotype, e.g., impaired insulin secretion, hyperglucagonemia, and obesity. Moreover, changes in GIP secretion could contribute to the loss of incretin effect that invariably characterizes patients with type 2 diabetes (9). However, the vast amount of data regarding GIP secretion published during the past decades have been inconsistent and confusing, showing impaired, normal, or increased responses after oral glucose or mixed meals in patients with type 2 diabetes.The aim of this meta-analysis was to systematically compile human GIP secretory data to compare the secretion of GIP in patients with type 2 diabetes and matched control individuals without diabetes.