Administration Of Glucose-dependent Insulinotropic Polypeptide Research Articles

Safety of native glucose-dependent insulinotropic polypeptide in humans

In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1−42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1−42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1−42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1−42) and reported safety events. Clearance rates of GIP(1−42) were similar between participant groups. In conclusion, the available data indicate that GIP(1−42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1−42) administration is unknown.

Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes

The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.

Pharmacokinetics of exogenous GIP(1-42) in C57Bl/6 mice; Extremely rapid degradation but marked variation between available assays

Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 ± 2 s, which was extended to 5 ± 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1–42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.

Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients With Type 2 Diabetes.

ContextIn healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP’s insulinotropic effect is impaired and effects on bone may be reduced.ObjectiveTo investigate GIP’s effect on bone biomarkers in patients with T2D.DesignRandomized, double-blinded, crossover study investigating 6 interventions.PatientsTwelve male patients with T2D.InterventionsA primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with “insulin-induced hypoglycemia” (PG lowered to 3 mmol/L), “fasting hyperglycemia” (mean PG ~8 mmol/L), or “aggravated hyperglycemia” (mean PG ~12 mmol/L).Main Outcome MeasuresBone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.ResultsOn days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.ConclusionsShort-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.PrécisShort-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

No evidence of tachyphylaxis for insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) in subjects with type 2 diabetes, their first-degree relatives, or in healthy subjects

Background, aimsIn patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects. Patients and MethodsIn a two-way crossover design, insulinotropic responses to repeated bolus injection (50 pmol/kg body weight at 30 and 120 min) and continuous infusion of GIP (2 pmol.kg-1.min-1 from 30 to 180 min) under hyperglycaemic clamp conditions (8.5 mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects. ResultsInsulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, −13.2 %, p < 0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP. ConclusionsRapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives.

Ghrelin Does Not Directly Stimulate Secretion of Glucagon-like Peptide-1.

The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1). To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro. A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively. Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0-120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells. Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

Separate and Combined Effects of GIP and GLP-1 Infusions on Bone Metabolism in Overweight Men Without Diabetes.

The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, but the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown. To investigate the effect of separate and combined infusions of the incretin hormones GIP and GLP-1 on bone resorption and formation. Randomized, double-blinded, placebo-controlled, crossover study including five study days. Seventeen overweight/obese men. On the first study day, a 50-g oral glucose tolerance test (OGTT) was performed. On the next four study days, isoglycemic IV glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, were performed with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively), or placebo, respectively. Changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type 1 N-terminal propeptide (P1NP) concentrations. During the OGTT, CTX was significantly lowered by 54 ± 13% from baseline (mean ± SD) compared with 28 ± 12% during IIGI + saline (P < 0.0001). During IIGI+GLP-1 and IIGI+GIP, CTX was lowered by 65 ± 16% and 74 ± 9%, respectively, from baseline, whereas IGII+GIP+GLP-1 lowered CTX by 84 ± 4% from baseline. P1NP levels were unaffected by the interventions. Our data suggest that GLP-1, like GIP, may be involved in regulation of bone resorption and that GIP and GLP-1 together have partially additive inhibitory effects.

Anorectic response to the trichothecene T-2 toxin correspond to plasma elevations of the satiety hormone glucose-dependent insulinotropic polypeptide and peptide YY3-36

T-2 toxin, a potent type A trichothecene mycotoxin, is produced by various Fusarium species and can negatively impact animal and human health. Although anorexia induction is a common hallmark of T-2 toxin-induced toxicity, the underlying mechanisms for this adverse effect are not fully understood. The goal of this study was to determine the roles of two gut satiety hormones, glucose-dependent insulinotropic polypeptide (GIP) and Peptide YY3-36 (PYY3-36) in anorexia induction by T-2 toxin. Elevations of plasma GIP and PYY3-36 markedly corresponded to anorexia induction following oral exposure to T-2 toxin using a nocturnal mouse anorexia model. Direct administration of exogenous GIP and PYY3-36 similarly induced anorectic responses. Furthermore, the GIP receptor antagonist Pro3GIP dose-dependently attenuated both GIP- and T-2 toxin-induced anorectic responses. Pretreatment with NPY2 receptor antagonist JNJ-31020028 induced a dose-dependent attenuation of both PYY3-36- and T-2 toxin-induced anorectic responses. To summarize, these findings suggest that both GIP and PYY3-36 might be critical mediators of anorexia induction by T-2 toxin.

Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats.

Mild traumatic brain injury (mTBI) is a major public health issue, representing 75–90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13–15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.

Effects of glucose-dependent insulinotropic polypeptide on gastric emptying, glycaemia and insulinaemia during critical illness: a prospective, double blind, randomised, crossover study.

IntroductionInsulin is used to treat hyperglycaemia in critically ill patients but can cause hypoglycaemia, which is associated with poorer outcomes. In health glucose-dependent insulinotropic polypeptide (GIP) is a potent glucose-lowering peptide that does not cause hypoglycaemia. The objectives of this study were to determine the effects of exogenous GIP infusion on blood glucose concentrations, glucose absorption, insulinaemia and gastric emptying in critically ill patients without known diabetes.MethodsA total of 20 ventilated patients (Median age 61 (range: 22 to 79) years, APACHE II 21.5 (17 to 26), BMI 28 (21 to 40) kg/m2) without known diabetes were studied on two consecutive days in a randomised, double blind, placebo controlled, cross-over fashion. Intravenous GIP (4 pmol/kg/min) or placebo (0.9% saline) was infused between T = −60 to 300 minutes. At T0, 100 ml of liquid nutrient (2 kcal/ml) containing 3-O-Methylglucose (3-OMG), 100 mcg of Octanoic acid and 20 MBq Tc-99 m Calcium Phytate, was administered via a nasogastric tube. Blood glucose and serum 3-OMG (an index of glucose absorption) concentrations were measured. Gastric emptying, insulin and glucagon levels and plasma GIP concentrations were also measured.ResultsWhile administration of GIP increased plasma GIP concentrations three- to four-fold (T = −60 23.9 (16.5 to 36.7) versus T = 0 84.2 (65.3 to 111.1); P <0.001) and plasma glucagon (iAUC300 4217 (1891 to 7715) versus 1232 (293 to 4545) pg/ml.300 minutes; P = 0.04), there were no effects on postprandial blood glucose (AUC300 2843 (2568 to 3338) versus 2819 (2550 to 3497) mmol/L.300 minutes; P = 0.86), gastric emptying (AUC300 15611 (10993 to 18062) versus 15660 (9694 to 22618) %.300 minutes; P = 0.61), glucose absorption (AUC300 50.6 (22.3 to 74.2) versus 64.3 (9.9 to 96.3) mmol/L.300 minutes; P = 0.62) or plasma insulin (AUC300 3945 (2280 to 6731) versus 3479 (2316 to 6081) mU/L.300 minutes; P = 0.76).ConclusionsIn contrast to its profound insulinotropic effect in health, the administration of GIP at pharmacological doses does not appear to affect glycaemia, gastric emptying, glucose absorption or insulinaemia in the critically ill patient.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12612000488808. Registered 3 May 2012.

Beneficial metabolic actions of a stable GIP agonist following pre-treatment with a SGLT2 inhibitor in high fat fed diabetic mice

The purpose of the present study was to examine if a stable glucose-dependent insulinotropic polypeptide (GIP) agonist could exert beneficial metabolic control in diabetic mice which had been pre-treated with sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA). High fat fed mice administered low dose streptozotocin (STZ) received vehicle, DAPA once-daily over 28 days, or DAPA once-daily for 14 days followed by (dAla2)GIP once-daily for 14 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin tolerance test, dual-energy X-ray absorptiometry (DEXA) and pancreatic histology were examined. Once-daily administration of (dAla2)GIP for 14 days in high fat fed diabetic mice pre-treated with DAPA demonstrated significant decrease in body weight, blood glucose and increased insulin concentrations which were independent of changes in energy intake. Similarly, glucose tolerance, glucose-stimulated insulin secretion, insulin sensitivity and HOMA-β were significantly enhanced in (dAla2)GIP-treated mice. DEXA analysis revealed sustained percentage body fat loss with no changes in lean mass, bone mineral content and density. Pancreatic immunohistochemical analysis revealed decreased islet number and increases in islet area, beta cell area and pancreatic insulin content. The DAPA-induced increase in alpha cell area was also reversed. Additional acute in vitro and in vivo experiments confirmed that the impaired action of (dAla2)GIP under hyperglycaemic-induced conditions was significantly reversed by DAPA treatment. These data demonstrate that (dAla2)GIP can exert beneficial metabolic control in high fat fed diabetic mice pre-treated with DAPA. The results highlight possibility of a targeted and personalized approach using a GIP agonist and SGLT2 inhibitor for the treatment of type 2 diabetes.

Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process.

Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans.

In humans, the pronounced postprandial reduction in bone resorption (decreasing bone resorption markers by around 50%) has been suggested to be caused by gut hormones. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone secreted postprandially from the small intestine. The hormone is known as an incretin hormone, but preclinical studies have suggested that it may also influence bone metabolism, showing both antiresorptive and anabolic effects as reflected by changes in biomechanical measures, microarchitecture, and activity of the bone cells in response to GIP stimulation. Its role in human bone homeostasis, however, is unknown. To examine the effect of GIP administration on bone resorption in humans. Plasma samples were obtained from 10 healthy subjects during four conditions: euglycemic (5 mmol/L) and hyperglycemic (12 mmol/L) 90-minute glucose clamps with co-infusion of GIP (4 pmol/kg/min for 15 min, followed by 2 pmol/kg/min for 45 min) or placebo. The samples were analyzed for concentrations of degradation products of C-terminal telopeptide of type I collagen (CTX), a bone resorption marker. RESULTS regarding effects on pancreatic hormone secretion have been published. During euglycemia, the decremental area under the curve in CTX was significantly (P < .001) higher during GIP infusion (2084 ± 686 % × min) compared to saline infusion (656 ± 295 % × min). During hyperglycemia, GIP infusion significantly (P < .001) augmented the decremental area under the curve to 2785 ± 446 % × minutes, compared to 1308 ± 448 % × minutes during saline infusion, with CTX values corresponding to 49% of basal values. We conclude that GIP reduces bone resorption in humans, interacting with a possible effect of hyperglycemia.

Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes.

Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m(2), HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase." During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg(-1), P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.

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Introduction: Insulin is used to treat hyperglycemia in critical illness, but can cause hypoglycaemia which is associated with poor outcomes. In health, glucose-dependent insulinotropic polypeptide (GIP) is a potent glucose-lowering hormone that does not induce hypoglycaemia. GIP may also accelerate gastric emptying and thereby improve nutrient absorption. Our objective was to determine whether exogenous GIP affects fasting or nutrient-stimulated glycaemia, glucose absorption and/or gastric emptying in critically ill patients. Methods: Twenty mechanically ventilated hyperglycaemic patients (Median age 61.5 range [22.0-79.0] years, BMI 27.9 [20.7-39.9] kg/m², HbA1c 5.9 [5.3-9.1] %), without known pre-existing diabetes, were studied on consecutive days in a randomised, double blind, placebo controlled, cross over fashion. Intravenous GIP (4 pmol/kg/min), or placebo (0.9% saline) was infused between T=0-360min. At T=60min, 100ml of liquid nutrient (2 kcal/ml), labeled with 3-O-Methylglucose (3-OMG) and 20 MBq 99mTc Calcium phytate was administered via a nasogastric tube. Blood glucose and serum 3-OMG (an index of glucose absorption) concentrations were measured. Gastric emptying was quantified using scintigraphy. Results are presented as medians (quartiles) and analysed using Wilcoxon paired tests. Results: Baseline glucose concentrations were comparable (T=0min; GIP 7.5 [6.5-9.5] vs. control 7.6 [7.0-9.4] mmol/L; P=0.68). GIP had no effect on fasting (T=60min, GIP 8.1 [6.3-9.0] vs. control 7.8 [6.8-9.5] mmol/L; P=0.53) or 'postprandial' glycaemia (AUC0-360: P=0.86). Neither gastric emptying (Gastric retention at T60min: GIP 80 [66-89] vs. control 84 [60-96] %; P=0.88. Gastric retention at T360min: GIP 26 [10-63] vs. control 37 [7-92] %; P=0.33) nor glucose absorption (3-OMG concentrations AUC60-360: GIP 50.6 [22.3-74.2] vs. control 64.3 [9.9-96.3] mmol/L/min; P=0.62) were affected by administration of GIP. Plasma GIP levels were significantly higher on days when GIP was infused. Serum insulin levels were not affected (P=0.76). Conclusions: Exogenous GIP does not affect glycaemia, glucose absorption or gastric emptying in the critically ill.

Role of glucose-dependent insulinotropic polypeptide in adipose tissue inflammation of dipeptidylpeptidase 4-deficient rats

Dipeptidyl peptidase 4 (DPP4) inhibitors, used in obese diabetic patients, reduce inflammation in several models. The role of chronic DPP4-deficiency (DPP4-) in diet-induced obesity with respect to insulin sensitivity and adipose tissue inflammation was investigated. Insulin resistance was induced by 2 months high fat diet (HFD). In vitro effects of glucose-dependent insulinotropic polypeptide (GIP) were assessed in adipose tissue explants and stromal vascular fraction (SVF). HFD-fed DPP4-rats gained significantly more weight and visceral fat mass, yet were more insulin sensitive. Adipose tissue of DPP4- rats demonstrated increased adipocyte maturation and increased expression of enzymes involved in triglyceride uptake and synthesis, yet increased adiponectin mRNA, reduced mRNA of proinflammatory cytokines and reduced vascular adhesion molecules, suggesting reduced inflammation. In vitro and in vivo experiments explored the role of GIP in inducing this phenotype. Indeed, we demonstrated that GIP directly enhanced adiponectin expression in rat and human adipose tissue explants and in SVF. Lastly, GIP administration to normal or HFD-fed rats elevated serum adiponectin and improved their glucose tolerance test. In a HFD model, DPP4-rats exhibited reduced adipose tissue inflammation and improved insulin resistance, which may be mediated in part by GIP induction of adiponectin.

A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores

BackgroundRapid enzymatic degradation of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), limits therapeutic use of the native peptide for diabetes. However, enzymatically stable analogues of GIP, such as (d-Ala2)GIP, have been generated, but are still susceptible to renal filtration. MethodsThe present study examines the in vitro and in vivo biological actions of a novel, acylated GIP analogue, (d-Ala2)GIP[Lys37PAL]. ResultsIn BRIN-BD11 cells, (d-Ala2)GIP[Lys37PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala2)GIP[Lys37PAL] to normal mice 8h prior to a glucose load significantly reduced (p<0.05) the overall glycaemic excursion compared to controls, and increased (p<0.001) the insulinotropic response compared to (d-Ala2)GIP and saline treated high fat control mice. Once daily administration of (d-Ala2)GIP[Lys37PAL] for 21days in high fat fed mice did not affect energy intake, body weight or fat deposition. However, circulating blood glucose was significantly lower (p<0.05) accompanied by increased (p<0.05) insulin concentrations by day 21. In addition, (d-Ala2)GIP[Lys37PAL] treatment significantly (p<0.01) reduced the overall glycaemic excursion and increased pancreatic insulin content (p<0.05) and the insulinotropic response (p<0.01) to an exogenous glucose challenge on day 21. Chronic treatment with (d-Ala2)GIP[Lys37PAL] did not result in resistance to the metabolic effects of a bolus injection of native GIP. Finally, insulin sensitivity was significantly improved (p<0.001) in (d-Ala2)GIP[Lys37PAL] treated mice compared to high fat controls. ConclusionsThese data confirm that (d-Ala2)GIP[Lys37PAL] is a stable, long-acting potent GIP agonist. General significance(d-Ala2)GIP[Lys37PAL] may be suitable for further evaluation and future clinical development.

Dipeptidyl peptidase-4 inhibitors and prevention of bone fractures: Effects beyond glyemic control.

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by preventing degradation of two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the intestine on ingestion of various nutrients, and enhance insulin secretion from pancreatic β-cells glucose-dependently1. Both incretin hormones show various biological functions in addition to their glucose-dependent insulinotropic action. Thus, DPP-4 inhibitors are expected to exert extra effects on various tissues and cell types. Among them, their effects on bones are of particular interest. A recent meta-analysis of randomized clinical trials comparing DPP-4 inhibitors with placebo or active comparator drugs in patients with type 2 diabetes suggested that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures2. Type 2 diabetes is associated with higher bone mineral density and, paradoxically, with increased fracture risk, presumably because of impaired bone quality that causes fragility fractures even when bone mass remains normal3. Duration of more than 10 years, presence of diabetic nephropathy, presence of diabetic neuropathy and high serum levels of pentosidine are shown to be risk factors for bone fractures3. One plausible mechanism of increased risk of bone fractures in patients with type 2 diabetes relates to chronic hyperglycemia, raising concentrations of advanced glycation end-products, such as pentosidine, that increases non-enzymatic collagen cross-linking and impairs bone quality. Furthermore, accumulating evidence shows negative impacts of antidiabetic drugs, thiazolidinediones, on bone turnover and bone fractures in patients with type 2 diabetes. However, so far, no oral antidiabetic drugs have been associated clinically with a reduction of bone fractures. Thus, the current finding on DPP-4 inhibitors by Monami et al. is highly promising despite some limitations, including short duration of the trials included, bone fractures being not principal end-points, and no discrimination between sexes and between pre- and postmenopausal women; and the Monami study provides a premise to initiate randomized, prospective, long-term clinical trials evaluating the effects of DPP-4 inhibitors on bone metabolism and bone fractures in patients with type 2 diabetes. The effects of GIP and GLP-1 on bone metabolism have been well characterized mainly in rodents (Figure 1)1. Investigations on GIP receptor-deficient mice and GIP transgenic mice showed that GIP increases bone mass by acting on osteoblasts to promote bone formation after meal ingestion, and inhibiting parathyroid hormone-induced bone resorption. Furthermore, GIP administration has been shown to attenuate ovariectomy-induced bone loss in rats. In contrast, studies on GLP-1 receptor-deficient mice showed that GLP-1 controls bone resorption, likely through a calcitonin-dependent pathway. Administration of GLP-1 receptor agonist exenatide has been shown to promote bone formation in normal and streptozotocin-induced diabetic rats, suggesting its insulin-independent action. Although these lines of evidence suggest an association of GIP and GLP-1 with bone turnover, the effects of GIP and GLP-1 on human bone turnover are largely unknown. A recent study showed that 44-week exenatide treatment did not affect bone mineral density in patients with type 2 diabetes4. As aforementioned, GLP-1 action on the bone is presumably mediated through calcitonin. A series of clinical trials on liraglutide, another GLP-1 receptor agonist, showed few changes in serum calcitonin levels in patients with type 2 diabetes, suggesting that GLP-1 might not play a role in human bone metabolism. Regarding GIP, Henriksen et al.5 previously reported that postprandial reduction of bone resorption was not mediated by GIP, but GLP-2 – another intestinal hormone cosecreted with GLP-1. However, caution should be taken when interpreting their results, as they investigated the effects of subcutaneous single injections of native GIP that should be rapidly inactivated by DPP-4 before it reaches the bones. Therefore, further investigations are definitely required to understand GIP and GLP-1 actions on bone metabolism in humans. The effects of two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1), on bone metabolism. GIP binds to GIP receptors expressed on osteoblasts, thereby activating new bone formation. GIP also acts on osteocrasts, presumably through osteoblasts, to suppress bone resorption. In contrast, GLP-1 stimulates calcitonin secretion from the thyroid gland, which then suppresses bone resorption by osteocrasts. Prevention of bone fractures could be the tip of the iceberg among potentially beneficial effects of DPP-4 inhibitors in patients with type 2 diabetes. It has been shown that DPP-4 inhibitors target not only two incretin hormones, GIP and GLP-1, but also other DPP-4 substrates, such as pituitary adenylate cyclase-activating peptide and stromal cell-derived factor-1α in patients with type 2 diabetes. Enhancement of these bioactive polypeptides could prevent progression of diabetic micro- and macrovascular complications independently of improvement in glycemic control. In the future, clinical trials with adequately powered, prospective, controlled relevant end-points will clarify the effects of DPP-4 inhibitors beyond glycemic control. The authors have no competing financial interests to disclose.

Dissociated effects of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide–1 on β-cell secretion and insulin clearance in mice

Glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) potently augment insulin response to glucose. It is less known what their effects are insulin clearance, which also contributes to peripheral hyperinsulinemia observed after administration of incretins together with glucose. The aims of this study were the quantification of C-peptide secretion and the evaluation of insulin clearance after administration of GIP with glucose. This allows the assessment of GIP's effects on hyperinsulinemia. In addition, GIP's effects were compared with those of GLP-1. Anesthetized female NMRI mice were injected intravenously with glucose alone (1 g/kg, n = 35) or glucose together with GIP (50 μg/kg, n = 12). Samples were taken through the following 50 minutes, and C-peptide and insulin concentrations were used to reconstruct C-peptide secretion rate and insulin clearance. In a previous study, GLP-1 (10 μg/kg) was used in 12 mice; and we used those GLP-1 results to compare GIP effects with those of GLP-1. C-peptide secretion rate peaked at 1 minute after glucose injection, and the immediate part of the insulin-releasing process was markedly augmented by both incretin hormones (1-minute suprabasal increment secretory rate was 20 ± 2 pmol/min for GIP and 28 ± 2 pmol/min for GLP-1, vs only 9 ± 1 pmol/min for glucose alone; P < .001). Until 10 minutes after administration, C-peptide secretion remained higher with incretins ( P < .0001), whereas starting from 20 minutes, the 3 patterns were undistinguishable ( P > .2). Insulin clearance, previously shown to be abridged by 46% with GLP-1, was reduced only by a nonsignificant ( P = .27) 21% with GIP. This study thus shows that the 2 incretins markedly augment glucose-stimulated insulin secretion in mice by a preferential action on the immediate response to glucose of insulin secretion. However, the action of GIP is less effective than that of GLP-1. Insulin clearance with GIP is not significantly reduced. We conclude that GIP is less potent than GLP-1 in inducing glucose-stimulated hyperinsulinemia in the mouse.

Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties

C-terminal acylation of Lys 37 with myristic (MYR; tetradecanoic acid), palmitic (PAL; hexadecanoic acid) and stearic (octadecanoic acid) fatty acids with or without N-terminal acetylation was employed to develop long-acting analogues of the glucoregulatory hormone, glucose-dependent insulinotropic polypeptide (GIP). All GIP analogues exhibited resistance to dipeptidylpeptidase-IV (DPP-IV) and significantly improved in vitro cAMP production and insulin secretion. Administration of GIP analogues to ob/ob mice significantly lowered plasma glucose—GIP(Lys 37MYR), N-AcGIP(Lys 37MYR) and GIP(Lys 37PAL) increased plasma insulin concentrations. GIP(Lys 37MYR) and N-AcGIP(Lys 37MYR) elicited protracted glucose-lowering effects when administered 24 h prior to an intraperitoneal glucose load. Daily administration of GIP(Lys 37MYR) and N-AcGIP(Lys 37MYR) to ob/ob mice for 24 days decreased glucose and significantly improved plasma insulin, glucose tolerance and beta-cell glucose responsiveness. Insulin sensitivity, pancreatic insulin content and triglyceride levels were not changed. These data demonstrate that C-terminal acylation particularly with myristic acid provides a class of stable, longer-acting forms of GIP for further evaluation in diabetes therapy.