Plasma Glucagon-like Peptide-1 Research Articles

Determinants of blood glucose concentrations following a high carbohydrate meal in type 2 diabetes: A multiple linear regression analysis

This study showed that in relatively well-controlled type 2 diabetes blood glucose levels after a high carbohydrate meal were associated positively with fasting blood glucose, but also positively with gastric emptying in the first hour and negatively with the increments in plasma glucagon-like peptide-1 (GLP-1) in the later postprandial phase.

Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice.

Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism. Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR. Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice. Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity.

Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury Was Associated with Persistent Hyperglycemia in Humans

Introduction: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. Methods: Metabolic, inflammatory, and hematologic profiles were examined in 73 patients with TBI in neurological intensive care unit. Factors that discriminate non-survivors from survivors were determined by two-way ANOVA. Biomarkers associated with mortality were determined by binary logistic regression and Cox proportional hazard regression. Results: The non-survivors had higher infectious SOFA scores (p < 0.001), lower first 3 days’ body temperature (p = 0.017), greater chance of cerebral hernia (p = 0.048), and decompressive craniectomy (p = 0.001) than the survivors. Higher 14-day plasma GLP-1 (p < 0.0001), glucose (p = 0.002), and IL-6 (p = 0.005) levels, in contrast with lower insulin level at days 4–7 (p = 0.020) were found in non-survivors than in survivors. Except the survivors who had an increased 14-day platelet number (p < 0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8–10 and IL-6 on days 1–3 were positively, while insulin on days 4–7 was negatively associated with mortality. Conclusion: Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Phosphate Accelerates Cellular Cholesterol Efflux in THP-1 Cells.

Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with 3H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (p < 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux.

The role of preproglucagon peptides in regulating β-cell morphology and responses to streptozotocin-induced diabetes.

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. GcgNull and GcgΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the GcgNull mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes.NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.

Development of sandwich ELISAs for detecting glucagon-like peptide-1 secretion from intestinal L-cells and their application in STC-1 cells and mice.

Certain nutrients stimulate glucagon-like peptide-1 (GLP-1) secretion from the intestinal enteroendocrine L-cells, but due to rapid degradation by the DPP-4 enzyme, >90% is converted to inactive metabolite before reaching the target organs via circulation. Plants are a source of potent bioactive compounds that promote endogenous secretion of GLP-1 from L-cells. To search for the effective bioactive compound from a vast library of natural compounds, a reliable and low-cost assay is required considering the high cost of commercial assays. We developed a low-cost sandwich enzyme-linked immunosorbent assays (s-ELISAs) for detecting 'total', 'sensitive active', and 'wide-range active' GLP-1. The s-ELISAs exhibited high sensitivity with measurement ranges between 0.94~240, 0.98~62.5, and 4.8~4,480 pmol/L, respectively. High precision was observed; i.e., CVs within 5% and 20% for intra- and inter-assay variations, respectively, and excellent recovery of exogenous GLP-1 from assay buffer. The developed s-ELISAs had the same performance as the commercial kits and approximately 80% cheaper cost. For their application, cinnamtannin A2-induced GLP-1 secretion was confirmed in STC-1 cells consistent with our previous findings. The s-ELISAs were further validated by measuring plasma GLP-1 level in mice after oral administration of black soy bean seed coat extract containing cinnamtannin A2.

Circulating GLP-1 Levels in Patients with Pheochromocytoma/Paraganglioma.

The sympathoadrenal system has been shown to stimulate the secretory activity of enteroendocrine cells, although the response is transient. Our aim was to investigate the effects of long-term catecholamine excess on circulating glucagon-likepeptide-1 (GLP-1) levels in patients with pheochromocytoma/paraganglioma (PPGL). Thirty patients diagnosed with PPGL were analyzed. A significant negative association was observed between fasting plasma GLP-1 levels and elevated plasma-free metanephrine (r = -0.407, p = 0.026). After adjustment for age, sex, body mass index (BMI), serum creatinine, and the presence of hyperglycemia, the negative association between plasma GLP-1 and metanephrine persisted by multiple linear regression analysis (β = -0.493, p = 0.013). Positive correlations between fasting glucose and plasma metanephrine (r = 0.380, p = 0.038) and normetanephrine levels (r = 0.450, p = 0.013) were also found. Mean fasting levels of total GLP-1 increased significantly from 25.81 to 39.01 pmol/L (p = 0.017) after PPGL resection. In conclusion, long-term overproduction of catecholamines appears to induce suppression of GLP-1 production compared to an acute response to a stress stimulus. Further studies are required to elucidate the mechanism of GLP-1 secretion with chronic exposure to catecholamine.

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

Thyroid hormones (TH) regulate systemic glucose metabolism through incompletely understood mechanisms. Here, we show that improved glucose metabolism in hypothyroid mice after T3 treatment is accompanied with increased glucagon-like peptide-1 (GLP-1) production and insulin secretion, while co-treatment with a GLP-1 receptor antagonist attenuates the effects of T3 on insulin and glucose levels. By using mice lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is required for both the regulation of GLP-1 production and the insulinotropic and glucose-lowering effects of T3. Moreover, administration of a liver-targeted TRβ-selective agonist increases GLP-1 and insulin levels and alleviates hyperglycemia in diet-induced obesity. Mechanistically, T3 suppresses Cyp8b1 expression, resulting in increased the levels of Farnesoid X receptor (FXR)-antagonistic bile acids, thereby potentiating GLP-1 production and insulin secretion by repressing intestinal FXR signalling. T3 correlates with both plasma GLP-1 and fecal FXR-antagonistic bile acid levels in people with normal thyroid function. Thus, our study reveals a role for hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.

Effects of Elobixibat, an Inhibitor of Ileal Bile Acid Transporter, on Glucose and Lipid Metabolism: A Single-arm Pilot Study in Patients with T2DM

PurposeThe ileal bile acid transporter inhibitor elobixibat was recently approved in Japan for use in the treatment of patients with chronic constipation. Elobixibat has been associated with increased plasma glucagon-like peptide 1 level through Takeda G protein receptor 5, which is a membrane receptor of bile acids. The present study assessed the metabolic effects of elobixibat in patients with type 2 diabetes mellitus (T2DM)-related constipation. MethodsIn this single-arm pilot study, 21 patients with T2DM and constipation were administered elobixibat 10 mg/d for 12 weeks (period 1). The primary end point was the change in hemoglobin (Hb) A1c at week 12. Secondary end points included physical parameters; constipation symptoms; and blood parameters, such as low-density lipoprotein cholesterol (LDL-C), arachidonic acid (AA), and fatty acid fractions. Thereafter, the study participants chose whether to continue therapy for an additional 12 weeks (period 2), at which point HbA1c and lipid levels were reevaluated. Safety information, including adverse events, discontinuation and interruption of the drug, was collected at each visit during the trial. FindingsPeriod 1: the levels of HbA1c, LDL-C, and AA were significantly reduced after administration of elobixibat for 12 weeks (–0.2%, –21.4 mg/dL, and –16.1 µg/dL, respectively; P = 0.016, P < 0.001, and P = 0.010). Period 2: at week 24, the change from baseline in HbA1c was significantly greater among those who continued elobixibat treatment than in those who discontinued after 12 weeks (–0.23% vs +0.21%; P = 0.038). No serious or severe adverse events were observed. ImplicationsElobixibat may benefit patients with T2DM by improving glucose metabolism and lowering serum LDL-C and AA levels, in addition to ameliorating constipation. This single-arm pilot study was of a small sample size. The findings provide a basis for designing a larger-scale study to confirm the effects of elobixibat on glucose and lipid metabolism. (UMIN Clinical Trials Registry identifier: UMIN000045508; https://www.umin.ac.jp/ctr/index.htm)

Chlorogenic Acid: a Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson’s Disease by GLP-1 Secretion

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50mg/kg, orally for 13weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3β through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.

Insulin Secretory Actions of Ethanol Extract of Eucalyptus citriodora Leaf, including Plasma DPP-IV and GLP-1 Levels in High-Fat-Fed Rats, as Well as Characterization of Biologically Effective Phytoconstituents.

Due to the numerous adverse effects of synthetic drugs, researchers are currently studying traditional medicinal plants to find alternatives for diabetes treatment. Eucalyptus citriodora is known to be used as a remedy for various illnesses, including diabetes. This study aimed to explore the effects of ethanol extract of Eucalyptus citriodora (EEEC) on in vitro and in vivo systems, including the mechanism/s of action. The methodology used involved the measurement of insulin secretion from clonal pancreatic β-cells, BRIN BD11, and mouse islets. Other in vitro systems further examined EEEC’s glucose-lowering properties. Obese rats fed a high-fat-fed diet (HFF) were selected for in vivo evaluation, and phytoconstituents were detected via RP-HPLC followed by LC-MS. EEEC induced insulin secretion in a concentration-dependent manner with modulatory effects, similar to 1 µM glucagon-like peptide 1 (GLP-1), which were partly declined in the presence of Ca2+-channel blocker (Verapamil), KATP-channel opener (Diazoxide), and Ca2+ chelation. The insulin secretory effects of EEEC were augmented by isobutyl methylxanthine (IBMX), which persisted in the context of tolbutamide or a depolarizing concentration of KCl. EEEC enhanced insulin action in 3T3-L1 cells and reduced glucose absorption, and protein glycation in vitro. In HFF rats, it improved glucose tolerance and plasma insulin, attenuated plasma DPP-IV, and induced active GLP-1 (7-36) levels in circulation. Rhodomyrtosone B, Quercetin-3-O-β-D-glucopyranoside, rhodomyrtosone E, and quercitroside were identified as possible phytoconstituents that may be responsible for EEEC effects. Thus, these findings revealed that E. citriodora could be used as an adjunct nutritional supplement to manage type 2 diabetes.

Improved systemic half-life of glucagon-like peptide-1-loaded carbonate apatite nanoparticles in rats.

BACKGROUNDGlucagon-like peptide-1 (GLP1) is an endogenous peptide that regulates blood glucose level. But its susceptibility to rapid metabolic degradation limits its therapeutic use. AIMTo prepare GLP1-encapsulated nanosize particle with controlled release property to improve the systemic half-life of GLP1. METHODSGLP1 nanoparticles were prepared by complexation of GLP1 with carbonate apatite nanoparticles (CA NPs). The physicochemical properties of the CA NPs, the effects of GLP1-loaded CA NPs on cell viability, and the systemic bioavailability of GLP1 after CA NPs administration were determined. RESULTSThe GLP1-loaded CA NPs was within 200 nm in size and stable in fetal bovine serum. The formulation did not affect the viability of human cell lines suggesting that the accumulation of CA NPs in target tissues is safe. In Sprague Dawley rats, the plasma GLP1 Levels as measured from the GLP1-loaded CA NPs-treated rats, were significantly higher than that of the control rats and free GLP1-treated rats at 1 h post-treatment (P < 0.05), and the level remained higher than the other two groups for at least 4 h. CONCLUSIONThe GLP1-loaded CA NPs improved the plasma half-life of GLP1. The systemic bioavailability of GLP1 is longer than other GLP1 nanoparticles reported to date.

Roux-en-Y gastric bypass alters intestinal glucose transport in the obese Zucker rat.

IntroductionThe gastrointestinal tract plays a major role in regulating glucose homeostasis and gut endocrine function. The current study examines the effects of Roux-en-Y gastric bypass (RYGB) on intestinal GLP-1, glucose transporter expression and function in the obese Zucker rat (ZR).MethodsTwo groups of ZRs were studied: RYGB and sham surgery pair-fed (PF) fed rats. Body weight and food intake were measured daily. On post-operative day (POD) 21, an oral glucose test (OGT) was performed, basal and 30-minute plasma, portal venous glucose and glucagon-like peptide-1 (GLP-1) levels were measured. In separate ZRs, the biliopancreatic, Roux limb (Roux) and common channel (CC) intestinal segments were harvested on POD 21.ResultsBody weight was decreased in the RYGB group. Basal and 30-minute OGT plasma and portal glucose levels were decreased after RYGB. Basal plasma GLP-1 levels were similar, while a 4.5-fold increase in GLP-1 level was observed in 30-minute after RYGB (vs. PF). The increase in basal and 30-minute portal venous GLP-1 levels after RYGB were accompanied by increased mRNA expressions of proglucagon and PC 1/3, GPR119 protein in the Roux and CC segments. mRNA and protein levels of FFAR2/3 were increased in Roux segment. RYGB decreased brush border glucose transport, transporter proteins (SGLT1 and GLUT2) and mRNA levels of Tas1R1/Tas1R3 and α-gustducin in the Roux and CC segments.ConclusionsReductions in intestinal glucose transport and enhanced post-prandial GLP-1 release were associated with increases in GRP119 and FFAR2/3 after RYGB in the ZR model. Post-RYGB reductions in the regulation of intestinal glucose transport and L cell receptors regulating GLP-1 secretion represent potential mechanisms for improved glycemic control.

GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1.

Glucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4). To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4. Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60-minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline. The main outcome measures were arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg). Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested more GLP-1r activation with DPP4i treatment in subjects with diabetes. GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.

Relationships of Glucose, GLP-1, and Insulin Secretion With Gastric Emptying After a 75-g Glucose Load in Type 2 Diabetes.

ContextThe relationships of gastric emptying (GE) with the glycemic response at 120 minutes, glucagon-like peptide-1 (GLP-1), and insulin secretion following a glucose load in type 2 diabetes (T2D) are uncertain.ObjectiveWe evaluated the relationship of plasma glucose, GLP-1, and insulin secretion with GE of a 75-g oral glucose load in T2D.DesignSingle-center, cross-sectional, post hoc analysis.SettingInstitutional research center.Participants43 individuals with T2D age 65.6 ± 1.1 years, hemoglobin A1c 7.2 ± 1.0%, median duration of diabetes 5 years managed by diet and/or metformin. InterventionParticipants consumed the glucose drink radiolabeled with 99mTc-phytate colloid following an overnight fast. GE (scintigraphy), plasma glucose, GLP-1, insulin, and C-peptide were measured between 0 and 180 minutes.Main Outcome MeasuresThe relationships of the plasma glucose at 120 minutes, plasma GLP-1, and insulin secretion (calculated by Δinsulin0-30/ Δglucose0-30 and ΔC-peptide0-30/Δglucose0-30) with the rate of GE (scintigraphy) were evaluated.ResultsThere were positive relationships of plasma glucose at 30 minutes (r = 0.56, P < 0.001), 60 minutes (r = 0.57, P < 0.001), and 120 minutes (r = 0.51, P < 0.001) but not at 180 minutes (r = 0.13, P = 0.38), with GE. The 120-minute plasma glucose and GE correlated weakly in multiple regression models adjusting for age, GLP-1, and insulin secretion (P = 0.04 and P = 0.06, respectively). There was no relationship of plasma GLP-1 with GE. Multiple linear regression analysis indicated that there was no significant effect of GE on insulin secretion.ConclusionIn T2D, while insulin secretion is the dominant determinant of the 120-minute plasma glucose, GE also correlates. Given the relevance to interpreting the results of an oral glucose tolerance test, this relationship should be evaluated further. There appears to be no direct effect of GE on either GLP-1 or insulin secretion.

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice.

BACKGROUNDObesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIMTo address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODSMale C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTSThe HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSIONPPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.

Oral Intake of Slowly Digestible α-Glucan Such as Resistant Maltodextrin Leads to Increased Secretion of Glucagon-Like Peptide-2 in Rats and Helps Thicken Their Ileal Mucosae.

To investigate whether the oral intake of slowly digestible α-glucan (SDG) could have a trophic (i.e., thickening) effect on their ileal mucosae, for 10 d, rats were given control (non-SDG), 10% isomaltodextrin (IMD) or 10% resistant maltodextrin (RMD) diets. In addition, experimental rat groups were further divided into two groups each and their diets either had or had not 1% sodium carboxymethylcellulose (CMC) added as a thickening agent. In the jejuna and the ilea, compared with control rats, the villus length and the mucosal thickness, but not the crypt depth, were significantly greater in the RMD-fed rats, with the trophic effect being weaker in the IMD-fed rats than in the RMD-fed rats. The colonic crypt depth was significantly greater in SDG groups than in the control group. The concentration of plasma glucagon-like peptide (GLP)-2 in the portal veins of the RMD group but not the IMD group was significantly higher than in the control group, with no effect of CMC supplementation on its concentration. The concentrations of cecal short-chain fatty acids did not significantly increase with SDG supplementation except for propionate concentration of the IMD-supplemented rats, compared with those in the control rats. We concluded that SDGs, especially RMD, thickened the mucosae of the rat distal small intestines. In particular, this effect of RMD but not IMD could have resulted from increased glucose available as a secretagogue of the trophic hormone GLP-2, in the ileum.

Co-Crystal of Rosiglitazone With Berberine Ameliorates Hyperglycemia and Insulin Resistance Through the PI3K/AKT/TXNIP Pathway In Vivo and In Vitro.

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by insulin resistance and hyperglycemia. This study examined the effect and elucidated the mechanism of improvement of hyperglycemia and insulin resistance by a co-crystal of rosiglitazone with berberine (RB) in high-sugar high-fat diet (HSHFD)-induced diabetic KKAy mice. Methods: Diabetic KKAy mice were randomly divided into seven groups: KKAy model control group (DM control) treated with 3% sodium carboxymethyl cellulose; RB groups, administered daily with RB 0.7 mg/kg (RB-L), 2.11 mg/kg (RB-M), or 6.33 mg/kg (RB-H); positive control groups, administered daily with rosiglitazone 1.04 mg/kg (RSG), berberine 195 mg/kg (BBR), or combination of 1.04 mg/kg RSG and 1.08 mg/kg BBR (MIX). Test compounds were administered orally for 8 weeks. Non-diabetic C57BL/6J mice were used as normal control (NC). Blood glucose, food intake, body weight, glucose-lipid metabolism, and pathological changes in the pancreas and liver were examined. We further evaluated the mechanism of action of RB in C2C12 and HepG2 cells stimulated with high glucose and palmitate. Results: RB treatment improved glucolipid metabolism and insulin resistance in diabetic KKAy mice. RB reduced blood glucose levels, white fat index, plasma triglyceride (TG), low-density lipoprotein (LDL), gastric inhibitory peptide (GIP), and insulin levels, increased the levels of plasma glucagon-like peptide-1 (GLP-1), high-density lipoprotein (HDL), and glycogen content in the liver and muscle; and improved oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and pathological changes in the pancreas and liver of KKAy mice. Moreover, RB upregulated p-PI3K and p-AKT levels and reduced TXNIP expression in KKAy mice and in HepG2 and C2C12 cells. Conclusion: These data indicate that RB ameliorates insulin resistance and metabolic disorders, and the mechanism might be through regulating the PI3K/AKT/TXNIP signaling pathway . Thus, the co-crystal drug RB may be considered as a potential antidiabetic agent for future clinical therapy.

Interrupting Prolonged Sitting with Intermittent Walking Increases Postprandial Gut Hormone Responses.

Continuous exercise can increase postprandial gut hormone such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) responses, but it is unknown whether interrupting prolonged sitting with intermittent walking elicits this effect. Ten participants with central overweight/obesity (7 men and 3 postmenopausal women, 51 ± 5 yr; mean ± SD) completed a randomized crossover study in which they consumed breakfast and lunch in the laboratory while either sitting continuously for the entire 5.5-h period (SIT) or the prolonged sitting interrupted every 20 min by walking briskly (6.4 km·h-1) for 2 min (BREAKS). Blood samples were collected at regular intervals to examine postprandial plasma GLP-1, PYY, and glucose-dependent insulinotropic polypeptide concentrations. Adipose tissue samples were collected at baseline and at the end of the trials to examine changes in net dipeptidyl peptidase 4 secretion from primary explants. Mean (95% confidence interval) postprandial GLP-1 and PYY incremental area under curve values were elevated by 26% and 31% in the BREAKS trial versus SIT (8.4 [0.7, 16.1] vs 6.7 [-0.8, 14.2], P = 0.001, and 26.9 [8.1, 45.6] vs 20.4 [5.1, 35.8] nmol·330 min·L-1, P = 0.024, respectively) but without any such effect on glucose-dependent insulinotropic polypeptide (P = 0.076) or net adipose tissue dipeptidyl peptidase 4 secretion (P > 0.05). Interrupting prolonged sitting with regular short bouts of brisk walking increases postprandial GLP-1 and PYY concentrations in healthy middle-age men and women with central adiposity.

Effects of ileal glucose infusion on enteropancreatic hormone secretion in humans: relationship to glucose absorption

BackgroundsThe distal small intestine plays an important role in regulating the secretion of entero-pancreatic hormones that are critical to the control of glucose metabolism and appetite, but the quantitative contribution of a specific segment to these effects is unknown. PurposesTo determine the effects of 30 cm of the ileum exposed to glucose on the secretion of ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) insulin, C-peptide and glucagon, in relation to glucose absorption in non-diabetic subjects. Basic procedures10 non-diabetic subjects with a loop ileostomy after early-stage rectal cancer resection were studied on 2 days in a double-blind, randomized and crossover fashion, when a catheter was inserted retrogradely 30 cm from the ileostomy for infusion of a glucose solution containing 30 g glucose and 3 g 3-O-methylglucose (as a marker of active glucose absorption), or 0.9% saline, over 60 min. Ghrelin, GIP, GLP-1, insulin, C-peptide, glucagon and ileal glucose absorption (from concentrations of 3-O-methylglucose in serum and glucose in ileostomy effluent) were measured over 180 min. Main findings12.0 ± 1.2 g glucose was absorbed over 180 min. Compared to saline, ileal glucose resulted in minimal increases in blood glucose and plasma insulin and C-peptide, but substantial increases in plasma GLP-1, without affecting ghrelin, GIP or glucagon. The magnitude of the GLP-1 response to glucose was strongly related to the increase in serum 3-O-methylglucose. Principal conclusionsStimulation of the terminal ileum by glucose, even over a short length (30 cm), induces substantial GLP-1 release, coupled primarily to active glucose absorption.Clinical registration:NCT05030376 (ClinicalTrials.gov).