Insulinotropic Effect Of Glucose-dependent Insulinotropic Polypeptide Research Articles

Twincretin therapy for type 2 diabetes: how do two do?

GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which are released from the intestines after meals, are responsible for augmenting insulin secretion (ie, the incretin effect). Because the insulinotropic effect of GIP is markedly attenuated in type 2 diabetes, therapeutic development to date has focused on GLP-1, which also lowers blood glucose by suppressing glucagon and energy intake, and slowing gastric emptying.1 Use of GLP-1 receptor agonists for the management of type 2 diabetes is increasing rapidly, and is associated with weight loss, negligible risk of hypoglycaemia, and potential cardiovascular protection.

DPP-4 Inhibition and the Known Unknown

Science sometimes moves very slowly. Observations in 1964 (1,2) that the insulin response to oral (and enteral) glucose is substantially greater than that to an isoglycemic intravenous glucose infusion (the incretin effect), followed by characterization of the two known incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) (1973) and glucagon-like peptide 1 (GLP-1) (1985), have only recently led to the development of two classes of antidiabetes drugs, GLP-1 agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, now used widely in the management of type 2 diabetes. GIP and GLP-1 are predominantly released from the proximal and distal intestine, respectively, primarily in response to enteral nutrients, and stimulate insulin secretion in a glucose-dependent manner (3). Attenuation of the incretin effect is probably an early marker of β-cell dysfunction (4). In type 2 diabetes, the incretin effect is markedly reduced (5), partly because the insulinotropic effect of GIP is essentially lost, whereas pharmacological doses of GLP-1 still stimulate insulin secretion substantially (6). GLP-1 also suppresses glucagon and slows gastric emptying (3,7). Following their release, GLP-1 and GIP are rapidly degraded by the ubiquitous enzyme, DPP-4. The concept that inhibition of DPP-4 may represent a therapy for type 2 diabetes was expressed in a seminal article by Deacon et al. (8) in 1995. DPP-4 inhibition markedly increases circulating intact (active) GLP-1 and GIP concentrations. In 2006, the first DPP-4 inhibitor, sitagliptin, was approved by the U.S. Food and Drug Administration, and some 11 different DPP-4 inhibitors are now available worldwide. Their efficacy …

Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models.

The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), were discovered 45 and 30 years ago. Initially, only their insulinotropic effect on pancreatic β cells was known. Over the years, physiological and pharmacological effects of GIP and GLP1 in numerous extrapancreatic tissues were discovered which partially overlap, but may also be specific for GIP or GLP1 in certain target tissues. While the insulinotropic effect of GIP was found to be blunted in patients with type 2 diabetes, the function of GLP1 is preserved and GLP1 receptor agonists and dipeptidyl-peptidase 4 (DPP4) inhibitors, which prolong the half-life of incretins, are widely used in diabetes therapy. Wild-type and genetically modified rodent models have provided important mechanistic insights into the incretin system, but may have limitations in predicting the clinical efficacy and safety of incretin-based therapies. This review summarizes insights from rodent and non-rodent models (pig, non-human primate) into physiological and pharmacological incretin effects, with a focus on the pancreas. Similarities and differences between species are discussed and the increasing potential of genetically engineered pig models for translational incretin research is highlighted.

Incretin Hormones and the Up-Regulation of Insulin Secretion in Insulin Resistance

The incretin effect is the augmented insulin secretion that is elicited by oral compared with iv administration of glucose, when glucose levels during the two challenges are matched. The incretin effect has been documented in humans (1) and in experimental animals (2). The underlying reason for the incretin effect is attributed to the release of incretin hormones from the gut during oral glucose administration [mainly glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1)]; these incretin hormones potentiate the glucose-stimulated insulin secretion. It has been estimated that the incretin effect is responsible for at least 60–70% of insulin secretion after oral glucose in normal humans (3). Recently, it was demonstrated that an incretin effect also exists after oral fat administration, i.e. it is not specific for glucose (4). It is now well documented that the incretin effect is reduced in type 2 diabetes (3). This impairment could be due to impaired incretin hormone secretion (i.e. incretin hormone deficiency) and/or to a defective insulinotropic action of the incretin hormones (i.e. incretin hormone resistance). Although some controversy still exists in the literature, most data support that the impaired incretin effect in type 2 diabetes is due to defective insulin secretory effects of GIP and GLP-1, rather than to defective secretion of the two incretin hormones (3, 5). Still, GLP-1 retains a high efficacy in type 2 diabetes, which is a rationale behind the incretin-based therapy (6). The defective incretin effect in type 2 diabetes has raised two fundamental questions of importance for the understanding of diabetes pathophysiology. One question is whether a defective incretin effect is involved in the pathophysiology of the disease, i.e. whether defective incretin effect participates in the development of the disease itself or is merely a consequence of the disease (7). A second question is whether the defective insulinotropic actions of GIP and GLP-1 in type 2 diabetics, compared with healthy individuals, are due to specific defects in the -cell effects of the hormones or reflect a more generalized -cell dysfunction (8). In regard to the potential pathophysiological contribution of defective incretin effect, only a few studies have explored this important question, and the results have been controversial. For example, on the one hand, it has been shown that the insulin stimulatory effect of GIP is impaired in first-degree relatives of type 2 diabetic patients (9), which would suggest a pathophysiological involvement. On the other hand, it has also been shown that the insulinotropic effect of GIP is normal in women with a history of gestational diabetes (10), which instead suggests that the defect is secondary to developed diabetes. In regard to the question of a specific defect in incretin hormone effect in type 2 diabetes vs. a generalized -cell defect, no studies have directly focused on this issue. In the present issue of the JCEM, a novel study by Hansen et al. (11) has addressed these two fundamental questions by a novel and interesting approach. The authors examined the insulin secretory responses to iv GIP and GLP-1 (given in physiological concentrations) during a hyperglycemic clamp (10 mmol/liter) in healthy subjects before and after experimental induction of insulin resistance. In insulin resistance, insulin secretion is up-regulated, and in healthy subjects, the disposition index (i.e. insulin sensitivity insulin secretion) remains normal (12). The investigators compared the up-regulated insulin secretion after glucose vs. incretin hormones. If there is a defective up-regulation of insulin secretion to insulin resistance in response to the incretin hormones, but not to

Impaired Incretin-Induced Amplification of Insulin Secretion after Glucose Homeostatic Dysregulation in Healthy Subjects

The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects. The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d. The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant). These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.

Glucose Intolerance and Reduced Proliferation of Pancreatic β-Cells in Transgenic Pigs With Impaired Glucose-Dependent Insulinotropic Polypeptide Function

OBJECTIVEThe insulinotropic action of the incretin glucose-dependent insulinotropic polypeptide (GIP) is impaired in type 2 diabetes, while the effect of glucagon-like peptide-1 (GLP-1) is preserved. To evaluate the role of impaired GIP function in glucose homeostasis and development of the endocrine pancreas in a large animal model, we generated transgenic pigs expressing a dominant-negative GIP receptor (GIPRdn) in pancreatic islets.RESEARCH DESIGN AND METHODSGIPRdn transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the different endocrine islet cell populations were performed, and β-cell proliferation and apoptosis were quantified to characterize this novel animal model.RESULTSEleven-week-old GIPRdn transgenic pigs exhibited significantly reduced oral glucose tolerance due to delayed insulin secretion, whereas intravenous glucose tolerance and pancreatic β-cell mass were not different from controls. The insulinotropic effect of GIP was significantly reduced, whereas insulin secretion in response to the GLP-1 receptor agonist exendin-4 was enhanced in GIPRdn transgenic versus control pigs. With increasing age, glucose control deteriorated in GIPRdn transgenic pigs, as shown by reduced oral and intravenous glucose tolerance due to impaired insulin secretion. Importantly, β-cell proliferation was reduced by 60% in 11-week-old GIPRdn transgenic pigs, leading to a reduction of β-cell mass by 35% and 58% in 5-month-old and 1- to 1.4-year-old transgenic pigs compared with age-matched controls, respectively.CONCLUSIONSThe first large animal model with impaired incretin function demonstrates an essential role of GIP for insulin secretion, proliferation of β-cells, and physiological expansion of β-cell mass.

The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance

Background The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM). Objective and design To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5–6.0) mM (mean (range); HbA 1c: 5.8 (5.4–6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0–8.8) mM; HbA 1c: 7.0 (5.8–10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP. Results The initial (0–20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline ( P < 0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20–120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20–120 min) was 3.1 ± 1.0 fold greater than during saline infusion in the group of patients with CP and NGT ( P < 0.05), whereas there was no significant differences in patients with CP and DM. Conclusions The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.

4 IMPAIRED INCRETIN EFFECT IN TRANSGENIC PIGS EXPRESSING A DOMINANT NEGATIVE RECEPTOR FOR GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE IN THE PANCREATIC ISLETS

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by specific cell types in the intestine and are responsible for the so-called incretin effect, the phenomenon that an oral glucose load elicits a higher insulin response than does an intravenous glucose load. In patients with type 2 diabetes mellitus the overall incretin effect is reduced. This fact is mostly attributed to a lowered insulinotropic effect of GIP, while the effect of GLP-1 is preserved. In order to better understand the consequences of impaired function of GIP, knockout mice lacking a functional GIP receptor (GIPR–/–) as well as transgenic mice expressing a dominant negative GIPR (GIPRdn) were established. While GIPR–/– mice show only relatively mild changes in glucose homeostasis, GIPRdn mice display a distinct diabetic phenotype due to disturbed development of the endocrine pancreas (Herbach et al. 2005 Regul. Pept. 125, 103–117). To further clarify the underlying mechanisms, we used a novel, highly efficient gene transfer technology based on lentiviral vectors (Hofmann et al. 2003 EMBO Rep. 4, 1054–1060; Hofmann et al. 2006 Mol. Ther. 13, 59–66) to generate transgenic pigs expressing a GIPRdn under the control of the rat Ins2 promoter (RIP). RIP-GIPRdn transgenic pigs develop normally and do not display diabetes mellitus up to at least one year of age. Weekly measured fasting blood glucose levels in transgenic animals did not show a significant difference compared to control pigs. The same was true for monthly determined fructosamine levels. However, RIP-GIPRdn transgenic pigs exhibited reduced insulin release and higher glucose levels than non-transgenic littermate controls in an oral glucose tolerance test. The area under the curve (AUC) for insulin was 49% smaller (P &lt; 0.01) and the AUC for glucose 26% larger (P &lt; 0.05) in RIP-GIPRdn transgenic pigs (n = 5) than in their non-transgenic littermate controls (n = 5). These findings demonstrate that expression of a GIPRdn, which was shown by RT-PCR in isolated pancreatic islets, disturbs the function of GIP in transgenic pigs. Thus we have created a novel, clinically relevant animal model for studying the roles of the GIP/GIPR system. Quantitative morphological studies of the pancreas are being performed to clarify whether GIPR function is essential for pancreatic islet development and maintenance.

Distinct Effects of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 on Insulin Secretion and Gut Motility

Glucose-induced insulin secretion from pancreatic beta-cells depends critically on ATP-sensitive K(+) channel (K(ATP) channel) activity, but it is not known whether K(ATP) channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K(ATP) channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the K(ATP) channel differently.

GIP as a Potential Therapeutic Agent?

Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity.