GIP Responses Research Articles

Positively Selected PPARG and GIP Variants Impart Phenotypic Variations after a Glucose Challenge Test in Pregnant Women.

Recent studies have revealed that variants within or surrounding more than three dozen genes are associated with risk of diabetes, obesity, and/or a number of metabolic parameters. However, genetic variants responsible for variations in energy-balance regulation during pregnancy are largely unknown. To uncover common single nucleotide polymorphisms (SNPs) that may contribute to phenotypic variations in energy-balance regulation, or impaired glucose metabolism during human pregnancy, we hypothesized variants that confer adaptation in energy-balance regulation are associated with a partial selection because selection pressures associated with such variants likely fluctuated over time in response to recent changes in human culture. To identify SNPs that were subject to moderate environmental selection, we screened for variants that have moderately divergent allele frequencies and extended haplotypes in select human population(s) using the HapMap II and III dataset. To investigate whether the differentially selected variants contribute to phenotypic variations in energy-balance regulation during pregnancy, we analyzed levels of sugar and serum hormones in 123 unrelated pregnant women who underwent a 1-hr oral glucose tolerance test for gestational diabetes during the 23rd-29th weeks of pregnancy. Based on the screening of >1000 candidate genes, we identified three dozen SNPs in CDKAL1, CYB5R4, GAD2, GIP, and PPARG as prime candidates. Among these SNPs, GIP and PPARG variants were positively selected in European and Asian populations. Based on functional testing, we showed that more than two dozen GIP variants within a selected haplotype impart phenotypic variations in GIP response and glucose metabolism after the 1-hr OGTT (p<0.05). In addition, we found that PPARG variants (rs2920500 and rs2920502) are associated with serum insulin levels (p<0.05), but not levels of GIP or C-peptide. Our study demonstrated that genetic variants stemmed from prior gene–environmental interactions in GIP and PPARG are associated with glucose and/or insulin metabolism during pregnancy. Because PPARG has been associated with the development of T2DM and that PPARG modulates GIP receptor expression in beta cell, these data indicate that the enteroinsular axis in humans and the treatment of T2DM by PPARG ligands (e.g., thiazolidinedione) could be subject to heterogeneous regulation by multiple adaptive variants.

Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial

Observational studies indicate that sugar-sweetened soft drinks (SSSD) may promote obesity, among other factors, owing to low-satiating effects. The effect of energy in drinks on appetite is still unclear. We examined the effect of two isocaloric, but macronutrient, different beverages (SSSD versus semi-skimmed milk) and two non-energy-containing beverages (aspartame-sweetened soft drink (ASSD) and water) on appetite, appetite-regulating hormones and energy intake (EI). In all, 24 obese individuals were included in a crossover trial. Each subject was served either 500 ml of SSSD (regular cola: 900 kJ), semi-skimmed milk (950 kJ), ASSD (diet cola: 7.5 kJ), or water. Subjective appetite scores, ghrelin, GLP-1, and GIP concentrations were measured at baseline and continuously 4-h post intake. Ad libitum EI was measured 4 h after intake of the test drinks. Milk induced greater subjective fullness and less hunger than regular cola (P<0.05). Also, milk led to 31% higher GLP-1 (95% CI: 20, 44; P<0.01) and 45% higher GIP (95% CI: 23, 72; P<0.01) concentrations compared with SSSD. Ghrelin was equally 20% lower after milk and SSSD compared with water. The total EI (ad libitum EI+EI from the drink) was higher after the energy-containing drinks compared with diet cola and water (P<0.01). Milk increased appetite scores and GLP-1 and GIP responses compared with SSSD. The energy containing beverages were not compensated by decreased EI at the following meal, emphasizing the risk of generating a positive energy balance by consuming energy containing beverages. Furthermore, there were no indications of ASSD increased appetite or EI compared with water.

Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection

The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703.8, T2D: 556.4 ± 698.2, HNF4A MODY: 1,257.0 ± 999.3, HNF1A MODY: 697.1 ± 818.4) but with a different secretion pattern. The AUC insulin during the test meal was strongly correlated with the GIP secretion (Correlation coefficient 1.0, P < 0.001). No such correlation was seen for insulin and GLP-1. Patients with HNF4A and HNF1A MODY showed an attenuated early phase of insulin secretion similar to T2Ds. AUC insulin during the test meal was strongly correlated with GIP secretion, whereas no such correlation was seen for insulin and GLP-1. Thus, GIP may be a more important factor for insulin secretion than GLP-1 in MODY patients.

GIP and GLP Responses to a Glucose Challenge after Seven Days of Exercise Training

GIP and GLP Responses to a Glucose Challenge after Seven Days of Exercise Training

The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity

Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P < 0.05). Furthermore, after the intervention, changes in insulin (DeltaI(0-30)/DeltaG(0-30)) and GIP (Delta(0-30)) secretion were correlated (r = 0.69, P = 0.05). The PYY(3-36) (Delta(0-30)) response to glucose was increased after both interventions (P < 0.05). We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.

Postprandial glucose-dependent insulinotropic polypeptide and insulin responses in patients with chronic pancreatitis with and without secondary diabetes

Objective: To study GIP and insulin release after a test meal in patients with chronic pancreatitis with and without secondary diabetes mellitus. Methods: 28 patients with chronic pancreatitis were classified in groups I and II according to the presence or absence of secondary diabetes mellitus. Twelve healthy subjects were included as controls. After a test meal plasma GIP levels and serum insulin levels were determined at 0, 30, 60, 120 and 180 min. Results: A significant diminished GIP response was found in the groups of patients with respect to the control group. No association could be detected with severity of pancreatic insufficiency. Higher values of GIP were demonstrated at 60 and 120 min in patients without diabetes than in patients with it. Conclusions: An abnormal GIP response is present in cases of chronic pancreatitis irrespective of the presence or severity of pancreatic insufficiency. This response is further affected if secondary diabetes mellitus is present.

Acute and 24-hour GLP-1 and GIP responses to individual macronutrients and whole food in man

Acute and 24-hour GLP-1 and GIP responses to individual macronutrients and whole food in man

Post-prandial GIP responses to a mixed meal in lean and obese subjects

Post-prandial GIP responses to a mixed meal in lean and obese subjects

The effect of high-fat diets on gastric inhibitory polypeptide (gip) and insulin secretion in growing pigs

Hyperinsulinaemia, which is associated with obesity and type II diabetes (Gama and Marks, 1989), may be due in part to an overactive enteroinsular axis. The gut hormone GIP is a potent stimulator of insulin secretion and is currently thought to be one of the main components of the enteroinsular axis. Exaggerated GIP responses have been observed after a mixed meal in obese subjects (Hampton, Kwasowski, Tan, Morgan and Marks, 1983), and a high-fat diet increases fat-stimulated GIP secretion in rats (Ebert, Willms, Brown and Creutzfeldt, 1976) and glucose stimulated GIP secretion in man (Morgan, Tredger, Hampton, Kwasowski, Wright, Dunn and Marks, 1983). This experiment was designed to investigate the effects of high-fat diets on the development of the biochemical parameters which are characteristic of obesity.

Effect of enprostil on plasma glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.

Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.

The effect of dexamethasone on the enteroinsular axis

In order to examine whether hyperinsulinaemia induced glucocorticoid therapy involves alterations of the enteroinsular axis glucose, insulin, C-peptide, glucagon and GIP responses to a test meal with and without prior intake of dexamethasone (2 + 2 mg) in 13 healthy subjects were measured. Dexamethasone caused impaired glucose tolerance, which was associated with an exaggerated insulin (0.61 +/- 0.05 vs. 0.38 +/- 0.05 nmol/l; p less than 0.001). C-peptide (0.97 +/- 0.08 vs. 0.71 +/- 0.06 nmol/l; p less than 0.001) and glucagon response to a test meal. In contrast, the GIP response to the test meal was blunted after dexamethasone (126 +/- 17 vs. 177 +/- 23 pmol/l; p less than 0.001). It therefore follows that alterations in the enteroinsular axis, that is, GIP secretion, cannot be responsible for the enhancement of insulin secretion observed after dexamethasone. The mechanism(s) for the decreased GIP response after dexamethasone could involve (1) a direct inhibitory effect on GIP secretion by dexamethasone, and/or (2) a negative feedback of elevated glucose and insulin levels on GIP secretion.

Gastric inhibitory polypeptide and insulin response to increasing doses of oral glucose: Dependency on glucose amount and volume of the test drink

The plasma levels of glucose, immunoreactive insulin (IRI), and immunoreactive GIP (IR-GIP) of eight healthy normal-weight subjects were compared following administration of oral glucose load of 10, 30, 60, 90, and 120 g, each given in a volume of 300 and 600 mL of water. By increasing the glucose load from 30 to 60 g, the integrated glucose response was more than doubled, irrespective of the volume. If more than 60 g glucose was given, the venous blood glucose levels did not significantly increase further. The IRI concentrations peaked between 30 and 40 minutes, irrespective of the size and volume of the glucose load. The peak values were significantly higher if 30, 60, and 90 g glucose was given in 600 mL than in 300 mL water. The integrated IRI output increased gradually if the glucose concentration of the 300 mL load was increased, whereas a maximal IRI response occurred already with 60 g glucose if dissolved in 600 mL water. At identical amounts of glucose (60 g) the integrated IRI response was doubled by increasing the ingested volume of the drink from 300 to 600 mL. Also the peak and integrated IR-GIP response increased in a dose-dependent manner by increasing the size of the glucose load. Larger amounts of glucose mainly prolong the GIP response. Significantly greater amounts of IR-GIP were released with 60 and 90 g glucose when given in 600 mL instead of 300 mL water. The parallel increment of IR-GIP and IRI is compatible with an important role of GIP as an insulinotropic gut factor. However, the time and magnitude of the response of glucose, IRI, and IR-GIP to an oral glucose load are not only dependent on the amount of glucose, but also on the volume of the load.

Somatostatin response to a mixed meal in normals and in type I diabetics

Somatostatin has been proposed as a regulatory peptide of nutrient entry and fuel homeostasis because of its ability to inhibit the release of substances involved in food digestion and metabolism. The aim of the study was to evaluate the somatostatin response to a test meal in type I diabetics at the clinical onset of the disease and after two months of intensive insulin therapy. Normal subjects and diabetics in good metabolic control showed a characteristic biphasic somatostatin rise after a test meal; this response was lacking in diabetics at the onset of the disease. The response of somatostatin to a mixed meal in normals confirms its involvement in nutrient digestion and metabolism. The lacking somatostatin response in newly diagnosed type I diabetics might be related to deficient GIP response to the test meal or to other factors such as the insulinopenia or metabolic derangement characteristic of the clinical onset of the disease.

Macronutrients have different metabolic effects in nondiabetics and diabetics.

The glycemic and hormonal responses to protein, fat and carbohydrate alone and together were studied in normal, noninsulin-dependent (NIDD) and insulin-dependent (IDD) diabetic subjects. Fat and protein markedly reduced the glycemic response to oral carbohydrate in nondiabetics. In NIDD, the presence of protein and fat had no significant effect on the glycemic response. In IDD, while fat had no effect, protein enhanced the glycemic response. The insulin and GIP responses to the macronutrients together and individually were remarkably similar in all subject groups. Protein behaved as an insulin secretagogue in normal and NIDD while fat acted as a GIP secretagogue in normal and both diabetic groups. Protein appeared to function as a GIP secretagogue when combined with both fat and carbohydrate. It is concluded that caution is required when the glycemic responses to foods observed in nondiabetics are extended to diabetics.

Optimum effectiveness of intestinal α-glucosidase inhibitors: Importance of uniform distribution through a meal

A major barrier to the widespread clinical use of an alpha-glucosidase inhibitor such as Acarbose, is the unpleasant gastrointestinal symptoms of carbohydrate malabsorption associated with its use. Acarbose is usually administered as a tablet and eaten with the first mouthful of the meal, making its uniform distribution through the meal unlikely. In the present study, Acarbose was crushed to a powder and mixed through a test meal before it was consumed. Six healthy young men consumed test meals containing 75 g carbohydrate either as whole brown rice or as ground brown rice. When Acarbose was uniformly mixed through a ground rice meal prior to digestion it produced dose-dependent reductions in the postprandial glucose, insulin and GIP responses which were evident at doses as low as 12.5 mg. The responses to whole brown rice were intermediate between those to 12.5 and 25 mg Acarbose in ground brown rice. In tablet form Acarbose was only one quarter as effective in flattening the post prandial glucose and insulin responses as it was in powder form. These results highlight the importance of uniform distribution of Acarbose through a carbohydrate meal in order to achieve maximum effectiveness in delaying digestion and absorption and yet not promoting carbohydrate malabsorption.

The effect of total parenteral nutrition (TPN) on the enteroinsular axis in the rat.

The effect of 6 days of total parenteral nutrition (TPN) on the enteroinsular axis was studied in vivo and in vitro in the rat. During the TPN period, blood samples were taken from control and TPN animals to determine the comparative pattern of GIP release. Glucose, insulin and GIP responses to oral glucose (OGTT) were compared in TPN and control rats. The effect of glucose and GIP on insulin release from the isolated perfused pancreas of the same animals was investigated to determine if TPN altered the sensitivity of the beta cell. In conjunction with these studies the number and distribution of GIP-containing cells were compared in control and TPN animals. TPN resulted in no change in basal levels of glucose, insulin and IR-GIP. An exaggerated insulin response to OGTT occurred after TPN whereas the glucose response was reduced. The IR-GIP response to glucose was normal following TPN. The isolated perfused pancreas showed a 30% increase in insulin release in response to GIP after TPN. The insulin response to glucose appeared normal as did the number and distribution of GIP cells. Fluctuations in GIP and insulin levels in control animals were diurnal in nature, whereas IR-GIP levels in TPN animals remained near fasting levels. It was hypothesized that the increase in beta cell sensitivity to GIP may be causally connected to the exposure of the pancreas to chronically low levels of GIP during TPN.

Effects of exogenous and endogenous gastric inhibitory polypeptide in obese hyperglycaemic (ob/ob) mice

Gastric inhibitory polypeptide, also commonly referred to as glucose-dependent insulinotropic polypeptide or GIP, is a 42 amino acid hormone synthesized and released by the Kcells of the small intestine in response to nutrients. Previous studies have shown that plasma GIP concentrations are inordinately raised in obese hyperglycaemic (oblob) mice, and that oral administration of carbohydrate, protein and especially fat evokes marked plasma GIP responses (Flatt et al., 1983a; P. R. Flatt, C. J. Bailey, P. Kwasowski, T. Page & V. Marks, unpublished work). Overfeeding, K-cell hyperplasia and insensitivity of these cells to suppression by endogenous insulin are envisaged to generate the hypergipaemia (Flatt et al., 1983a,b). Since GIP is a recognized component of the entero-insular axis (Brown, 1982), the raised concentrations in ob/ob mice suggest an important pathogenic role in the promotion of hyperinsulinaemia and related metabolic abnormalities of the ob/ob syndrome (Flatt et al., 1983~). The present study examines the insulinotropic action of exogenous and endogenous GIP in relation to the prevailing hyperglycaemia in ob/ob mice. Obese (oblob) mice from the Aston colony were supplied with a standard pellet diet and maintained as described previously (Flatt & Bailey, 1981a; Bailey et al., 1982). The mice were used at 10-12 weeks of age and starved for 18 h before experimentation. The insulin response to exogenous GIP was examined by intraperitoneal administration of porcine GIP (40pg/kg) (Professor J. C. Brown, University of British Columbia, Canada) together with either glucose (2g/kg) or an equivalent volume of saline (O.l54mmol/l NaC1). Blood samples for determination of plasma concentrations of glucose, insulin and GIP were taken from the cut tail-tips of conscious mice at 0, 5, 15, and 30min. Plasma disappearance of GIP was followed until 180min. The insulin response to endogenous GIP was examined by oral administration of fat (Intralipid, 870mg/kg) followed at 30min by an intraperitoneal injection of either glucose (2g/kg) or an equivalent volume of saline (0.154mmol/l NaCl). Blood samples for plasma glucose, insulin and GIP determination were taken at 0, 30, 60, and 90min. Insulin and GIP were measured by radioimmunoassay (Flatt et al., 1983~). Statistical evaluation was made by Student’s t-test. As shown in Fig. la, intraperitoneal administration of GIP with saline evoked a marked but transient plasma insulin response. Plasma glucose concentrations (not illustrated) were not significantly changed, being within the range 7-l0mmol/l. When GIP was administered with

Influence of vagotomy upon GIP release in patients with peptic ulcer.

Twenty-two vagotomized peptic ulcer patients were studied on the influence of vagotomy on the release of GIP. Moreover, the relationship between acid output and GIP release was analyzed. These patients underwent one of the three types of operation; truncal vagotomy with pyloroplasty (TV + P) selective vagotomy with pyloroplasty (SV + P) and selective vagotomy with antrectomy (SV + A). Before and after surgery, a gastric juice study and an oral glucose tolerance test were performed on separate days. Maximum acid output in response to tetragastrin correlated significantly with integrated GIP response after oral glucose loading. In the SV + P group, the response of GIP was slightly greater after surgery. In the SV + A group, the integrated GIP response diminished postoperatively, although, after surgery, GIP reached its peak sooner. The integrated GIP response was greater in the SV + P group than in the TV + P group. The response of GIP was less in the SV + A group than in the SV + P group. These changes were insignificant. In conclusion, it is presumed that GIP release is affected by gastric acid, gastric emptying time, intestinal transit time and vagal nerve action.

Failure of fasting to influence the GIP response to oral glucose in non-obese human subjects.

The plasma GIP response to an oral 50 g glucose tolerance test has been compared in eight non-obese human subjects after 12 and 36 h of fasting. Basal plasma GIP and basal plasma insulin concentrations were similar after 12 and 36 h of fasting. Basal blood glucose was lower after 36 h fasting than after 12 h fasting (p less than 0.0125). After 36 h fasting the oral glucose tolerance test stimulated higher blood glucose concentrations at 60, 90 and 120 min (p less than 0.0125) and higher plasma insulin concentrations at similar time points (p less than 0.05), but stimulated plasma GIP concentrations were similar after 12 and 36 h fasts. These findings show that the increased insulinotrophic effect of oral glucose after 36 h fasting in non-obese subjects is not due to an associated augmentation of the glucose-induced GIP response.

Modulation of GIP responses to fat ingestion : D. Elahi, D. Muller, D. Andersen R. Hershcopf, J. Tobin and R. Andres. Gerontology research center, national institute on aging, NIH, baltimore, maryland, USA

Modulation of GIP responses to fat ingestion : D. Elahi, D. Muller, D. Andersen R. Hershcopf, J. Tobin and R. Andres. Gerontology research center, national institute on aging, NIH, baltimore, maryland, USA