incretins and Overweight

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Overweight; Weight Loss

Topics: Cholecystitis; Combined Modality Therapy; Diet Therapy; Exercise Therapy; Humans; Hypoglycemia; Incretins; Liraglutide; Obesity; Overweight; Pancreatitis

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Life Style; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the Kcells of the duodenum, while GLP-1 is released by the Lcells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review.

Topics: Adipose Tissue; Body Weight; Diabetes Mellitus, Type 2; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Overweight; Receptors, Glucagon

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Incretins; Insulin; Insulin Secretion; Life Style; Liraglutide; Obesity; Overweight; Peptides; Prevalence; Venoms

The vast majority of patients with type 2 diabetes are overweight or obese. Lifestyle intervention to lose weight is recommended in most diabetic patients to improve glycaemic control and reduce associated risk factors for microvascular and macrovascular complications. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors, although achieving this level of weight reduction remains difficult for many patients. Complicating the matter, many agents used to target hyperglycaemia are associated with weight gain, making management of overweight or obese patients with type 2 diabetes quite challenging. Incretin-based therapies with the new classes of glucagon-like peptide-1 mimetics (e.g. exenatide, liraglutide) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin) may be of particular value in the treatment of overweight/obese type 2 diabetic patients because of their efficacy in improving glycaemic control and their favourable or neutral effects on body weight. In addition, DPP-4 inhibitors have a low risk for causing hypoglycaemia, undesirable gastrointestinal effects, or other prominent adverse effects that might limit their use. These classes of drugs hold promise for the treatment of type 2 diabetes, alone or in combination with other classes of antidiabetic agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Obesity; Overweight; Weight Gain

To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4.. Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At -30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done.. PNO-FFA augmented GLP-1 secretion from 0-360 min compared to no oil and PNO-OO (. In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

Topics: Appetite; Blood Glucose; Cross-Over Studies; Delayed-Action Preparations; Dietary Fats, Unsaturated; Dietary Supplements; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Nuts; Obesity; Olive Oil; Overweight; Pinus; Plant Oils; Postprandial Period

To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance.. In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants underwent ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle.. Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA diet (by 50%, 25% and 9%, respectively), and the SFA diet increased plasma glucose during the IST (by 36%; all P < .01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (-9.4% vs baseline; P < .01) was ameliorated by liraglutide (-4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs -3%; P = .04 vs placebo).. Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.

Topics: Adult; Aged; Body Mass Index; Cohort Studies; Cross-Over Studies; Diet, High-Fat; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Male; Microvessels; Middle Aged; Muscle, Skeletal; Overweight; Postprandial Period; Prediabetic State; Subcutaneous Fat, Abdominal; Vasodilation

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

To investigate the effects of 24 weeks of treatment with liraglutide added to basal/bolus insulin on anthropometric and metabolic parameters in overweight participants with type 1 diabetes.. In a double-blinded cross-over fashion, 15 participants were randomly assigned (1:1) to receive placebo (saline solution) or liraglutide for 24 weeks including a 1-month titration period from 0.6 to 1.2 to 1.8 mg, in addition to their insulin. The treatment was followed by a 1-month wash-out period. Participants were then assigned to the other treatment for another 24 weeks. Paired rank tests were used to compare the metabolic parameters.. There was no treatment effect on HbA1c nor on insulin dose. Heart rate was increased by about 8 beats per minute with liraglutide. There were significant reductions in metabolic measures: weight, body mass index, waist and hip circumferences, body fatness, computed tomography scan abdominal and mid-thigh measurements, systolic and diastolic blood pressures (all P ≤ .05). There was no increase in time spent in hypoglycaemia with liraglutide.. The addition of liraglutide to basal/bolus insulin therapy for 24 weeks in overweight/obese individuals with type 1 diabetes improved the anthropometric and metabolic profiles without an increase in hypoglycaemia. Clinical Trials.gov No: NCT01787916.

Topics: Adiposity; Adult; Anti-Obesity Agents; Body Mass Index; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Liraglutide; Male; Overweight

After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through generation of 2-monoacylglycerol, an agonist for the intestinal G protein-coupled receptor 119 (GPR119). Enhanced incretin release may have beneficial metabolic effects. However, dietary fat may promote weight gain and should therefore be restricted in obesity. We designed C4-dietary oil (1,3-di-butyryl-2-oleoyl glycerol) as a 2-oleoyl glycerol (2-OG)-generating fat type, which would stimulate incretin release to the same extent while providing less calories than equimolar amounts of common triglycerides, e.g., olive oil.. We studied the effect over 180 min of (a) 19 g olive oil plus 200 g carrot, (b) 10.7 g C4 dietary oil plus 200 g carrot and (c) 200 g carrot, respectively, on plasma responses of gut and pancreatic hormones in 13 overweight patients with type 2 diabetes (T2D). Theoretically, both oil meals result in formation of 7.7 g 2-OG during digestion.. Both olive oil and C4-dietary oil resulted in greater postprandial (P ≤ 0.01) glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses (incremental area under curve (iAUC)): iAUC. C4-dietary oil enhanced secretion of GLP-1 and GIP to almost the same extent as olive oil, in spite of liberation of both 2-OG and oleic acid, which also may stimulate incretin secretion, from olive oil. Thus, C4-dietary oil is more effective as incretin releaser than olive oil per unit of energy and may be useful for dietary intervention.

Topics: Aged; Area Under Curve; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycerides; Glycerol; Humans; Incretins; Male; Meals; Middle Aged; Obesity; Oleic Acid; Olive Oil; Overweight; Postprandial Period; Prodrugs; Receptors, G-Protein-Coupled; Single-Blind Method; Triglycerides

Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion.. We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372).. There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population.. These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

Topics: Appetite Depressants; Body Mass Index; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Sex Characteristics; Weight Loss

It is not known whether calorie restriction (CR) has additive benefits to those from exercise (EX)-induced weight loss. We hypothesized that weight loss from CR and EX (CREX) improves insulin sensitivity more than matched weight loss induced by EX or CR alone and that the incretin system may be involved in adaptations to CR.. Sedentary, overweight men and women (n = 52, 45-65 years of age) were randomized to undergo 6-8% weight loss by using CR, EX, or CREX. Glucose, insulin, C-peptide, insulin sensitivity, and incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) were measured during frequently sampled oral glucose tolerance tests (FSOGTTs). Incretin effects on insulin secretion were measured by comparing insulin secretion rates from the FSOGTTs to those from a glycemia-matched glucose infusion.. Despite similar weight losses in all groups, insulin sensitivity index values increased twofold more in the CREX group (2.09 ± 0.35 μM/kg/pM × 100) than in the CR (0.89 ± 0.39 μM/kg/pM × 100) and EX (1.04 ± 0.39 μM/kg/pM × 100) groups. Postprandial GLP-1 concentrations decreased only in the CR group (P = 0.04); GIP concentrations decreased in all groups. Incretin effects on insulin secretion were unchanged.. CR and EX have additive beneficial effects on glucoregulation. Furthermore, the adaptations to CR may involve reductions in postprandial GLP-1 concentrations. These findings underscore the importance of promoting both CR and EX for optimal health. However, because data from participants who withdrew from the study and from those who did not adhere to the intervention were excluded, the results may be limited to individuals who are capable of adhering to a healthy lifestyle intervention.

Topics: Adaptation, Physiological; Aged; Blood Glucose; C-Peptide; Caloric Restriction; Energy Intake; Energy Metabolism; Exercise Therapy; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Life Style; Male; Middle Aged; Overweight; Postprandial Period; Weight Loss

To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with α-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D).. In this multicenter open-label 24-week trial, Japanese over-weight (BMI ≥ 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated.. During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S.. In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins.

Topics: 1-Deoxynojirimycin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incretins; Intra-Abdominal Fat; Japan; Male; Middle Aged; Overweight; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid (r = -0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.

Topics: Adult; Energy Intake; Gastric Emptying; Gastrointestinal Transit; Glycemic Index; Humans; Incretins; Insulin; Male; Middle Aged; Overweight; Thinness

Topics: Appetite; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity; Overweight; Receptors, Gastrointestinal Hormone

Topics: Adult; Blood Glucose; Female; Glucose; High-Intensity Interval Training; Humans; Incretins; Insulin; Male; Middle Aged; Overweight

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

Topics: Adult; Bone and Bones; Bone Resorption; Collagen Type I; Cross-Over Studies; Double-Blind Method; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Male; Middle Aged; Obesity; Osteogenesis; Overweight; Peptide Fragments; Peptides; Procollagen; Random Allocation

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.

Topics: Adult; Alkaline Phosphatase; Arachidonic Acids; Dietary Fats; Duodenum; Endocannabinoids; Female; Gastric Inhibitory Polypeptide; Gene Expression; Glucagon-Like Peptide 1; Glycerides; GPI-Linked Proteins; Humans; Incretins; Inflammation; Male; Obesity; Occludin; Oleic Acids; Overweight; Permeability; Polyunsaturated Alkamides; Thinness; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein

Subjects with type-2 diabetes are typically obese with dysfunctional adipose tissue (AT). Glucagon-like peptide-1 (GLP-1) analogues are routinely used to improve glycaemia. Although, they also aid weight loss that improves AT function, their direct effect on AT function is unclear. To explore GLP-1 analogues' influence on human AT's cytokine and extracellular matrix (ECM) regulation, we therefore obtained and treated omental (OMAT) and subcutaneous (SCAT) AT samples with Exendin-4, an agonist of the GLP-1 receptor (GLP-1R).. OMAT and abdominal SCAT samples obtained from women during elective surgery at the Royal Devon & Exeter Hospital (UK) were treated with increasing doses of Exendin-4. Changes in RNA expression of adipokines, inflammatory cytokines, ECM components and their regulators were assessed and protein secretion analysed by ELISA. GLP-1R protein accumulation was compared in paired AT depot samples.. Exendin-4 induced an increase in OMAT adiponectin (P=0.02) and decrease in elastin expression (P=0.03) in parallel with reduced elastin secretion (P=0.04). In contrast to OMAT, we did not observe an effect on SCAT. There was no change in the expression of inflammatory markers (CD14, TNFA, MCP-1), collagens, TGFB1 or CTGF. GLP-1R accumulation was higher in SCAT.. Independently of weight loss, which may bias findings of in vivo studies, GLP-1 analogues modify human OMAT physiology favourably by increasing the insulin-sensitising cytokine adiponectin. However, the reduction of elastin and no apparent effect on AT's inflammatory cytokines suggest that GLP-1 analogues may be less beneficial to AT function, especially if there is no associated weight loss.

Topics: Adipokines; Adiponectin; Adipose Tissue; Aged; Cytokines; Dose-Response Relationship, Drug; Elastin; Exenatide; Extracellular Matrix; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Inflammation; Middle Aged; Overweight; Peptides; Venoms

To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes.. A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). β-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied.. Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups.. We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.

Topics: Adult; Age of Onset; Autoantibodies; Autoimmune Diseases; Blood Glucose; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Matched-Pair Analysis; Obesity; Overweight; Postprandial Period

Impairment of the incretin effect is one of the hallmarks of type 2 diabetes mellitus (T2DM). However, it is unknown whether this abnormality is specific to incretin-stimulated insulin secretion or a manifestation of generalized β-cell dysfunction. The aim of this study was to determine whether improved glycemic control restores the incretin effect.. Fifteen T2DM subjects were studied before and after 8 weeks of intensified treatment with insulin. The incretin effect was determined by comparing plasma insulin and C-peptide levels at clamped hyperglycemia from iv glucose, and iv glucose plus glucose ingestion.. Long-acting insulin, titrated to reduce fasting glucose to 7 mM, lowered hemoglobin A1c from 8.6% ± 0.2% to 7.1% ± 0.2% over 8 weeks. The incremental C-peptide responses and insulin secretion rates to iv glucose did not differ before and after insulin treatment (5.6 ± 1.0 and 6.0 ± 0.9 nmol/L·min and 0.75 ± 0.10 and 0.76 ± 0.11 pmol/min), but the C-peptide response to glucose ingestion was greater after treatment than before (10.9 ± 2.2 and 7.1 ± 0.9 nmol/L·min; P = .03) as were the insulin secretion rates (1.11 ± 0.22 and 0.67 ± 0.07 pmol/min; P = .04). The incretin effect computed from plasma C-peptide was 21.8% ± 6.5% before insulin treatment and increased 40.9% ± 3.9% after insulin treatment (P < .02).. Intensified insulin treatment to improve glycemic control led to a disproportionate improvement of insulin secretion in response to oral compared with iv glucose stimulation in patients with type 2 diabetes. This suggests that in T2DM the impaired incretin effect is independent of abnormal glucose-stimulated insulin secretion.

Topics: Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Drug Monitoring; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Glargine; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Insulin, Long-Acting; Male; Middle Aged; Overweight

(1) When type 2 diabetes is inadequately controlled with oral antidiabetic therapy, one option is to add subcutaneous insulin injections (or to accept less stringent glycaemic control). However, since the effects of adding insulin have only been evaluated in the short-term, effects on long-term clinical outcomes remain unknown. (2) Exenatide, a drug belonging to a new pharmacological class (incretin analogues), is marketed as a subcutaneously administered adjunct to inadequately effective oral antidiabetic therapy in adults with type 2 diabetes. (3) Three placebo-controlled trials lasting 7 months showed that adding exenatide to metformin and/or a glucose-lowering sulphonylurea yielded an HbA1c level of 7% or less in about 40% of patients treated with exenatide 10 micrograms twice a day, versus about 10% of patients on placebo. The potential impact of exenatide on morbidity and mortality is not known. (4) In two trials versus insulin glargine and in one trial versus insulin aspart (+ isophane insulin), exenatide was as effective as the various insulins in controlling HbA1c levels. (5) During clinical trials, patients receiving exenatide lost an average of about 2 kg after 6 months, while insulin was associated with a weight gain of about 2 kg. (6) There was a similar incidence of hypoglycaemia with exenatide and insulin. In patients treated with exenatide, concomitant use of glucose-lowering sulphonylurea increases the risk of hypoglycaemia. (7) More than half of patients on exenatide experienced nausea, versus fewer than 10% of patients on insulin glargine. (8) The long-term consequences of the presence of antiexenatide antibodies on the effectiveness of treatment are not known. (9) Exenatide is administered in two subcutaneous injections a day, at fixed doses. Insulin is administered in one or several injections a day, at doses adjusted to self-monitored blood glucose levels. (10) Adding insulin rather than exenatide is a better option in general when oral antidiabetic therapy fails in patients with type 2 diabetes, as we have more experience with insulin and there is no evidence of important advantages with exenatide. The latter should be reserved for situations in which weight gain is a major problem.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Metformin; Overweight; Peptides; Sulfonylurea Compounds; Venoms; Weight Gain; Weight Loss