1.
Weight-loss diets modify glucose-dependent insulinotropic polypeptidereceptor rs2287019 genotype effects on changes in body weight, fasting glucose, and insulin resistance: the Preventing Overweight Using Novel Dietary Strategies trial.
Source
Department of Nutrition, Harvard School of Public Health, Boston, MA.
Abstract
BACKGROUND:
Glucose-dependent insulinotropic polypeptide [also known as gastric inhibitory polypeptide (GIP)] and its receptor (GIPR) may link overnutrition to obesity, insulin resistance, and type 2 diabetes. A GIPR variant rs2287019 was recently associated with obesity and glucose metabolism.
OBJECTIVE:
We aimed to examine whether weight-loss diets that vary in fat content may modify the effect of this variant on changes in body weight, fasting glucose, and insulin resistance in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial.
DESIGN:
We genotyped the GIPR rs2287019 in 737 overweight adults who were randomly assigned to 1 of 4 weight-loss diets that varied in macronutrient contents for 2 y. We assessed the percentage changes in body weight, fasting glucose, and insulin resistance (HOMA-IR) across genotypes by the low-fat and high-fat diets.
RESULTS:
At 6 mo of diet intervention, the T allele of rs2287019 was associated with greater weight loss (β ± SE: -1.05 ± 0.56%; P = 0.06) and greater decreases in fasting glucose (β ± SE: -2.33 ± 0.86%; P = 0.006), fasting insulin (β ± SE: -8.76 ± 4.13%; P = 0.03), and HOMA-IR (β ± SE: -10.52 ± 4.39%; P = 0.01) in participants who were assigned to low-fat diets, whereas there was no significant genotype effect on changes in these traits in the group assigned to the high-fat diet (all P > 0.44; P-interaction = 0.08, 0.04, 0.10, and 0.07, respectively). After correction for multiple tests (significant P = 0.008), the genotype effect on changes in fasting glucose remained significant. Sensitivity analysis in white participants showed that the interactions were more evident on changes in insulin and HOMA-IR (P-interaction < 0.008).
CONCLUSION:
The T allele of GIPR rs2287019 is associated with greater improvement of glucose homeostasis in individuals who choose a low-fat, high-carbohydrate, and high-fiber diet. The POUNDS LOST trial was registered at clinicaltrials.gov as NCT00072995.
[The physiology of incretins].
Source
Fovarosi Szent Janos Korhaz es Eszak-budai Egyesitett Intezmenyei, Budapest. gabor.winkler@janoskorhaz.hu
Abstract
The discovery of incretins-glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrop peptide (GIP)-, clarification of their physiological properties as well as therapeutic application of incretin-based blood glucose lowering drugs opened new perspectives in the medical management of type 2 diabetes. New results of basic research investigations led to revaluation of the role of GIP in metabolic processes and a more established use of GLP-1 action. The article overviews the most relevant data of production and effects of incretins, as well as future possibilities of their therapeutic use.
- PMID:
- 22167829
- [PubMed - indexed for MEDLINE]
Acute effect of whey peptides upon blood pressure of hypertensive rats, and relationship with their angiotensin-converting enzyme inhibitory activity.
Source
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
Abstract
Scope: The aim of this study was to investigate the antihypertensive effect of a peptide fraction (PepC) obtained from a whey protein concentrate following hydrolysis by Cynara cardunculus, as well as of its fraction with MW below 3 kDa (PepCF). Both these concentrates encompassed peptides that exhibited potent in vitro inhibition of angiotensin-converting enzyme (ACE): two were released from α-lactalbumin - KGYGGVSLPEW and DKVGINYW, and one from β-lactoglobulin - DAQSAPLRVY. Methods and results: Upon oral administration, by gastric intubation, of 400 mg/kg body weight (bw) of those peptide concentrates, or 5 mg/kg bw of the corresponding synthetic peptides, to 12 wk-old spontaneously hypertensive rats (SHR), the systolic and diastolic blood pressures were monitored by the tail-cuff method - before, and 2, 4, 6, 8 and 24 h afterwards. Water and zofenopril (5 mg/kg bw) - a known ACE-inhibitor, were used as negative and positive controls, respectively. Acute administration of PepC, PepCF, KGYGGVSLPEW, DKVGINYW and DAQSAPLRVY caused antihypertensive effects in SHR; the maximum effect occurred by 4 h and 6 h after administration of the peptide concentrates and the synthetic peptides, respectively. PepC and KGYGGVSLPEW also showed ACE-inhibitory activity in vivo: the pressor effect of angiotensin I was significantly lower, and the response to bradykinin increased when the rats were pre-treated with either product. Conclusion: Our results strongly suggest that PepC will be effective as nutraceutical ingredient for the formulation of functional foods aimed at hypertension control.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Lateral Allosterism in the Glucagon Receptor Family: GLP-1 Induces GPCR Heteromer Formation.
Source
Addex Pharmaceuticals.
Abstract
Activation of a G-protein coupled receptor (GPCR) results in a variety of cellular responses, for example, through binding of different ligands to the same receptor that activate distinct downstream cascades. Additional signaling complexity is achieved when two or more receptors are integrated into one signaling unit. Lateral receptor interactions can allosterically modulate the receptor response to a ligand thereby create a mechanism of tissue specific fine tuning, depending on the cellular receptor co-expression pattern. GPCR homo- or heteromers have been explored widely in GPCR class A and C, but to lesser extent in class B. In the present study, we used Bioluminescence Resonance Energy Transfer (BRET) techniques, calcium flux measurements, and microscopy to study receptor interactions within the glucagon receptor family. We found basal BRET interactions in some of the receptor combinations tested that decreased upon ligand binding. A BRET increase was exclusively observed between the gastric-inhibitory-peptide-receptor (GIPR) and the glucagon-like-peptide-1-receptor (GLP 1R) upon binding of GLP-1, and could be reversed by GIP addition. The interactions of GLP-1R and GIPR were characterized by BRET-donor saturation studies, shift experiments, and testing of glucagon-like ligands. The heteromer displayed a specific pharmacology in GLP-1 induced β-arrestin recruitment and calcium flux, suggesting a form of allosteric regulation between the receptors. This study provides the first example of ligand-induced heteromer formation in GPCR class B. In the body, both receptors are functionally related and co-expressed in the same cells. The physiological evidence of this heteromerization remains to be determined.
Glucagon-Like Peptide-1 Modulates Neurally-Evoked Mucosal Chloride Secretion in Guinea Pig Small Intestine In Vitro.
Source
1Universita' di Palermo.
Abstract
Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLR-1 effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (Isc), which served as a marker for chloride secretion. Transmural EFS evoked neurally-mediated biphasic increases in Isc that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in concentration-dependent manner. The GLP-1 receptor antagonist, exendin (9-39), suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic and vasoactive intestinalpeptide receptor antagonists, but not muscarinic antagonists. GLP-1 significantly reduced EFS-evoked release of ACh. In the submucosal plexus, GLP-1R-immunoreactivity (-IR) was expressed in choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and its activation leads to a decrease in neurally-evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions and at nicotinic synapses in the enteric neural networks that control secretomotor funcions.
Physiology of weight loss surgery.
Source
Duke Endosurgery, Department of Surgery, Duke University, DUMC 3351, Duke University Medical Center, Durham, NC 27713, USA.
Abstract
The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.
Copyright © 2011 Elsevier Inc. All rights reserved.
Comparisons of the effects of 12-week administration of miglitol and voglibose on the responses of plasma incretins after a mixed meal in Japanese type 2 diabetic patients.
Source
Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan Jiyugaoka Medical Clinic, Internal Medicine, Obihiro, Japan Department of Metabolism and Clinical Nutrition, Akita University School of Medicine, Akita, Japan.
Abstract
To compare the effects of miglitol [an alpha-glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12-week administration of both drugs, during 2-h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP-1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP-1. In conclusion, both drugs can enhance postprandial GLP-1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP-reducing efficacy.
© 2011 Blackwell Publishing Ltd.
Glucagon-like peptide 1 (GLP-1) in the gastrointestinal tract of the pheasant (Phasianus colchicus).
Source
Department of Physiological Science, University of Pisa, Pisa, Italy.
Abstract
The distribution of Glucagon-like peptide 1 (GLP-1) was investigated in the gastrointestinal tract of the pheasant using immunohistochemistry. GLP-1 immunoreactive cells were common in the small intestine, in the proventriculus and in the pancreas. Immunostained cells were not seen in the crop, in the gizzard and in the large intestine. Double labelling demonstrated that GLP-1 and pituitary adenylate cyclase-activating polypeptide (PACAP) were occasionally co-localized only in the duodenal villi. In contrast to what was previously described in the chicken and ostrich, we noted GLP-1 positive cells in the duodenum. These data were consistent with the presence of proglucagon mRNA in the chicken duodenum. Our findings indicate that GLP-1 might have an inhibitory effect on gastric and crop emptying and on acid secretion also in the pheasant. Moreover, the results of the present research regarding the initial region of the small intestine suggest a further direct mechanism of the GLP-1 release during the early digestion phase and an enhancement of its incretin role.
Copyright © 2011 Elsevier GmbH. All rights reserved.
Long-term persistence of hormonal adaptations to weight loss.
Source
Department of Medicine (Austin and Northern Health), University of Melbourne, Melbourne, VIC, Australia.
Abstract
BACKGROUND:
After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.
METHODS:
We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.
RESULTS:
Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).
CONCLUSIONS:
One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.).
Gastric Inhibitory Peptide Controls Adipose Insulin Sensitivity via Activation of cAMP-response Element-binding Protein and p110β Isoform of Phosphatidylinositol 3-Kinase.
Source
From the Departments of Biochemistry.
Abstract
Gastric inhibitory peptide (GIP) is an incretin hormone secreted in response to food intake. The best known function of GIP is to enhance glucose-dependent insulin secretion from pancreatic β-cells. Extra-pancreatic effects of GIP primarily occur in adipose tissues. Here, we demonstrate that GIP increases insulin-dependent translocation of the Glut4 glucose transporter to the plasma membrane and exclusion of FoxO1 transcription factor from the nucleus in adipocytes, establishing that GIP has a general effect on insulin action in adipocytes. Stimulation of adipocytes with GIP alone has no effect on these processes. Using pharmacologic and molecular genetic approaches, we show that the effect of GIP on adipocyte insulin sensitivity requires activation of both the cAMP/protein kinase A/CREB signaling module and p110β phosphoinositol-3' kinase, establishing a novel signal transduction pathway modulating insulin action in adipocytes. This insulin-sensitizing effect is specific for GIP because isoproterenol, which elevates adipocyte cAMP and activates PKA/CREB signaling, does not affect adipocyte insulin sensitivity. The insulin-sensitizing activity points to a more central role for GIP in intestinal regulation of peripheral tissue metabolism, an emerging feature of inter-organ communication in the control of metabolism.
Changes in postprandial gut hormones after metabolic surgery: a comparison of gastric bypass and sleeve gastrectomy.
Source
Department of Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan.
Abstract
BACKGROUND:
Laparoscopic gastric bypass (GB) is reportedly more effective than laparoscopic sleeve gastrectomy (SG) in the treatment of patients with a low body mass index and type 2 diabetes mellitus. However, the mechanism remains speculative. We compared the postprandial gut hormone patterns between patients undergoing laparoscopic GB and laparoscopic SG at 2 years after surgery in a hospital-based, prospective study.
METHODS:
A total of 16 laparoscopic GB and 16 laparoscopic SG patients were followed up and appraised for glucose homeostasis. Two years after surgery, the mixed meal test and gut hormones were evaluated in 13 laparoscopic GB and 13 laparoscopic SG patients who had been included in the previous randomized trial.
RESULTS:
The preoperative characteristics, such as body mass index, body weight, waist circumference, and duration of T2DM were comparable between the 2 groups. T2DM remission was achieved in 13 (81%) laparoscopic GB and 3 (19%) laparoscopic SG patients (P < .05) 2 years after surgery. The laparoscopic GB patients had lost more weight and had a smaller waist circumference and lower levels of glucose and hemoglobin A1c, and lower insulin resistance than the SG patients. Significant differences were found in acyl ghrelin, des-acyl ghrelin, cholecystokinin, and resistin between the 2 groups, but none in obestatin, gastric inhibitory peptide, glucagon-like peptide-1, and leptin.
CONCLUSIONS:
Both laparoscopic GB and laparoscopic SG have strong hindgut effects after surgery, but GB has a significant duodenal exclusion effect on cholecystokinin. The laparoscopic SG group had lower acyl ghrelin and des-acyl ghrelin levels but greater concentrations of resistin than the laparoscopic GB group.
Copyright © 2011 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.
Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.
Source
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, Pennsylvania, USA. LKatz3@its.jnj.com
Abstract
The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-likepeptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.
Diabetes remission after bariatric surgery: is it just the incretins?
Source
New York Obesity Nutrition Research Center, Division of Endocrinology and Diabetes, Department of Medicine, St Luke's Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, USA. BBL14@columbia.edu
Abstract
Gastric bypass surgery (GBP) results in important and sustained weight loss and remarkable improvement of Type 2 diabetes. The favorable change in the incretin gut hormones is thought to be responsible, in part, for diabetes remission after GBP, independent of weight loss. However, the relative role of the change in incretins and of weight loss is difficult to differentiate. After GBP, the plasma concentrations of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide increase postprandially by three- to fivefold. The postprandial incretin effect on insulin secretion, blunted in diabetes, improves rapidly after the surgery. In addition to the change in incretins, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase and significant decrease in postprandial glucose levels. These changes were not seen after an equivalent weight loss by diet. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist, demonstrating that the favorable metabolic changes after GBP are, in part, GLP-1 dependent. The improved incretin levels and effect persist years after GBP, but their long-term effect on glucose metabolism, and on hypoglycemia post GBP are yet unknown. Understanding the mechanisms by which incretin release is exaggerated postprandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Changes in rate of eating, gastric emptying, intestinal transit time, nutrient absorption and sensing, as well as bile acid metabolism, may all be implicated.
A common variant upstream of the PAX6 gene influences islet function in man.
Source
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, CRC at Skåne University Hospital, 205 02 Malmö, Sweden. Emma.Ahlqvist@med.lu.se
Abstract
AIMS/HYPOTHESIS:
Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man.
METHODS:
A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets.
RESULTS:
rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro.
CONCLUSIONS/INTERPRETATION:
A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
Gastric Inhibitory Polypeptide and its Receptor are Expressed in the Central Nervous System and Support Neuronal Survival.
Source
Istituto di Scienze Neurologiche, CNR, Via Paolo Gaifami, 18, 95125 Catania, Italy. s.cavallaro@isn.cnr.it.
Abstract
The development of neuronal apoptosis depends on an intrinsic transcriptional program. By DNA microarray technology, we have previously implicated a number of genes in different paradigms of neuronal apoptosis. In the present study, we investigated the spatiotemporal pattern of expression of two of these genes, gastric inhibitory polypeptide (Gip) and its receptor (Gipr) in the rat central nervous system. The levels of their transcripts were measured with real-time quantitative polymerase chain reaction and in situ-hybridization. Widespread expression of Gip and Gipr was found in adult rat brain, whereas during postnatal cerebellum development, they were highly expressed in the external and internal granule layer, and in Purkinje cells. To investigate the possible biological function of Gip we examined its effects in vitro. Addition of Gip to cultured cerebellar granule neurons reduced the extent of apoptotic death induced by switching the growing medium from 25 to 5 mM K+. This neurotrophic effect was mimicked by that of PACAP38 and IGF1. We conclude that Gip acts as an endogenous neurotrophic factor and supports neuronal survival.
Effects of high-fat overfeeding on mitochondrial function, glucose and fat metabolism, and adipokine levels in low-birth-weight subjects.
Source
Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark. charlotte.broens@rh.regionh.dk.
Abstract
Low birth weight (LBW) is associated with an increased risk of insulin resistance and downregulation of oxidative phosphorylation (OXPHOS) genes when exposed to a metabolic challenge of high-fat overfeeding (HFO). To elaborate further on the differential effects of HFO in LBW subjects, we measured in vivo mitochondrial function, insulin secretion, hepatic glucose production, and plasma levels of key regulatory hormones before and after 5 days of HFO in 20 young LBW and 26 normal-birth-weight (NBW) men. The LBW subjects developed peripheral insulin resistance after HFO due to impaired endogenous glucose storage (9.42 ± 4.19 vs. 5.91 ± 4.42 mg·kg FFM(-1)·min(-1), P = 0.01). Resting muscle phosphorcreatine and total ATP in muscle increased significantly after HFO in LBW subjects only, whereas additional measurements of mitochondrial function remained unaffected. Despite similar plasma FFA levels, LBW subjects displayed increased fat oxidation during insulin infusion compared with normal-birth-weight (NBW) subjects after HFO (0.37 ± 0.35 vs. 0.17 ± 0.33 mg·kg FFM(-1)·min(-1), P = 0.02). In contrast to NBW subjects, the plasma leptin levels of LBW subjects did not increase, and the plasma gastric inhibitory polypeptide (GIP) as well as pancreatic polypeptide(PP) levels increased less in LBW compared with NBW subjects during HFO. In conclusion, HFO unmasks dissociation between insulin resistance and mitochondrial dysfunction in LBW subjects, suggesting that insulin resistance may be a cause, rather than an effect, of impaired muscle OXPHOS gene expression and mitochondrial dysfunction. Reduced increments in response to HFO of fasting plasma leptin, PP, and GIP levels may contribute to insulin resistance, lower satiety, and impaired insulin secretion in LBW subjects.
Cellular glucose availability and glucagon-like peptide-1.
Source
Department of Physiology, Keimyung University School of Medicine, 2800 Dalgubeoldae-Ro, Dalseo-Gu, Daegu 704-701, Republic of Korea.
Abstract
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Insulin modulates glucose-dependent insulinotropic polypeptide (GIP) secretion from enteroendocrine K cells in rats.
Source
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK. n.irwin@ulster.ac.uk
Abstract
Effects of insulin excess and deficiency on glucose-dependent insulinotropic polypeptide (GIP) was examined in rats following insulinoma transplantation or streptozotocin (STZ) administration. Over 14 days, food intake was increased (p < 0.001) in both groups of rats, with decreased body weight (p < 0.01) in STZ rats. Non-fasting plasma glucose levels were decreased (p < 0.01) and plasma insulin levels increased (p < 0.001) in insulinoma-bearing rats, whereas STZ treatment elevated glucose (p < 0.001) and decreased insulin (p < 0.01). Circulating GIP concentrations were elevated (p < 0.01) in both animal models. At 14 days, oral glucose resulted in a decreased glycaemic excursion (p < 0.05) with concomitant elevations in insulin release (p < 0.001) in insulinoma-bearing rats, whereas STZ-treated rats displayed similar glucose-lowering effects but reduced insulin levels (p < 0.01). GIP concentrations were augmented in STZ rats (p < 0.05) following oral glucose. Plasma glucose and insulin concentrations were not affected by oral fat, but fat-induced GIP secretion was particularly (p < 0.05) increased in insulinoma-bearing rats. Exogenous GIP enhanced (p < 0.05) glucose-lowering in all groups of rats accompanied by insulin releasing (p < 0.001) effects in insulinoma-bearing and control rats. Both rat models exhibited increased (p < 0.001) intestinal weight but decreased intestinal GIP concentrations. These data suggest that circulating insulin has direct and indirect effects on the synthesis and secretion of GIP.
Contributions of fat and protein to the incretin effect of a mixed meal.
Source
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Abstract
BACKGROUND:
The relative contributions of fat and protein to the incretin effect are still largely unknown.
OBJECTIVE:
This study assessed the incretin effects elicited by a mixed meal, and by its fat and protein components alone, with the use of a hyperglycemic clamp combined with oral nutrients.
DESIGN:
Eight healthy volunteers were studied over 6 h after ingestion of a sandwich containing 1) dried meat, butter, and white bread; 2) dried meat alone; 3) butter alone; or 4) no meal (fasting control). Meals were ingested during a hyperglycemic clamp, and the incretin effect was calculated as the increment in plasma insulin after food intake relative to the concentrations observed during the control study.
RESULTS:
A significant augmentation of postprandial insulin secretion, independent of plasma glycemia, occurred after ingestion of the mixed nutrients and the lipid component of the mixed meal (203 ± 20.7% and 167.4 ± 22.9% of control, respectively; both P < 0.05), whereas the protein component did not induce a significant incretin effect (129.0 ± 7.9% of control; P = 0.6)
CONCLUSIONS:
Fat ingestion, in an amount typical of a standard meal, increases insulin secretion during physiologic hyperglycemia and thus contributes to the incretin effect. In contrast, ingestion of protein typical of normal meals does not contribute to the augmentation of postprandial insulin secretion. This trial was registered at clinicaltrials.gov as NCT00869453.
Umami receptor activation increases duodenal bicarbonate secretion via glucagon-like peptide-2 release in rats.
Source
Department of Medicine, School of Medicine, University of California, Los Angeles, California, USA.
Abstract
Luminal nutrient chemosensing during meal ingestion is mediated by intestinal endocrine cells, which regulate secretion and motility via the release of gut hormones. We have reported that luminal coperfusion of L-Glu and IMP, common condiments providing the umami or proteinaceous taste, synergistically increases duodenal bicarbonate secretion (DBS) possibly via taste receptor heterodimers, taste receptor type 1, member 1 (T1R1)/R3. We hypothesized that glucose-dependent insulinotropic peptide (GIP) or glucagon-like peptide (GLP) is released by duodenal perfusion with L-Glu/IMP. We measured DBS with pH and CO(2) electrodes through a perfused rat duodenal loop in vivo. GIP, exendin (Ex)-4 (GLP-1 receptor agonist), or GLP-2 was intravenously infused (0.01-1 nmol/kg/h). l-Glu (10 mM) and IMP (0.1 mM) were luminally perfused with or without bolus intravenous injection (3 or 30 nmol/kg) of the receptor antagonists Pro(3)GIP, Ex-3(9-39), or GLP-2(3-33). GIP or GLP-2 infusion dose-dependently increased DBS, whereas Ex-4 infusion gradually decreased DBS. Luminal perfusion of l-Glu/IMP increased DBS, with no effect of Pro(3)GIP or Ex-3(9-39), whereas GLP-2(3-33) inhibited L-Glu/IMP-induced DBS. Vasoactive intestinal peptide (VIP)(6-28) intravenously or N(G)-nitro-L-arginine methyl ester coperfusion inhibited the effect of L-Glu/IMP. Perfusion of L-Glu/IMP increased portal venous concentrations of GLP-2, followed by a delayed increase of GLP-1, with no effect on GIP release. GLP-1/2 and T1R1/R3 were expressed in duodenal endocrine-like cells. These results suggest that luminal L-Glu/IMP-induced DBS is mediated via GLP-2 release and receptor activation followed by VIP and nitric oxide release. Because GLP-1 is insulinotropic and GLP-2 is intestinotrophic, umami receptor activation may have additional benefits in glucose metabolism and duodenal mucosal protection and regeneration.
- PMID:
- 21846840
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3199979
- [Available on 2012/11/1]
No comments:
Post a Comment