Acute overfeeding impairs meal-stimulated adipose tissue microvascular blood flow in healthy adults independent of changes in adiposity.

The responses of gastric inhibitory polypeptide (GIP) and insulin to intraduodenal and IV triglyceride infusions were measured in 11 late fetal and 10 neonatal pigs. Basal plasma glucose, insulin, and GIP concentrations were lower in fetal than in neonatal pigs. In the fetal pigs, plasma glucose increased slightly during intraduodenal and IV triglyceride infusions, whereas plasma insulin remained unchanged during the tests. No significant changes were observed in plasma GIP concentration following intraduodenal triglyceride infusion in the fetal pigs, but plasma GIP fell during the IV infusion of triglyceride in these pigs (p less than 0.01). In the neonatal pigs, plasma glucose and insulin remained unaffected by intraduodenal and triglyceride infusions. Plasma GIP did not change during the IV triglyceride infusion, but exhibited a paradoxical decline after the intraduodenal triglyceride infusion (p less than 0.05). It is concluded that the GIP-cell response to an oral triglyceride load is suppressed in late fetal and neonatal pigs. The abolished GIP response to oral triglycerides could play a causal role in the inactivity of the enteroinsular axis which is seen in both human and animal neonates.

The term "enteroinsular axis" refers to the enhancement of insulin release by hormones secreted from the gut. Gastric inhibitory polypeptide (GIP) is one of the major hormones that mediates this function. The purpose of the present study was to examine whether the enteroinsular axis is functional in newborn infants born at term gestation. Between d 2 and d 4 of life, glucose was infused for 2 h intravenously or orogastrically to 44 fullterm newborn infants, of whom 18 were appropriate for gestational age, nine large for gestational age, eight small for gestational age; nine infants were born to diabetic mothers. Glucose was infused at either 8 mg/kg/min intravenously or 16 mg/kg/min orogastrically to achieve similar plasma glucose concentrations. Plasma insulin and GIP concentrations were compared. Plasma GIP concentration increased significantly with enteral glucose administration in all infants but remained unchanged with parenteral glucose infusion. The responses of plasma insulin and the insulin/glucose ratio were significantly greater in infants receiving enterally than parenterally infused glucose. However, when glucose was infused orogastrically at a lower rate (8 mg/kg/min), plasma GIP concentrations rose, but no enhancement of insulin response was detected, suggesting the importance of the role of circulating glucose in the "enteroinsular axis". The infants of diabetic mothers and the large-for-gestational-age infants had more rapid insulin response to orogastrically administered glucose, but their GIP responses were similar to that of normal infants. These findings suggest that, at term gestation, the newborn infants have a "functional" enteroinsular axis in response to glucose, i.e. the rising plasma GIP contributed in part to the enhanced insulin response to enterally infused glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the experiment was to test the theory that accustoming pigs to a high-fat diet causes exaggerated gastric inhibitory polypeptide (GIP) secretion in response to a high-fat meal, and to determine whether hypersecretion of GIP could be related to an increase in the GIP content of the small intestine. Twenty-four pigs were fed one of three dietary regimens for 11 weeks: a high-carbohydrate diet (CL), or a high-fat diet (FL), both fed at 1.46 MJ gross energy (GE)/kg live weight0.75 per d, or a high-fat diet (FH) fed at 2.10 MJ GE/kg live weight0.75 per d. At the end of the period two acute tests were performed. For acute test 1 the accustomed meal (diets CL, FL and FH) and for acute test 2 a standard high-fat meal (diet FL) were given; blood samples were taken during the next 5 h and analysed for GIP, insulin and glucose. Integrated increases in hormone and glucose levels were compared by analysis of variance (0-300 min). In acute test 1 there were significantly different plasma GIP concentrations between groups (CL greater than FH greater than FL; P less than 0.05). Plasma insulin concentrations were significantly higher in group CL compared with groups FL and FH (P less than 0.002). There were no differences in glucose levels. In acute test 2 integrated increases in plasma GIP (0-300 min) concentrations were not significantly different; however, GIP (0-45 min) concentrations were significantly higher in group FH than in groups CL and FL (P less than 0.05). There were no differences in plasma insulin concentrations. Plasma glucose (0-300 min) concentrations were significantly higher in groups FL and FH compared with group CL (P less than 0.05). The GIP content of tissue samples taken at the end of the experiment from the duodenum, jejunum, upper and lower ileum decreased significantly in a proximal to distal direction (P less than 0.001). Diet FH significantly increased the average GIP content of the small intestine compared with diets CL and FL (P less than 0.05). It is concluded that fat meal-stimulated GIP secretion was enhanced by increased feeding level during a pre-treatment phase, possibly due to an increase in GIP synthesis in the small intestine. The high-fat diet caused glucose intolerance after a high-fat meal. This may be due in part to the action of dietary fat on glucose transport and metabolism.

The responses of gastric inhibitory polypeptide (GIP) and insulin to intraduodenal (OGTT) and iv (IVGI) glucose infusions were measured in 14 late fetal and 9 neonatal pigs. Basal plasma glucose (P < 0.01) and GIP (P < 0.001) concentrations were lower in the fetal than in the neonatal pigs, while basal plasma insulin was not significantly different in the two groups. In the fetal pigs, almost identical plasma glucose curves were obtained during the OGTT and the IVGI, but plasma insulin did not change during either test. In these pigs, plasma GIP increased 3-fold (P < 0.01) during the OGTT, whereas no significant changes in plasma GIP were observed during the IVGI. In the neonatal pigs, plasma glucose increased more during the OGTT than during the IVGI, but plasma insulin exhibited similar increments during both tests. Thus, the insulinogenic index of the IVGI was almost 3 times higher than that of the OGTT (P < 0.05). In contrast to the normal increment in plasma GIP observed in fetal pigs, plasma GIP decreased significantly during both tests in the neonatal pigs. It is concluded that beta-cells of fetal pigs are unresponsive to acute elevations of plasma glucose with or without a concomitant increase in plasma GIP. Conversely, beta-cells of neonatal pigs exhibit a significant response to hyperglycemia, but the enteroinsular axis is defective, since more insulin is released after iv than during intraduodenal glucose administration. The defective enteroinsular axis in neonatal pigs might be due to the observed fall in plasma GIP during the OGTT.

Adipose tissue microvascular blood flow (MBF) is stimulated postprandially to augment delivery of nutrients and hormones to adipocytes. Adipose tissue MBF is impaired in type 2 diabetes (T2D). Whether healthy individuals at-risk of T2D show similar impairments is unknown. We aimed to determine whether adipose tissue MBF is impaired in apparently healthy individuals with a family history of T2D. Overnight-fasted individuals with no family history of T2D for two generations (FH-, n = 13), with at least one parent with T2D (FH+, n = 14) and clinically diagnosed T2D (n = 11) underwent a mixed meal challenge (MMC). Metabolic responses [blood glucose, plasma insulin, plasma nonesterified fatty acids (NEFAs), and fat oxidation] were measured before and during the MMC. MBF in truncal subcutaneous adipose tissue was assessed by contrast ultrasound while fasting and 60 min post-MMC. FH+ had normal blood glucoses, increased adiposity, and impaired post-MMC adipose tissue MBF (Δ0.70 ± 0.22 vs. 2.45 ± 0.60 acoustic intensity/s, P = 0.007) and post-MMC adipose tissue insulin resistance (Adipo-IR index; Δ45.5 ± 13.9 vs. 7.8 ± 5.1 mmol/L × pmol/L, P = 0.007) compared with FH-. FH+ and T2D had an impaired ability to suppress fat oxidation post-MMC. Fat oxidation incremental area under the curve (iAUC) (35-55 min post-MMC, iAUC) was higher in FH+ and T2D than in FH- (P = 0.005 and 0.009, respectively). Postprandial MBF was negatively associated with postprandial fat oxidation iAUC (P = 0.01). We conclude that apparently healthy FH+ individuals display blunted postprandial adipose tissue MBF that occurs in parallel with adipose tissue insulin resistance and impaired suppression of fat oxidation, which may help explain their heightened risk for developing T2D.NEW & NOTEWORTHY Adipose tissue blood flow plays a key role in postprandial nutrient storage. People at-risk of type 2 diabetes have impaired postmeal adipose tissue blood flow. Impaired adipose tissue blood flow is associated with altered fat oxidation. Risk of type 2 diabetes may be elevated by poor adipose tissue blood flow.

The correlation between the peripheral concentrations of gastric inhibitory polypeptide (GIP), insulin, and glucose has not previously been quantified. This paper describes the association among the peripheral concentrations of GIP, insulin and glucose during 50-g oral glucose tolerance tests (OGTT) in healthy volunteers and in patients with gastrointestinal disorders, obesity, and uremia. It was found that the correlation between insulin/glucose and plasma GIP concentrations during an OGTT can be expressed by the equation: log y = log a + bx, where y = [insulin]/[glucose], and x is the plasma GIP concentration. This empirical correlation between [insulin]/[glucose] and [GIP] reduces the plasma parameters measured during OGTT to a simple relationship. It may prove valuable in the analysis of differences in the relationship glucose-insulin-GIP between groups of subjects and in the description of alterations in glucose homeostasis longitudinally in individuals undergoing therapy.

Plasma gastric inhibitory polypeptide (GIP) concentrations following an oral glucose load were measured in 27 diabetics and 10 normal subjects. Plasma GIP concentrations increased significantly from the mean basal value following an oral glucose load in both groups. Diabetics showed significantly higher levels of plasma GIP in association with delayed and diminished peak increases in plasma insulin levels. When diabetics were divided into two groups according to their basal levels of blood glucose, moderate and severe diabetics exhibited more exaggerated increments of plasma GIP than mild diabetics. This exaggerated GIP response to an oral glucose load in proportion to the glucose intolerance indicates a relative failure of the beta cell response to GIP in diabetics and that the mechanism involved in hypersecretion of GIP would be diminution of the inhibition of GIP release caused by insulin in diabetics.

To investigate the insulinotropic effect of gastric inhibitory polypeptide (GIP) in chronic pancreatitis (CP), we examined the GIP response to 75 g oral glucose in 18 CP patients and 7 normal subjects (controls) by a radioimmunoassay for human GIP. The GIP response of CP patients was correlated with the pancreatic exocrine function which was evaluated by the caerulein-secretin test (CS test). Plasma GIP concentrations following the oral administration of glucose were higher in CP patients than in controls, but the difference was not significant. When CP patients were divided into 3 groups according to their exocrine dysfunction (mild, moderate and severe), plasma GIP levels of CP patients with severe exocrine dysfunction were significantly higher than those of controls

Gastric Inhibitory Polypeptide and Insulin Responses to Orally Administered Amino Acids in Genetically Obese Hyperglycemic (ob/ob) Mice

Stimulation of Gastric Inhibitory Polypeptide Release in ob/ob Mice by Oral Administration of Sugars and Their Analogues

1. We assessed the variation in subcutaneous abdominal adipose tissue blood flow within and between subjects and investigated whether it is correlated with body mass index. 2. We measured body mass index and subcutaneous abdominal adipose tissue blood flow in 38 fasting subjects on the same day and on different days and, in a subgroup of 16 subjects, after a mixed meal. 3. In 190 measurements in the fasted state, subcutaneous abdominal adipose tissue blood flow was significantly more variable between subjects than could be accounted for by the within-subject variation alone. Subcutaneous abdominal adipose tissue blood flow was also significantly more variable between days within subjects than could be accounted for by within-day variation alone. Fasting and post-prandial subcutaneous abdominal adipose tissue blood flow were negatively correlated with body mass index, as was the post-prandial rise in subcutaneous abdominal adipose tissue blood flow. Multiple regression analysis showed that fasting blood flow was not dependent on insulin concentration after allowing for body mass index. There was no correlation between post-prandial subcutaneous abdominal adipose tissue blood flow and insulin concentration. 4. Insulin does not appear to have a direct vasodilatory effect in subcutaneous adipose tissue. Obese subjects have lower fasting and post-prandial subcutaneous abdominal adipose tissue blood flow. This may be because of a blunted response to sympathetic stimulation, or it may be another aspect of the insulin-resistant state.

Aims and hypothesis: Beyond the insulinotropic effects, glucose-dependent insulinotropic polypeptide (GIP) may regulate post-prandial lipid metabolism by promoting fat deposition and inflammation in adipose tissue after high fat diets. We hypothesised that GIP would have an anabolic action in subcutaneous adipose tissue (SAT) promoting non-esterified fatty acid (NEFA) re-esterification. We speculated these effects may be mediated by changes to the expression of key lipid metabolism enzymes and that GIP may promote inflammation by affecting the expression of key adipokines in SAT. We postulated that these effects may be different according to obesity status or glucose tolerance. Incretins and other gut hormones are affected by medications used in the treatment of T2DM. We hypothesised that metformin, a commonly used drug in T2DM, may influence the secretion of incretin and other gut hormones which may contribute to its pleotropic effects in glucose metabolism. Subjects/Methods: We recruited 31 participants, for 2 different studies. In the first study, 23 men in four categories, normoglycaemic lean (n=6), normoglycaemic obese, (n=6), obese with impaired glucose regulation (IGR) (n=6) and obese, T2DM (n=5) participated in a double-blind, randomised, crossover study involving a hyperglycaemic clamp with a 4-hour infusion of GIP or placebo (normal saline). Serum insulin, plasma NEFA concentrations, SAT triacylglycerol (TAG) content and gene expression of key lipid metabolism enzymes, lipoprotein lipase (LPL), adipose tissue triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) and adipokine gene expression (TNF-α, MCP-1, osteopontin and adiponectin) in SAT were determined before and after the GIP/placebo infusions. In the second study, eight subjects (6 male and 2 female) were studied on two occasions for 6 hours following a standard mixed meal, before and after metformin monotherapy for at least 3 months. Blood samples were taken in the fasted state and at multiple time points after the mixed meal for measuring incretin hormone, glucagon like peptide (GLP-1), ghrelin (appetite regulatory gut hormone) and dipeptidyl peptidase –IV (DPP-IV) activity. Results: Study-1 The insulinotropic effect of GIP vs. placebo was greater in lean, obese and obese IGR groups with no significant effect in obese T2DM. In contrast, GIP lowered NEFA concentrations in obese T2DM concomitantly increasing the SAT-TAG content. Such effects were not observed in other groups. There was no change in gene expression of LPL, ATGL and HSL with GIP or placebo infusions. The gene expression of TNF-α was significantly higher in obese T2DM group and the expression of MCP-1 was higher in lean and obese subjects. Study-2 Metformin monotherapy in obese patients with T2DM was associated with significantly increased postprandial active GLP-1 concentrations. Conclusion: In T2DM, although the insulinotropic effect of GIP is impaired, the ability of GIP to promote fat storage seems intact lowering NEFA concentrations and increasing SAT lipid deposition which may further exacerbate obesity and insulin resistance. Oral hypoglycaemic agent metformin influences the incretin system by increasing GLP-1 concentrations and this may represent another important mechanism of its glucose-lowering effect.

Visceral Adipose Tissue Attacks Beyond the Liver: Esophagogastric Junction as a New Target

We investigated the rs9939609 single nucleotide polymorphism of the FTO gene in relation to fat cell function and adipose tissue gene expression in 306 healthy women with a wide range in body mass index (18-53 kg/m(2)). Subcutaneous adipose tissue biopsies were taken for fat cell metabolism studies and in a subgroup (n = 90) for gene expression analyses. In homozygous carriers of the T-allele, the in vitro basal (spontaneous) adipocyte glycerol release was increased by 22% (P = 0.007) and the in vivo plasma glycerol level was increased by approximately 30% (P = 0.037) compared with carriers of the A allele. In contrast, there were no genotype effects on catecholamine-stimulated lipolysis or basal or insulin-induced lipogenesis. We found no difference between genotypes for adipose tissue mRNA levels of FTO, hormone-sensitive lipase, adipose triglyceride lipase, perilipin, or CGI-58. Finally, the adipose tissue level of FTO mRNA was increased in obesity (P = 0.002), was similar in subcutaneous and omental adipose tissue, was higher in fat cells than in fat tissue (P = 0.0007), and was induced at an early stage in the differentiation process (P = 0.004). These data suggest a role of the FTO gene in fat cell lipolysis, which may be important in explaining why the gene is implicated in body weight regulation.

HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.