Lack of effect of incretin hormones on insulin release from pancreatic islets in the bile duct-ligated rats

Hyperglycemia associated with obstructive jaundice seriously affects the prognosis of patients with hepatobiliary diseases. We investigated secretory properties of isolated islets from bile duct-ligated (BDL) rats. Pancreatic islets from BDL rats lost their secretory responses to glucagon-like peptide-1 (GLP-1), although their responses to glucose were normal. Loss of potentiation of insulin release was also observed in glucagon and glucose-dependent insulinotropic peptide (GIP), whereas modulation of the release by forskolin, dibutyryl cAMP, or epinephrine remained unaffected. cAMP production by BDL islets was not increased by these insulinotropic hormones. Serum levels of glucagon, but not GIP, were increased in BDL rats. GLP-1 levels were also elevated, although they did not reach statistical significance. Immunoblotting of trimeric G protein subunits demonstrated that G(s)alpha L and G(s)alpha S, but not G(i)alpha 1/2 and G(i)alpha 3/o alpha, were less expressed in BDL islets. Therefore, unresponsiveness of the beta-cell to cAMP-raising hormones is involved in glucose intolerance under cholestasis. It results from diminished expression of alpha-subunits of the relevant G protein, G(s), and desensitization of receptors of these hormones.     

Heterologous desensitization of insulin secretion by GIP (glucose-dependent insulinotropic peptide) in INS-1 cells: the significance of Galphai2 and investigations on the mechanism involved

Heterologous desensitization is a term that describes the observation that chronic exposure of a cell to an agonist attenuates its response to other agonists. To characterize the cellular mechanisms that might be responsible for heterologous desensitization in an insulin secretory cell system (INS-1), we investigated the link between G-protein alphai2 level and insulin secretion as the biological effect after prolonged incubation with glucose-dependent insulinotropic polypeptide (GIP). Persistent activation (8 h) of the GIP signalling pathway decreased the GLP (glucagon-like peptide)-1 dependent insulin secretion (specific radioimmunoassay) accompanied by an upregulation of G-protein alphai2 protein level to about 126% whereas G-protein alphai3 and alphas protein levels remained unchanged (assessed by Western blots using specific antibodies). This was accompanied by similar changes in Galphai2 mRNA. By using either the CaM kinase II inhibitor KN-62, the calcineurin inhibitor FK 506 or the protein kinase A (PKA) inhibitor Rp-8-Br-cAMPS, the GIP-mediated Galphai2 mRNA increase was fully reversed. Heterologous desensitization of GLP-1-dependent insulin secretion by pretreatment with GIP, however, was not inhibited by calcium/calmodulin-dependent enzymes (using KN-62 and FK 506), but only by suppressing the cAMP/PKA signalling pathway using Rp-8-Br-cAMPS. The outcome is not disturbed by effects initiated by these compounds per se since an 8-h preincubation of cells did not affect glucose-induced insulin secretion. We, therefore, suggest that heterologous desensitization in INS-1 cells may be mediated by Galphai2 changes but depend on the cAMP/PKA signalling pathway probably distant form the Galphai2 protein.     

Effect of glucagon-like peptide-1 on insulin secretion

The insulinotropic actions of two forms of glucagon-like peptide 1 (GLP-1) containing 31 and 37 amino acid residues on perfused rat pancreas were compared with that of gastric inhibitory polypeptide (GIP), hitherto the most potent intestinal insulinotropic polypeptide known. The smaller form, C-terminally amidated GLP-1-(7-36), strongly enhanced insulin secretion stimulated by 11.1 mM D-glucose at a concentration as low as 0.1 nM. Comparable effects of GIP and GLP-1-(1-37) on insulin secretion were observed at concentrations of 1.0 nM and 10.0 nM, respectively. At the doses tested, neither GLP-1s nor GIP had any effect on insulin secretion induced by 3.3 mM D-glucose. At a concentration of 1.0 nM, GLP-1-(7-36 amide) also enhanced insulin secretion induced by 5 mM L-arginine whereas at concentrations of up to 10.0 nM, GLP-1-(1-37) did not. The results show that the smaller form of GLP-1 is more strongly insulinotropic than GIP. These findings suggest that the smaller GLP-1 may have a physiologically more important role as a modulator of insulin release.     

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20-25 yr (n=12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P<0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P<0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r(2)=0.86; P=0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.     

Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans

The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the beta-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.     

Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans

Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)-1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future treatment of type 2 diabetes. Therefore, we determined insulin clearance in response to endogenously secreted and exogenously administered GIP and GLP-1. Insulin clearance was estimated from the molar C-peptide-to-insulin ratio calculated at basal conditions and from the respective areas under the curve after glucose, GIP, or GLP-1 administration. Oral glucose administration led to an approximately 60% reduction in the C-peptide-to-insulin ratio (P < 0.0001), whereas intravenous glucose administration had no effect (P = 0.09). The endogenous secretion of GIP or GLP-1 was unrelated to the changes in insulin clearance. The C-peptide-to-insulin ratio was unchanged after the intravenous administration of GIP or GLP-1 in the fasting state (P = 0.27 and P = 0.35, respectively). Likewise, infusing GLP-1 during a meal course did not alter insulin clearance (P = 0.87). An inverse nonlinear relationship was found between the C-peptide-to-insulin ratio and the integrated insulin levels after oral and during intravenous glucose administration. Insulin clearance is reduced by oral but not by intravenous glucose administration. Neither GIP nor GLP-1 has significant effects on insulin extraction. An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance.     

Cellular glucose availability and glucagon-like peptide-1

Glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide) are produced in enteroendocrine L-cells and K-cells, respectively. They are known as incretins because they potentiate postprandial insulin secretion. Although unresponsiveness of type 2 diabetes (T2D) patients to GIP has now been reconsidered, GLP-1 mimetics and inhibitors of the GLP-1 degradation enzyme dipeptidyl peptidase (DPP)-4 have now been launched as drugs against T2D. The major roles of GLP-1 in T2D are reduction of appetite, gastric motility, glucagon secretion, enhancement of insulin secretion and β-cell survival. For insulin secretion and peripheral insulin function, GLP-1 and its mimetics sensitise β-cells to glucose; accelerate blood glucose withdrawal, in-cell glucose utilisation and glycogen synthesis in insulin-sensitive tissues; and assist in the function and survival of neurons mainly using glucose as an energy source. Taken together, GLP-1 acts to potentiate glucose availability of various cells or tissues to assist with their essential functions and/or survival. Herein, we review the signalling pathways and clinical relevance of GLP-1 in enhancing cellular glucose availability. On the basis of our recent research results, we also describe a mechanism that regulates GLP-1 for glucokinase activity. Because diabetic tissues including β-cells resist glucose, GLP-1 may be useful for treating T2D.     

GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.     

Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice

Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1 in vitro in STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected for in vivo studies in normal and GLP-1R(-/-) mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal mice and by 27% in GLP-1R(-/-) mice, and plasma GLP-1 concentrations were significantly elevated 30 min post-gavage. Additional studies used incretin receptor antagonists to probe involvement of GLP-1 and GIP in taurocholic acid-induced glucose lowering. The findings suggest that bile acids partially aid glucose regulation by physiologically enhancing nutrient-induced GLP-1 secretion. However, GLP-1 secretion appears to be only part of the glucose-lowering mechanism and our studies indicate that the other major incretin GIP is not involved.     

Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

AIMS/HYPOTHESIS: Since insulin secretion in response to exogenous gastric inhibitory polypeptide (GIP) is diminished not only in patients with type 2 diabetes, but also in their normal glucose-tolerant first-degree relatives, it was the aim to investigate the integrity of the entero-insular axis in such subjects. METHODS: Sixteen first-degree relatives of patients with type 2 diabetes (4 male, 12 female, age 50+/-12 years, BMI 26.1+/-3.8 kg/m(2)) and 10 matched healthy controls (negative family history, 6 male, 4 female, 45+/-13 years, 26.1+/-4.2 kg/m(2)) were examined with an oral glucose load (75 g) and an "isoglycaemic" intravenous glucose infusion. Blood was drawn over 240 min for plasma glucose (glucose oxidase), insulin, C-peptide, GIP and glucagon-like peptide 1 (GLP-1; specific immunoassays). RESULTS: The pattern of glucose concentrations could precisely be copied by the intravenous glucose infusion (p=0.99). Insulin secretion was stimulated significantly more by oral as compared to intravenous glucose in both groups (p<0.0001). The percent contribution of the incretin effect was similar in both groups (C-peptide: 61.9+/-5.4 vs. 64.4+/-5.8%; p=0.77; insulin: 74.2+/-3.3 vs. 75.8+/-4.9; p=0.97; in first-degree relatives and controls, respectively). The individual responses of GIP and GLP-1 secretion were significantly correlated with each other (p=0.0003). The individual secretion of both GIP and GLP-1 was identified as a strong predictor of the integrated incremental insulin secretory responses as well as of the incretin effect. CONCLUSION/INTERPRETATION: Despite a lower insulin secretory response to exogenous GIP, incretin effects are similar in first-degree relatives of patients with type 2 diabetes and control subjects. This may be the result of a B cell secretory defect that affects stimulation by oral and intravenous glucose to a similar degree. Nevertheless, endogenous secretion of GIP and GLP-1 is a major determinant of insulin secretion after oral glucose.     

Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that act via the enteroinsular axis to potentiate insulin secretion from the pancreas in a glucose-dependent manner. Both GLP-1 receptor and GIP receptor knockout mice (GLP-1R(-/-) and GIPR(-/-), respectively) have been generated to investigate the physiological importance of this axis. Although reduced GIP action is a component of type 2 diabetes, GIPR-deficient mice exhibit only moderately impaired glucose tolerance. The present study was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Although serum total GLP-1 levels in GIPR knockout mice were unaltered, insulin responses to GLP-1 from pancreas perfusions and static islet incubations were significantly greater (40-60%) in GIPR(-/-) than in wild-type (GIPR(+/+)) mice. Furthermore, GLP-1-induced cAMP production was also elevated twofold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR(-/-) mice compared with GIPR(+/+) mice. Paradoxically, immunocytochemical studies showed a significant increase in beta-cell area in the GIPR-null mice but with less intense staining for insulin. In conclusion, GIPR(-/-) mice exhibit altered islet structure and topography and increased islet sensitivity to GLP-1 despite a decrease in pancreatic insulin content and gene expression.     

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.     

Simultaneous determination of incretin hormones and their truncated forms from human plasma by immunoprecipitation and liquid chromatography-mass spectrometry

The incretins, glucose-dependent insulinotropic peptide (GIP(1-42)) and glucagon-like peptide 1 (GLP-1(7-36)), are involved in regulation of gastric emptying, glucose homeostasis, body fat regulation and the glucose-induced insulin secretion from the endocrine pancreas. After release in the circulation both peptides are rapidly degraded by the exopeptidase dipeptidyl peptidase IV (DP IV) to the inactive polypeptides GIP(3-42) and GLP-1(9-36). In vivo stabilization of the active incretins by orally available DP IV-inhibitors is now widely accepted as a new therapeutic approach in antidiabetic treatment. In order to demonstrate the pharmacodynamic effect of DP IV-inhibitors, it is necessary to measure the plasma levels of active and inactive forms of GIP and GLP-1. We previously described an immunoprecipitation method as sample preparation and concentration in combination with a LC-MS analysis for determination of active and inactive GIP. We could improve the efficiency and suitability of this method by reduction of the necessary sample volume to 1.0 ml and simultaneous measurement of GIP(1-42), GIP(3-42) and GLP-1(7-36), GLP-1(9-36), without loss of sensitivity. An LOQ of approximately 5 and 11 pmol/l was maintained for GIP and GLP-1, respectively.     

Priming effect of glucagon-like peptide-1 (7-36) amide, glucose-dependent insulinotropic polypeptide and cholecystokinin-8 at the isolated perfused rat pancreas.

The priming effect of glucagon-like peptide-1 (7-36) amide (GLP-1 (7-36) amide), glucose-dependent insulin-releasing polypeptide (GIP) and cholecystokinin-8 (CCK-8) on glucose-induced insulin secretion from rat pancreas was investigated. The isolated pancreas was perfused in vitro with Krebs-Ringer bicarbonate buffer containing 2.8 mmol/l glucose. After 10 min this medium was supplemented with GLP-1 (7-36) amide, GIP or CCK-8 (10, 100, 1000 pmol/l) for 10 min. After an additional 10 min period with 2.8 mmol/l glucose alone, insulin secretion was stimulated with buffer containing 10 mmol/l glucose for 44 min. In control experiments the typical biphasic insulin response to 10 mmol/l glucose occurred. Pretreatment of the pancreas with GIP augmented insulin secretion: 10 pmol/l GIP enhanced only the first phase of the secretory response to 10 mmol/l glucose; 100 and 1000 pmol/l GIP stimulated both phases of hormone secretion. After exposure to CCK-8, enhanced insulin release during the first (at 10 and 1000 pmol/l CCK-8) and the second phase (at 1000 pmol/l) was observed. Priming with 100 pmol/l GLP-1 (7-36) amide significantly amplified the first and 1000 pmol/l GLP-1 (7-36) amide both secretion periods, 10 pmol/l GLP-1 (7-36) amide had no significant effect. All three peptide hormones influenced the first, quickly arising secretory response more than the second phase. Priming with forskolin (30 mM) enhanced the secretory response to 10 mM glucose plus 0.5 nM GLP-1 (7-36) amide 4-fold. With a glucose-responsive B-cell line (HIT cells), we investigated the hypothesis that the priming effect of GLP-1 (7-36) amide is mediated by the adenylate cyclase system. Priming with either IBMX (0.1 mM) or forskolin (2.5 microM) enhanced the insulin release after a consecutive glucose stimulation (5 mM). This effect was pronounced when GLP-1 (7-36) amide (100 pM) was added during glucose stimulation. Priming capacities of intestinal peptide hormones may be involved in the regulation of postprandial insulin release. The incretin action of these hormones can probably, at least in part, be explained by these effects. The priming effect of GLP-1 (7-36) amide is most likely mediated by the adenylate cyclase system.     

The biology of incretin hormones

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote β cell proliferation and inhibit apoptosis, leading to expansion of β cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.     

Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both incretin hormones regulating postprandial insulin secretion. Their relative importance in this respect under normal physiological conditions is unclear, however, and the aim of the present investigation was to evaluate this. Eight healthy male volunteers (mean age: 23 (range 20-25) years; mean body mass index: 22.2 (range 19.3-25.4) kg/m2) participated in studies involving stepwise glucose clamping at fasting plasma glucose levels and at 6 and 7 mmol/l. Physiological amounts of either GIP (1.5 pmol/kg/min), GLP-1(7-36)amide (0.33 pmol/kg/min) or saline were infused for three periods of 30 min at each glucose level, with 1 h "washout" between the infusions. On a separate day, a standard meal test (566 kcal) was performed. During the meal test, peak insulin concentrations were observed after 30 min and amounted to 223+/-27 pmol/l. Glucose+saline infusions induced only minor increases in insulin concentrations. GLP-1 and GIP infusions induced significant and similar increases at fasting glucose levels and at 6 mmol/l. At 7 mmol/l, further increases were seen, with GLP-1 effects exceeding those of GIP. Insulin concentrations at the end of the three infusion periods (60, 150 and 240 min) during the GIP clamp amounted to 53+/-5, 79+/-8 and 113+/-15 pmol/l, respectively. Corresponding results were 47+/-7, 95+/-10 and 171+/-21 pmol/l, respectively, during the GLP-1 clamp. C-peptide responses were similar. Total and intact incretin hormone concentrations during the clamp studies were higher compared to the meal test, but within physiological limits. Glucose infusion alone significantly inhibited glucagon secretion, which was further inhibited by GLP-1 but not by GIP infusion. We conclude that during normal physiological plasma glucose levels, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide contribute nearly equally to the incretin effect in humans, because their differences in concentration and potency outweigh each other.     

Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cAMP in pancreatic β cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 have been shown to preserve pancreatic β cell mass by inhibiting apoptosis of β cells and enhancing their proliferation. Due to such characteristics, incretin hormones have been gaining mush attention as attractive targets for treatment of type 2 diabetes, and indeed incretin-based therapeutics have been rapidly disseminated worldwide. However, despites of plethora of rigorous studies, molecular mechanisms underlying how GIPR and GLP-1R activation leads to enhancement of glucose-dependent insulin secretion are still largely unknown. Here, we summarize the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic actions and their effects on pancreatic β cell preservation. We then try to discuss potential of GLP-1 and GIP in treatment of type 2 diabetes.     

Inhibition of insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion by octreotide has no effect on post-heparin plasma lipoprotein lipase activity.

This study examines the immediate effect of modulating postprandial insulin and insulinotropic hormone (glucose-dependent insulinotropic polypeptide, GIP; glucagon-like peptide-1, GLP-1) secretion on the activation of lipoprotein lipase (LPL) in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal of carbohydrate alone or combined with an IV infusion of octreotide, (100 microg infusion from 30 min before the meal for 150 min). Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes post-carbohydrate. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p < 0.01). Glucose tolerance was slightly impaired in obese subjects. Insulin, GIP and GLP-1 secretion post-carbohydrate was markedly reduced by octreotide in lean and obese subjects. LPL activity was similar in the two groups after carbohydrate administration and was unaffected by octreotide. Inhibition of postprandial insulin, GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity either in lean or obese subjects.     

Comparison of the subchronic antidiabetic effects of DPP IV-resistant GIP and GLP-1 analogues in obese diabetic (ob/ob) mice.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two key incretin hormones released from the gastrointestinal tract that regulate blood glucose homeostasis through potent insulin secretion. The rapid degradation of GIP and GLP-1 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) renders both peptides noninsulinotropic. However, DPP IV stable agonists, such as N-AcGIP and (Val8)GLP-1, have now been developed. The present study has examined and compared the metabolic effects of subchronic administration of daily i.p. injections of N-AcGIP, (Val8) GLP-1 and a combination of both peptides (all at 25 nmol/kg bw) in obese diabetic (ob/ob) mice. Initial in vitro experiments confirmed the potent insulinotropic properties of N-AcGIP and (Val8)GLP-1 in the clonal pancreatic BRIN BD11 cell line. Subchronic administration of N-AcGIP, (Val8)GLP-1 or combined peptide administration had no significant effects on the body weight, food intake and plasma insulin concentrations. However, all treatment groups had significantly (p < 0.05) decreased plasma glucose levels and improved glucose tolerance by day 14. The effectiveness of the peptide groups was similar, and glucose concentrations were substantially reduced following injection of insulin to assess insulin sensitivity compared to control. These results provide evidence for an improvement of glucose homeostasis following treatment with enzyme-resistant GIP and GLP-1 analogues.     

Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to ingestion of meals. The mechanisms regulating its secretion are not clear, but local somatostatin (SS) restrains GLP-1 secretion. We investigated feedback and substrate regulation of GLP-1 and SS secretion, using isolated perfused porcine ileum (n=17). Effluents were measured for GLP-1 and SS. Perfusion pressure and motility were recorded. Investigated parameters included spontaneous fluctuations, changes in perfusate glucose concentrations (3.5, 5, 11 mM) and addition of insulin (1 nM). We also investigated the effect of proglucagon products, glucagon (10 nM), GLP-1 and GLP-2 (0.1, 1, and 10 nM) on GLP-1 and SS secretion, as well as on glucagon-like peptide-2 (GLP-2), peptide YY (PYY) and GIP secretion, all possible product of L-cells or neighbour cells. Perfusate glucose concentration dose-dependently stimulated GLP-1 secretion (p=0.011). Insulin had no effect. Glucagon weakly stimulated GIP secretion. GLP-1 stimulated SS secretion and motor activity, but inhibited GLP-2, GIP and PYY secretion and perfusion pressure. GLP-2 weakly stimulated SS secretion. We conclude (a) that GLP-1 secretion is influenced by perfusate glucose concentration and (b) that L-cell secretion is feedback regulated by GLP-1 itself, probably via paracrine SS activity.