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Tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, is approved for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM) in the USA, EU, Japan and other countries. It comes as single-dose prefilled pens and single-dose vials. In phase III SURPASS trials, once-weekly subcutaneous tirzepatide, as monotherapy or add-on-therapy to oral glucose-lowering medications and insulin, was superior to the GLP-1 receptor agonists (RAs) dulaglutide 0.75 mg and semaglutide 1 mg as well as basal and prandial insulin for glycaemic control and weight loss in adults with inadequately controlled T2DM. Tirzepatide was generally well tolerated, with a safety profile consistent with that of GLP-1 RAs. Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM. Plain Language Summary: Many people with type 2 diabetes mellitus (T2DM) do not achieve and maintain glycaemic and weight management goals using currently available treatments. Tirzepatide (Mounjaro®) is the first incretin-based glucose-lowering medication to be approved as an add-on to diet and exercise in adults with T2DM that targets both the glucose-dependent insulinotropic polypeptide receptor (GIP) and the glucagon-like peptide-1 (GLP-1) receptor. In patients with inadequately controlled T2DM, tirzepatide improved glycaemic control and body weight more so than dulaglutide 0.75 mg, semaglutide 1 mg and insulin when used on its own or in combination with other medications. Tirzepatide was generally well tolerated and had a low risk of hypoglycaemia. The most common adverse events were usually short-lived gastrointestinal-related events, which were generally mild to moderate in nature, including nausea, diarrhoea, decreased appetite and vomiting. Tirzepatide is a valuable addition to the treatment options for people with inadequately controlled T2DM. [ABSTRACT FROM AUTHOR]

Background: Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. Main text: Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: Allulose is a rare monosaccharide with almost zero calories. There is no study of short-term allulose consumption in patients with type 2 diabetes (T2D). Thus, we aimed to study the effect of allulose consumption for 12 weeks on glucose homeostasis, lipid profile, body composition, incretin levels, and inflammatory markers in patients with T2D. Methods: A double-blind, randomized, controlled crossover study was conducted on sixteen patients with T2D. Patients were randomly assigned to allulose 7 g twice daily or aspartame 0.03 g twice daily for 12 weeks. After a 2-week washout, patients were crossed over to the other sweetener for an additional 12 weeks. Oral glucose tolerance tests, laboratory measurements, and dual-energy X-ray absorptiometry were conducted before and after each phase. Results: This study revealed that short-term allulose consumption exerted no significant effect on glucose homeostasis, incretin levels, or body composition but significantly increased MCP-1 levels (259 ± 101 pg/ml at baseline vs. 297 ± 108 pg/mL after 12 weeks of allulose, p = 0.002). High-density lipoprotein cholesterol (HDL-C) significantly decreased from 51 ± 13 mg/dl at baseline to 41 ± 12 mg/dL after 12 weeks of allulose, p < 0.001. Conclusion: Twelve weeks of allulose consumption had a neutral effect on glucose homeostasis, body composition, and incretin levels. Additionally, it decreased HDL-C levels and increased MCP-1 levels. Trial registration: This trial was retrospectively registered on the Thai Clinical Trials Registry (TCTR20220516006) on December 5, 2022. [ABSTRACT FROM AUTHOR]

Incretin-based therapies, in particular glucagon-like peptide-1 (GLP-1) receptor agonists, have been evaluated in other forms of diabetes, but randomised controlled trials are mainly limited to people living with type 1 diabetes. In this review we present the evidence issuing from these trials and discuss their clinical implications as well as the difficulties in interpreting the data. In type 1 diabetes, the addition of GLP-1 receptor agonists to intensive insulin therapy lowers weight and required insulin doses compared with placebo, but the effects on glucose control (HbA1c, risk of hypoglycaemia) are dependent on the different study protocols. Side effects are limited to the gastrointestinal complaints of nausea, vomiting and diarrhoea. We briefly discuss the potential for using GLP-1 receptor agonists as (adjunct) therapies in other forms of diabetes, where the evidence to date is scarce. [ABSTRACT FROM AUTHOR]

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases. [ABSTRACT FROM AUTHOR]

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development. [ABSTRACT FROM AUTHOR]

DPP-4 inhibition is an incretin-based therapy that works on the principle of stopping the degradation of glucagon-like polypeptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) by the DPP-4 enzyme. DPP-4 inhibitors block the active site of the DPP-4 enzyme and thus increase these incretins' circulatory lifetime, allowing for longer and more effective glucose homeostasis. All the ligands bind within the binding pocket and interact with residues to prevent the proper orientation of incoming substrates, thus blocking the enzymatic activity of DPP-4. In addition, various descriptors of ADME studies were analysed and the pharmacological and pharmacokinetic properties of canagliflozin stood out among the five inhibitors studied. The authors have tried to see the potential of gliflozins as DPP-4 inhibitors. The in silico docking studies have shown promising results for the same. [ABSTRACT FROM AUTHOR]

Adults with obesity may develop asthma that is ineffectively controlled by inhaled corticosteroids and long-acting beta-adrenoceptor agonists. Mechanistic and translational studies suggest that metabolic dysregulation that occurs with obesity, particularly hyperglycemia and insulin resistance, contributes to altered immune cell function and low-grade systemic inflammation. Importantly, in these cases, the same proinflammatory cytokines believed to contribute to insulin resistance may also be responsible for airway remodeling and hyperresponsiveness. In the past decade, new research has emerged assessing whether hypoglycemic therapies impact comorbid asthma as reflected by the incidence of asthma, asthma-related emergency department visits, asthma-related hospitalizations, and asthma-related exacerbations. The purpose of this review article is to discuss the mechanism of action, preclinical data, and existing clinical studies regarding the efficacy and safety of hypoglycemic therapies for adults with obesity and comorbid asthma. [ABSTRACT FROM AUTHOR]

Aim: To determine the association of fasting glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) with dyslipidemia in newly diagnosed diabetes (NDD). Method: This collaborative prospective interventional clinical study was carried out by the Biochemistry Department, at the University of Karachi-Pakistan, Baqai Institute of Diabetology and Endocrinology, Karachi-Pakistan and Kansai Electric Power Medical Research Institute, Osaka, Japan. The study duration was from March 2019 to May 2020. Participants were identified on the basis of oral glucose tolerance test (OGTT) results. Of 34 participants, 17 were NDD and 17 were healthy. Demographics and anthropometric details were noted on a predesigned questionnaire. Blood samples were collected at fasting state for plasma glucose, lipid profile, HbA1c, and hormones (GIP and GLP-1). Results: The healthy participants included nine males and eight females, and the NDD participants included ten males and seven females. Mean age was 50.78±2.44 years and BMI was 28.41±0.76 kg/m2. Among healthy participants, both GIP and GLP-1 showed non-significant weak correlation for biochemical parameters. In NDD participants, GIP showed significantly negative moderate correlation with age and non-HDL and positive moderate correlation with LDL only. However, GLP-1 showed significantly positive moderate correlation with total cholesterol (r = 0.564, p = 0.018), LDL (r = 0.498, p = 0.042), HDL (r = 0.50, p = 0.041) and non-HDL (r = 0.503, p = 0.047) in NDD participants. Conclusion: The effect of GIP and GLP-1 measures on dyslipidemia were substantially different among NDD participants in our population. In the NDD group, GLP-1 is significantly moderately associated with dyslipidemia compared to GIP. [ABSTRACT FROM AUTHOR]

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Aims/hypothesis: The clinical importance of fat deposition in the liver and pancreas is increasingly recognised. However, to what extent deposition of fat in these two depots is affected by intermediate variables is unknown. The aim of this work was to conduct a mediation analysis with a view to uncovering the metabolic traits that underlie the relationship between liver fat and intrapancreatic fat deposition (IPFD) and quantifying their effect. Methods: All participants underwent MRI/magnetic resonance spectroscopy on the same 3.0 T scanner to determine liver fat and IPFD. IPFD of all participants was quantified manually by two independent raters in duplicate. A total of 16 metabolic traits (representing markers of glucose metabolism, incretins, lipid panel, liver enzymes, pancreatic hormones and their derivatives) were measured in blood. Mediation analysis was conducted, taking into account age, sex, ethnicity and BMI. Significance of mediation was tested by computing bias-corrected bootstrap CIs with 5000 repetitions. Results: A total of 353 individuals were studied. Plasma glucose, HDL-cholesterol and triacylglycerol mediated 6.8%, 17.9% and 24.3%, respectively, of the association between liver fat and IPFD. Total cholesterol, LDL-cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, insulin, glucagon, amylin, C-peptide, HbA1c, glucagon-like peptide-1 and gastric inhibitory peptide did not mediate the association between liver fat and IPFD. Conclusions/interpretation: At least one-quarter of the association between liver fat and IPFD is mediated by specific blood biomarkers (triacylglycerol, HDL-cholesterol and glucose), after accounting for potential confounding by age, sex, ethnicity and BMI. This unveils the complexity of the association between the two fat depots and presents specific targets for intervention. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is one the most common metabolic diseases, which is obviously the price of lifestyle changes for many people. While being dangerous in itself, this disease provokes other metabolic disorders, such as obesity and neurodegenerative diseases such as Alzheimer's disease. Pharmacologists are very active in creating drugs for these illnesses. The design of synthetic highly active and stable analogues of incretins, peptide hormones produced by neuroendocrine cells, is one of the most promising research areas. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are the best known incretin hormones. Analogues of the first peptide have already found application in medical practice. The next step in the creation of drugs for diabetes was the development of polyagonists, which combine the properties of several different peptide hormones responsible for glucose homeostasis. The combination of the properties of incretins gives hope for a synergetic network effect. In the past few years, the creation of such co-agonists has progressed very rapidly. In some cases, the results of clinical trials have already been obtained; however, they often contradict each other. This difficult situation was the main motivation for writing the present review. [ABSTRACT FROM AUTHOR]

Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM. [ABSTRACT FROM AUTHOR]

Nearly half of all adults with type 2 diabetes mellitus (T2DM) live in India and China. These populations have an underlying predisposition to deficient insulin secretion, which has a key role in the pathogenesis of T2DM. Indian and Chinese people might be more susceptible to hepatic or skeletal muscle insulin resistance, respectively, than other populations, resulting in specific forms of insulin deficiency. Cluster-based phenotypic analyses demonstrate a higher frequency of severe insulin-deficient diabetes mellitus and younger ages at diagnosis, lower β-cell function, lower insulin resistance and lower BMI among Indian and Chinese people compared with European people. Individuals diagnosed earliest in life have the most aggressive course of disease and the highest risk of complications. These characteristics might contribute to distinctive responses to glucose-lowering medications. Incretin-based agents are particularly effective for lowering glucose levels in these populations; they enhance incretin-augmented insulin secretion and suppress glucagon secretion. Sodium-glucose cotransporter 2 inhibitors might also lower blood levels of glucose especially effectively among Asian people, while α-glucosidase inhibitors are better tolerated in east Asian populations versus other populations. Further research is needed to better characterize and address the pathophysiology and phenotypes of T2DM in Indian and Chinese populations, and to further develop individualized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Type II diabetes mellitus onset is linked with hormonal imbalances. However, the knowledge about hormonal alterations in pre-diabetes is limited.The study aimed to examine type II diabetes mellitus-associated hormone levels during the pre-diabetes phase in participants aged 25–45 in a Durban-based clinical setting in South Africa.Stored plasma samples from a retrospective study collected 364 samples that were divided into pre-diabetes and non-pre-diabetes groups. From the 364, 38 samples from the group of persons without pre-diabetes and 38 from persons with glycated haemoglobin determined pre-diabetes were blindly selected. The hormone concentrations (C-peptide, cortisol, adipokines, thyroids, incretins, and sex steroids) of the study participants were measured using the BIO-RAD Bio-Plex MAGPIX instrument.Hormone imbalances in several hormones were detected in study participants with pre-diabetes. Most of the hormone dysregulation associated with T2DM begins in pre-diabetes but at a moderate level.The findings reveal new possible hormone therapy targets for pre-diabetes and contribute to the growing support for targeting pre-diabetes as a preventative measure for T2DM prevention.Objective: Type II diabetes mellitus onset is linked with hormonal imbalances. However, the knowledge about hormonal alterations in pre-diabetes is limited.The study aimed to examine type II diabetes mellitus-associated hormone levels during the pre-diabetes phase in participants aged 25–45 in a Durban-based clinical setting in South Africa.Stored plasma samples from a retrospective study collected 364 samples that were divided into pre-diabetes and non-pre-diabetes groups. From the 364, 38 samples from the group of persons without pre-diabetes and 38 from persons with glycated haemoglobin determined pre-diabetes were blindly selected. The hormone concentrations (C-peptide, cortisol, adipokines, thyroids, incretins, and sex steroids) of the study participants were measured using the BIO-RAD Bio-Plex MAGPIX instrument.Hormone imbalances in several hormones were detected in study participants with pre-diabetes. Most of the hormone dysregulation associated with T2DM begins in pre-diabetes but at a moderate level.The findings reveal new possible hormone therapy targets for pre-diabetes and contribute to the growing support for targeting pre-diabetes as a preventative measure for T2DM prevention.Methods: Type II diabetes mellitus onset is linked with hormonal imbalances. However, the knowledge about hormonal alterations in pre-diabetes is limited.The study aimed to examine type II diabetes mellitus-associated hormone levels during the pre-diabetes phase in participants aged 25–45 in a Durban-based clinical setting in South Africa.Stored plasma samples from a retrospective study collected 364 samples that were divided into pre-diabetes and non-pre-diabetes groups. From the 364, 38 samples from the group of persons without pre-diabetes and 38 from persons with glycated haemoglobin determined pre-diabetes were blindly selected. The hormone concentrations (C-peptide, cortisol, adipokines, thyroids, incretins, and sex steroids) of the study participants were measured using the BIO-RAD Bio-Plex MAGPIX instrument.Hormone imbalances in several hormones were detected in study participants with pre-diabetes. Most of the hormone dysregulation associated with T2DM begins in pre-diabetes but at a moderate level.The findings reveal new possible hormone therapy targets for pre-diabetes and contribute to the growing support for targeting pre-diabetes as a preventative measure for T2DM prevention.Results: Type II diabetes mellitus onset is linked with hormonal imbalances. However, the knowledge about hormonal alterations in pre-diabetes is limited.The study aimed to examine type II diabetes mellitus-associated hormone levels during the pre-diabetes phase in participants aged 25–45 in a Durban-based clinical setting in South Africa.Stored plasma samples from a retrospective study collected 364 samples that were divided into pre-diabetes and non-pre-diabetes groups. From the 364, 38 samples from the group of persons without pre-diabetes and 38 from persons with glycated haemoglobin determined pre-diabetes were blindly selected. The hormone concentrations (C-peptide, cortisol, adipokines, thyroids, incretins, and sex steroids) of the study participants were measured using the BIO-RAD Bio-Plex MAGPIX instrument.Hormone imbalances in several hormones were detected in study participants with pre-diabetes. Most of the hormone dysregulation associated with T2DM begins in pre-diabetes but at a moderate level.The findings reveal new possible hormone therapy targets for pre-diabetes and contribute to the growing support for targeting pre-diabetes as a preventative measure for T2DM prevention.Conclusion: Type II diabetes mellitus onset is linked with hormonal imbalances. However, the knowledge about hormonal alterations in pre-diabetes is limited.The study aimed to examine type II diabetes mellitus-associated hormone levels during the pre-diabetes phase in participants aged 25–45 in a Durban-based clinical setting in South Africa.Stored plasma samples from a retrospective study collected 364 samples that were divided into pre-diabetes and non-pre-diabetes groups. From the 364, 38 samples from the group of persons without pre-diabetes and 38 from persons with glycated haemoglobin determined pre-diabetes were blindly selected. The hormone concentrations (C-peptide, cortisol, adipokines, thyroids, incretins, and sex steroids) of the study participants were measured using the BIO-RAD Bio-Plex MAGPIX instrument.Hormone imbalances in several hormones were detected in study participants with pre-diabetes. Most of the hormone dysregulation associated with T2DM begins in pre-diabetes but at a moderate level.The findings reveal new possible hormone therapy targets for pre-diabetes and contribute to the growing support for targeting pre-diabetes as a preventative measure for T2DM prevention. [ABSTRACT FROM AUTHOR]

At early stages of severe type 1 diabetes mellitus (DM1), which is characterized by severe insulin deficiency, acute hyperglycemia and hyperphagia, there arise impaired incretin secretion and adipokine status, endocrine dysfunctions, and altered hypothalamic regulation. This is largely due to brain insulin deficiency. The use of intranasally administered insulin (I-I), which compensates for its deficiency, is able to prevent DM1 complications. Since in DM1 there is a deficiency of the proinsulin C-peptide, which can enhance insulin effects, it seems promising to co-use I-I with intranasally administered C-peptide (I-СP). This work aimed to study the effect of 7-day treatment of rats with short-term DM1 induced by high-dose streptozotocin (65 mg/kg) with I-I (20 µg/rat/day), including in combination with I-CP (36 µg/rat/day), on hormone and incretin blood levels and the expression of hypothalamic genes encoding food intake factors, insulin, leptin, serotonin and dopamine receptors, as well as regulators of mitochondrial dynamics and apoptosis. I-I alone and its combination with I-CP normalized glucagon-like peptide-1 (GLP-1) and ghrelin levels, which were elevated in DM1, and increased those of luteinizing and thyroid-stimulating hormones, as well as thyroid hormones, which were reduced in DM1, without affecting testosterone levels. One of the mechanisms behind these effects was an increase in the expression of anorexigenic genes encoding type 4 melanocortin receptor and pro-opiomelanocortin, a decrease in the gene expression of orexigenic neuropeptide Y, and normalization of the expression of genes responsible for mitochondrial dynamics (Mfn-1, Mfn-2, Drp-1), apoptosis (Bcl-2) and autophagy (Beclin-1) in the hypothalamus. I-I monotherapy was less effective, while I-СP monotherapy had no effect on the assessed parameters. Thus, combination therapy with I-I and I-CP and, to a lesser extent, I-I monotherapy normalize GLP-1 and ghrelin levels, restore luteinizing hormone levels and hormonal parameters of the thyroid system in male rats with severe short-term DM1, including due to the normalization of hypothalamic signaling. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a–f and 9a–h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 μM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM. [ABSTRACT FROM AUTHOR]

We studied the possibility of reverse transposition of the small intestine and its effect on glucose metabolism. The reverse transposition model proposed by us consists in a 180° turn of the small intestine after transection and antiperistaltic transposition of the entire intestinal tube. To this end, outbred white rats underwent reverse transposition of the small intestine, sham-operated rats served as the control. Both groups were monitored for body weight and blood glucose levels at fast and after oral glucose tolerance test. The groups did not differ by the duration of surgery, body weight, and blood glucose levels at fast and after glucose tolerance test. The reverse transposition technique proposed by us is reproducible, the anatomical changes lead to early contact of the chyme with the terminal portion of the small intestine, which can modulate absorption of nutrients and the release of ileal hormones (incretins) affecting glucose metabolism. [ABSTRACT FROM AUTHOR]

Introduction: The glucagon-like peptide-1 agonist (GLP1-RA) liraglutide is currently approved for the treatment of both obesity and type 2 diabetes (T2DM). We investigated whether the effect of this agent on cardiometabolic parameters in subjects with T2DM varied in relation to the concomitant presence of obesity. Methods: One hundred thirty-five subjects (78 men and 57 women; age: 62 ± 10 years) naïve to incretin-based therapies were treated with low-dose liraglutide (1.2 mg/day) as an add-on to metformin for 18 months. Patients were divided into two subgroups based on their body-mass index (BMI): (a) obese (BMI ≥ 30) and (b) non-obese (BMI < 30). Clinical and laboratory analyses were assessed at baseline and every 6 months. Results: During follow-up, significant improvements were seen in both groups in fasting glycemia, glycated hemoglobin, waist circumference, and carotid intima–media thickness (cIMT), while body weight, BMI, total cholesterol, and low-density lipoprotein cholesterol decreased significantly in obese subjects only. Correlation analysis revealed that changes in subclinical atherosclerosis (assessed by cIMT) were associated with changes in triglycerides (r = 0.488, p < 0.0001) in the obese group only. Conclusion: Liraglutide had beneficial actions on glycemic parameters and cardiometabolic risk factors in both non-obese and obese patients with T2DM, with a greater efficacy in the latter. These findings reinforce the benefits of liraglutide for the cardiometabolic outcomes of obese patients with T2DM in the real-world setting. This has critical importance during the current pandemic, since patients with diabetes and obesity are exposed globally to the most severe forms of COVID-19, related complications, and death. Trial registration: ClinicalTrials.gov identifier, NCT01715428. [ABSTRACT FROM AUTHOR]

The gut–brain–beta cell glucagon-like peptide-1 (GLP-1)-dependent axis and the clock genes both control insulin secretion. Evidence shows that a keystone of this molecular interaction could be the gut microbiota. We analyzed in mice the circadian profile of GLP-1 sensitivity on insulin secretion and the impact of the autonomic neuropathy, antibiotic treated in different diabetic mouse models and in germ-free colonized mice. We show that GLP-1sensitivity is maximal during the dark feeding period, i.e., the postprandial state. Coincidently, the ileum expression of GLP-1 receptor and peripherin is increased and tightly correlated with a subset of clock gene. Since both are markers of enteric neurons, it suggests a role in the gut–brain–beta cell GLP-1-dependent axis. We evaluated the importance of gut microbiota dysbiosis and found that the abundance of ileum bacteria, particularly Ruminococcaceae and Lachnospiraceae, oscillated diurnally, with a maximum during the dark period, along with expression patterns of a subset of clock genes. This diurnal pattern of circadian gene expression and Lachnospiraceae abundance was also observed in two separate mouse models of gut microbiota dysbiosis and of autonomic neuropathy with impaired GLP-1 sensitivity (1.high-fat diet-fed type 2 diabetic, 2.antibiotic-treated/germ-free mice). Our data show that GLP-1 sensitivity relies on specific pattern of intestinal clock gene expression and specific gut bacteria. This new statement opens opportunities to treat diabetic patient with GLP-1-based therapies by using on a possible pre/probiotic co-treatment to improve the time-dependent efficiency of these therapies. [ABSTRACT FROM AUTHOR]

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium–glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance. [ABSTRACT FROM AUTHOR]

Meal ingestion elicits a variety of neuronal, physiological and hormonal responses that differ in healthy, obese or diabetic individuals. The mixed meal tolerance test (MMTT) is a well-established method to evaluate pancreatic β-cell reserve and glucose homeostasis in both preclinical and clinical research in response to calorically defined meal. Nonhuman primates (NHPs) are highly valuable for diabetic research as they can naturally develop type 2 diabetes mellitus (T2DM) in a way similar to the onset and progression of human T2DM. The purpose of this study was to investigate the reproducibility and effects of a MMTT containing acetaminophen on plasma glucose, insulin, C-peptide, incretin hormones, lipids, acetaminophen appearance (a surrogate marker for gastric emptying) in 16 conscious obese cynomolgus monkeys (Macaca fascicularis). Plasma insulin, C-peptide, TG, aGLP-1, tGIP, PYY and acetaminophen significantly increased after meal/acetaminophen administration. A subsequent study in 6 animals showed that the changes of plasma glucose, insulin, C-peptide, lipids and acetaminophen were reproducible. There were no significant differences in responses to the MMTT among the obese NHPs with (n = 11) or without (n = 5) hyperglycemia. Our results demonstrate that mixed meal administration induces significant secretion of several incretins which are critical for maintaining glucose homeostasis. In addition, the responses to the MMTTs are reproducible in NHPs, which is important when the MMTT is used for evaluating post-meal glucose homeostasis in research. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand. [ABSTRACT FROM AUTHOR]

The current treatment options for neurodegenerative diseases in older adults rely mainly on providing symptomatic relief. Yet, it remains imperative to identify agents that slow or halt disease progression to avoid the most disabling features often associated with advanced disease stages. A potential overlap between the pathological processes involved in diabetes and neurodegeneration has been established, raising the question of whether incretin-based therapies for diabetes may also be useful in treating neurodegenerative diseases in older adults. Here, we review the different agents that belong to this class of drugs (GLP-1 receptor agonists, dual/triple receptor agonists, DPP-4 inhibitors) and describe the data supporting their potential role in treating neurodegenerative conditions including Parkinson's disease and Alzheimer's disease. We further discuss whether there are any distinctive properties among them, particularly in the context of safety or tolerability and CNS penetration, that might facilitate their successful repurposing as disease-modifying drugs. Proof-of-efficacy data will obviously be of the greatest importance, and this is most likely to be demonstrable in agents that reach the central nervous system and impact on neuronal GLP-1 receptors. Additionally, however, the long-term safety and tolerability (including gastrointestinal side effects and unwanted weight loss) as well as the route of administration of this class of agents may also ultimately determine success and these aspects should be considered in prioritising which approaches to subject to formal clinical trial evaluations. [ABSTRACT FROM AUTHOR]

Purpose: Many studies about bariatric surgery have analyzed the effect of sleeve gastrectomy (SG) on glucose improvement, beta-cell mass, and islet size modification. The effects of SG on the other endocrine cells of the pancreas, such as the alpha-cell population, and their regulatory mechanisms remain less studied. Materials and Methods: We focused our work on the changes in the alpha-cell population after SG in a healthy model of Wistar rats. We measured alpha-cell mass, glucose tolerance, and insulin release after oral glucose tolerance tests and plasma glucagon secretion patterns after insulin infusion. Three Wistar rat groups were employed: SG-operated, surgical control (Sham), and fasting control. Results: The results obtained showed significant increases in the alpha-cell population after SG. The result was an increase in beta-cell transdifferentiation; it was shown by some expressed molecules (the loss of expression of Pdx-1 and the increase in Arx and Pax6 cells/mm2 of islet). The serum results were enhanced plasma glucagon secretion pattern after insulin infusion assays and normal glucose tolerance and insulin release after OGTT. Conclusion: We concluded that SG leads to an expansion of the alpha-cell population, at expense of beta-cell; this expansion of alpha-cells is related to transdifferentiation. Plasma glucose level was not affected due to an increased glucagon response. [ABSTRACT FROM AUTHOR]

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney. [ABSTRACT FROM AUTHOR]

Incretin hormones analogues, including glucagon-like peptide type 1 (GLP-1), exhibit complex glucose-lowering, anorexigenic, and cardioprotective properties. Mechanisms of action of GLP-1 and its analogues are well known for pancreatic β-cells, hepatocytes, and other tissues. Nevertheless, local effects of GLP-1 and its analogues in adipose tissue remain unclear. In the present work effects of the GLP-1 synthetic analogue, liraglutide, on adipogenesis and insulin sensitivity of the 3T3-L1 adipocytes were examined. Enhancement of insulin sensitivity of mature adipocytes by the GLP-1 synthetic analogue liraglutide mediated by adenylate cyclase was demonstrated. The obtained results imply existence of the positive direct insulin-sensitizing effect of liraglutide on mature adipocytes. [ABSTRACT FROM AUTHOR]

The endogenous ligands of GPR40/FFA1 receptors, which are members of the G protein-coupled receptor class, are saturated and unsaturated free fatty acids (C6–C12) and long-chain (>C12) structures. The highest levels of expression of these receptors are seen in pancreatic β cells and neurons in various parts of the CNS. An enormous amount of experimental data on the functional roles of these receptors in the central and peripheral regulation of the body's metabolic status has been published since the "deorphanization" of these receptors in 2003. This review summarizes current understanding of the mechanisms regulating GPR40/FFA1 receptors by endogenous and synthetic ligands and the intracellular signal transduction systems activated on exposure to free fatty acids. The mechanisms of GPR40/FFA1-mediated effects of free fatty acids on glucose-stimulated insulin secretion by pancreatic β cells are addressed, along with the production of incretins by enteroendocrine cells; the mechanisms of actions on the support of neurogenesis and neurodifferentiation are also considered. Advances and potentials in the use of synthetic ligands of GPR40/FFA1 receptors in the treatment of metabolic disorders are assessed. [ABSTRACT FROM AUTHOR]

The purpose of this current opinion paper is to describe the journey of ingested carbohydrate from 'mouth to mitochondria' culminating in energy production in skeletal muscles during exercise. This journey is conveniently described as primary, secondary, and tertiary events. The primary stage is detection of ingested carbohydrate by receptors in the oral cavity and on the tongue that activate reward and other centers in the brain leading to insulin secretion. After digestion, the secondary stage is the transport of monosaccharides from the small intestine into the systemic circulation. The passage of these monosaccharides is facilitated by the presence of various transport proteins. The intestinal mucosa has carbohydrate sensors that stimulate the release of two 'incretin' hormones (GIP and GLP-1) whose actions range from the secretion of insulin to appetite regulation. Most of the ingested carbohydrate is taken up by the liver resulting in a transient inhibition of hepatic glucose release in a dose-dependent manner. Nonetheless, the subsequent increased hepatic glucose (and lactate) output can increase exogenous carbohydrate oxidation rates by 40–50%. The recognition and successful distribution of carbohydrate to the brain and skeletal muscles to maintain carbohydrate oxidation as well as prevent hypoglycaemia underpins the mechanisms to improve exercise performance. [ABSTRACT FROM AUTHOR]

Introduction: Older patients with type 2 diabetes (T2D) are at increased risk of diabetic nephropathy and mild renal insufficiency. This analysis compared the anti-hyperglycemic efficacy and safety of sitagliptin with dapagliflozin in patients ≥ 65 years of age with T2D and mild renal insufficiency. Methods: This was a post hoc analysis of data from 410 patients ≥ 65 years old who participated in a 24-week, randomized, double-blind clinical trial (CompoSIT-R [comparison of sitagliptin with dapagliflozin in mild renal impairment]; NCT02532855) in T2D patients with mild renal insufficiency and on metformin ± a sulfonylurea; the primary efficacy end point was change in HbA1c at week 24. Results: Treatment groups were well balanced at baseline (mean HbA1c = 7.7/7.7% and eGFR = 79/76 ml/min/1.73 m2 for sitagliptin/dapagliflozin). At week 24, LS mean (95% CI) change in HbA1c and percentage of patients with HbA1c < 7% were greater with sitagliptin, − 0.48% and 41%, respectively, compared with dapagliflozin, − 0.36% and 28%; between-group differences = − 0.12% (− 0.36, 0.01) and 12.8% (3.3, 22.2) for change in HbA1c and percentage with HbA1c < 7%, respectively. The sitagliptin group had greater reductions in PPG end points, while the dapagliflozin group had greater reductions in FPG. Treatments were generally well tolerated. There were fewer drug-related adverse events (AEs) with sitagliptin than with dapagliflozin but AE profiles were otherwise similar. Conclusions: In patients ≥ 65 years of age with T2D and mild renal insufficiency with inadequate glycemic control on metformin ± sulfonylurea, treatment with sitagliptin for 24 weeks resulted in improvement in HbA1c relative to treatment with dapagliflozin that is consistent with that previously observed in the overall population. Both treatments were generally well tolerated. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether calcium type and co-ingestion with protein alter gut hormone availability. Methods: Healthy adults aged 26 ± 7 years (mean ± SD) completed three randomized, double-blind, crossover studies. In all studies, arterialized blood was sampled postprandially over 120 min to determine GLP-1, GIP and PYY responses, alongside appetite ratings, energy expenditure and blood pressure. In study 1 (n = 20), three treatments matched for total calcium content (1058 mg) were compared: calcium citrate (CALCITR); milk minerals rich in calcium (MILK MINERALS); and milk minerals rich in calcium plus co-ingestion of 50 g whey protein hydrolysate (MILK MINERALS + PROTEIN). In study 2 (n = 6), 50 g whey protein hydrolysate (PROTEIN) was compared to MILK MINERALS + PROTEIN. In study 3 (n = 6), MILK MINERALS was compared to the vehicle of ingestion (water plus sucralose; CONTROL). Results: MILK MINERALS + PROTEIN increased GLP-1 incremental area under the curve (iAUC) by ~ ninefold (43.7 ± 11.1 pmol L−1 120 min; p < 0.001) versus both CALCITR and MILK MINERALS, with no difference detected between CALCITR (6.6 ± 3.7 pmol L−1 120 min) and MILK MINERALS (5.3 ± 3.5 pmol L−1 120 min; p > 0.999). MILK MINERALS + PROTEIN produced a GLP-1 iAUC ~ 25% greater than PROTEIN (p = 0.024; mean difference: 9.1 ± 6.9 pmol L−1 120 min), whereas the difference between MILK MINERALS versus CONTROL was small and non-significant (p = 0.098; mean difference: 4.2 ± 5.1 pmol L−1 120 min). Conclusions: When ingested alone, milk minerals rich in calcium do not increase GLP-1 secretion compared to calcium citrate. Co-ingesting high-dose whey protein hydrolysate with milk minerals rich in calcium increases postprandial GLP-1 concentrations to some of the highest physiological levels ever reported. Registered at ClinicalTrials.gov: NCT03232034, NCT03370484, NCT03370497. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF). Methods: A 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed. Results: The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min−1 m−2, p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min−1 m−2, p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min−1 m−2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min−1 m−2 [mmol/l]−1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively. Conclusions/interpretation: Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction. [ABSTRACT FROM AUTHOR]

Incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine cells after food ingestion, are currently recognized to regulate glucose metabolism through insulin secretion. We previously demonstrated that platelet-derived growth factor-BB (PDGF-BB) induces the migration of osteoblast-like MC3T3-E1 cells through mitogen-activated protein (MAP) kinases, including p38 MAP kinase. In the present study, we investigated whether or not incretins affect the osteoblast migration. The PDGF-BB-induced cell migration was significantly reinforced by GLP-1, GIP or cAMP analogues in MC3T3-E1 cells and normal human osteoblasts. The upregulated migration by GLP-1 or cAMP analogues was suppressed by H89, an inhibitor of protein kinase A. The amplification by GLP-1 of migration induced by PDGF-BB was almost completely reduced by SB203580, a p38 MAP kinase inhibitor in MC3T3-E1 cells and normal human osteoblasts. In addition, GIP markedly strengthened the PDGF-BB-induced phosphorylation of p38 MAP kinase. Exendin-4, a GLP-1 analogue, induced Rho A expression and its translocation from cytoplasm to plasma membranes in osteoblasts at the epiphyseal lines of developing mouse femurs in vivo. These results strongly suggest that incretins accelerates the PDGF-BB-induced migration of osteoblasts via protein kinase A, and the up-regulation of p38 MAP kinase is involved in this acceleration. Our findings may highlight the novel potential of incretins to bone physiology and therapeutic strategy against bone repair. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of hormones and the autonomic nervous system in the rapid remission of diabetes after Roux-en-Y Gastric Bypass (RYGB). Research design and methods: Nineteen obese patients with type 2 diabetes, 7 M/12 F, were randomized (2:1) to RYGB or standard-of-care medical treatment (control). At baseline and 4 and 24 weeks post surgery, fasting blood sampling, OGTT, intravenous arginine challenge, and heart-rate variability (HRV) assessments were performed. Results: At both 4 and 24 weeks post-RYGB the following effects were found: arginine-stimulated insulin secretion was reduced. GLP-1, GIP, and glucagon rise during OGTT was enhanced. IGF-1 and GH levels increased. In addition, total HRV and spectral components PLF (power of low frequency) and PHF (power of high frequency) increased. At 4 weeks, morning cortisol was lower than baseline and 24 weeks. At 24 weeks, NEFA levels during OGTT, and the PLF/PHF ratio decreased. None of these changes were seen in the control group. Conclusions: There were rapid changes within 4 weeks after RYGB: signs of enhanced parasympathetic nerve activity, reduced morning cortisol, and enhanced incretin and glucagon responses to glucose. The findings suggest that neurohormonal mechanisms can contribute to the rapid improvement of insulin resistance and glycemia following RYGB in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: About 20% of patients operated with Roux-en-Y gastric bypass (RYGBP) experience poor long-term weight result. This study compared levels of leptin and gut hormones in long-term weight responders with non-responders after RYGBP. In a subgroup analysis, hormone levels were assessed in T2DM (type 2 diabetes mellitus) and normoglycemic participants. Methods: Insulin, glucose, leptin, acyl-ghrelin, total PYY, active GLP-1, and GIP were measured during an oral glucose tolerance test (OGTT) in post-RYGBP subjects: 22 non-responders (BMI 40.6 ± 6.0 kg/m2 after an excess BMI loss [EBMIL] of 26.0 ± 15.9%) and 18 responders (BMI 29.5 ± 3.5 kg/m2 after an EBMIL of 74.9 ± 18.2%). Subjects were matched for preoperative age, BMI, and years of follow-up. Measures of glucose homeostasis were calculated, and body composition was measured. Results: Fat mass–adjusted fasting leptin correlated negatively with %EBMIL (r = − 0.57, p < 0.01). Non-responders presented higher levels of leptin during the OGTT. Leptin decreased and ghrelin returned to baseline levels earlier in non-responders. Despite having higher insulin resistance than responders, non-responders demonstrated similar OGTT responses of GLP-1, GIP, and PYY. T2DM participants demonstrated lower GLP-1 levels than normoglycemic participants of similar weight. Conclusion: Fasting leptin is associated with weight result after RYGBP, and hormonal responses to a glucose oral load might work towards promoting obesity in long-term non-responders after RYGBP. Poor long-term weight result and glycemic status after RYGBP are each associated with differences in peptide hormone levels. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory disorders with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role. Nowadays, a higher proportion of elderly IBD patients with coexisting conditions, such as cardiovascular disease and/or diabetes is recorded, who require more complex treatment and became a great challenge for gastroenterologists. Furthermore, some patients do not respond to anti-IBD therapy. These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Glucagon-like peptides (GLPs) possess numerous functions in the human body such as lowering blood glucose level, controlling body weight, inhibiting gastric emptying, reducing food ingestion, increasing crypt cell proliferation, and improving intestinal growth and nutrient absorption. Thus, GLPs and dipeptidyl peptidase IV (DPP-IV) inhibitors have recently gained attention in IBD research. Several animal models showed that treatment with GLPs may lead to improvement of colitis. This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases and summarizes the current knowledge on GLPs, which have the potential to become a novel therapeutic option in IBD therapy. [ABSTRACT FROM AUTHOR]

Aims: Eating protein before carbohydrate reduces postprandial glucose excursions by enhancing insulin and glucagon-like peptide-1 (GLP-1) secretion in type 2 diabetes (T2D). We tested the hypothesis that this insulinotropic effect depends on the elevation of plasma amino acids (AA) after the digestion of food protein. Methods: In 16 T2D patients, we measured plasma AA levels through the course of two 75-g oral glucose tolerance tests (OGTT) preceded by either 500-ml water or a high-protein nutrient preload (50-g Parmesan cheese, one boiled egg, and 300-ml water). Changes in beta cell function were evaluated by measuring and modelling plasma glucose, insulin, and C-peptide through the OGTT. Changes in incretin hormone secretion were assessed by measuring plasma GLP-1. Results: Plasma AA levels were 24% higher after the nutrient preload (p < 0.0001). This increment was directly proportional to both the enhancement of beta cell function (r = 0.58, p = 0.02) and the plasma GLP-1 gradients (r = 0.57, p = 0.02) produced by the nutrient preload. Among single AA, glutamine showed the strongest correlation with changes in beta cell function (r = 0.61, p = 0.01), while leucine showed the strongest correlation with GLP-1 responses (r = 0.74, p = 0.001). Conclusions: The elevation of circulating AA that occurs after a high-protein nutrient preload is associated with an enhancement of beta cell function and GLP-1 secretion in T2D. Manipulating the meal sequence of nutrient ingestion may reduce postprandial hyperglycaemia through a direct and GLP-1-mediated stimulation of insulin secretion by plasma AA. Trial registration number: NCT02342834. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Recent studies have demonstrated that residual beta cells may be present in some people with long-standing type 1 diabetes, but little is known about the potential impact of this finding on alpha cell function and incretin levels. This study aimed to evaluate whether insulin microsecretion could modulate glucagon and glucagon-like peptide-1 (GLP-1) responses to a mixed meal tolerance test (MMTT).Methods: Adults with type 1 diabetes onset after the age of 15 years (n = 29) underwent a liquid MMTT after an overnight fast. Insulin microsecretion was defined when peak C-peptide levels were >30 pmol/l using an ultrasensitive assay. Four individuals with recent-onset type 1 diabetes were included as controls. Glucagon and GLP-1 responses were analysed according to C-peptide patterns.Results: We found comparable peak values, Δ0-max levels and AUCs of glucagon and GLP-1 responses in C-peptide-positive participants (n = 9) and C-peptide-negative participants (n = 16) with long-standing diabetes and in participants with recent-onset diabetes (n = 4). Mean glucagon levels, however, differed (p = 0.01). Mean GLP-1 responses were significantly lower according to C-peptide positivity (p < 0.001, ANOVA). Interestingly, GLP-1 levels correlated to glucagon values in C-peptide-positive participants with long-standing diabetes (Pearson's r = 0.915, p = 0.004) and in participants with recent-onset diabetes (p < 0.001) but not in C-peptide-negative participants.Conclusions/interpretation: The glucagon response to an MMTT in people with long-standing type 1 diabetes is not reduced by the presence of residual beta cells. The reduction of GLP-1 responses according to residual C-peptide levels suggests specific regulatory pathways. [ABSTRACT FROM AUTHOR]

Higher incidence of diabetes along with increased use of pesticides is seen in Southeast Asia. Recent hypothesis postulated a link between acetylcholinesterase inhibitor insecticides and type 2 diabetes through the GLP-1 pathway. This study compares the GLP-1 response between groups with low and high red blood cell acetylcholinesterase (RBC-AChE) activity. A comparative cross-sectional study was conducted amongst patients who were within 3 months after an acute organophosphate or carbamate poisoning (acute group) and amongst vegetable farmers with low (chronic group) and high (control group) RBC-AChE activity. Acute (366 mU/μM Hb) and chronic (361 mU/μM Hb) groups had significantly lower RBC-AChE activity in comparison to the control (471 mU/μM Hb) group (P < 0.0001). Only the acute group, which has had atropine therapy, showed a significantly lower 120 min value in comparison to the control group (P = 0.0028). Also, the acute group had significantly low late (P = 0.0287) and total (P = 0.0358) responses of GLP-1 in comparison to the control group. The findings of the study allude towards attenuation of GLP-1 response amongst patients after acute organophosphate and carbamate poisoning. The possibility of an atropine-mediated attenuation of GLP-1 response was discussed. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide 1-receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 inhibitors (incretin enhancers) have been recently introduced in the treatment of diabetes mellitus. In particular, incretin mimetics seems to have ancillary antioxidant/antinflammatory properties that might be involved in endothelial protection.Aim: To investigate the effect of incretin mimetic therapy (liraglutide, exenatide) given to 11 patients with type 2 diabetes mellitus, on circulating endothelial progenitor cells (EPCs) (bone marrow-derived cells possibly participating in neovascularization and endothelial protection and repair) and capillary density.Methods: Four diabetic patients were treated with exenatide (5 μg twice daily for 4 weeks and then 10 μg twice daily for 3 weeks) and 7 with liraglutide (0.6 mg per day for 1 week and then 1.2 mg per day for 3 weeks). Peripheral venous blood samples were obtained before treatment (basal) and after 4 week in patients treated with liraglutide, and after 4 and 7 weeks in patients treated with exenatide, since drug titration is usually longer. EPCs were evaluated by flow cytometry as CD34+/KDR+ cells. Capillary density was evaluated by videomicroscopy, before and after venous congestion, in the dorsum of the 4th finger.Results: Patients treated with liraglutide (6 males 1 female, age 54 ± 12 years) showed a decrease in body mass index and blood pressure during treatment, while patients treated with exenatide (3 males 1 female, age 57 ± 6 years) did not show any relevant change. EPCs were significantly increased after treatment with exenatide, but not after treatment with liraglutide. Capillary density was slightly increased only after 4 weeks of treatment with exenatide, however the increase was no longer present at the final evaluation.Conclusions: Treatment with exenatide, but not with liraglutide, was able to increase the number of circulating EPCs, possibly through an antioxidative/antiinflammatory effect. [ABSTRACT FROM AUTHOR]

Introduction: Adequate persistence to antidiabetic treatment is highly important to achieve proper glycemic control. In this study we evaluate the persistence to treatment with dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists in a nationwide cohort of patients with type 2 diabetes.Methods: Using a central database in Hungary, we analyzed the persistence to the treatment with dipeptidyl peptidase-4 inhibitors (n = 59,900), sodium-glucose co-transporter-2 inhibitors (n = 26,052), and glucagon-like peptide-1 receptor agonists (n = 17,332) at treatment intensification between 2014 and 2016. We also compared the persistence of dipeptidyl peptidase-4 inhibitors (n = 9163) and sodium-glucose co-transporter-2 inhibitors (n = 1257) in initial therapy to that of metformin (n = 79,305) or sulfonylureas (n = 29,057). The rates of persistence to treatment and risk of non-persistence are reported.Results: The persistence rates of dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists at treatment intensification were 69.6%, 67.8%, and 66.3% at year 1 which decreased to 57.3%, 56.8%, and 52.1% by year 2, respectively. The risk of non-persistence was higher by 6.6% (95% CI 3.6-9.6) for sodium-glucose co-transporter-2 inhibitors and by 8.3% (95% CI 5.0-11.5) for glucagon-like peptide-1 receptor agonists as compared to dipeptidyl peptidase-4 inhibitors. Novel oral antidiabetic drugs in fixed versus free add-on combinations with metformin had higher persistence. The persistence to treatment with novel oral antidiabetic drugs in initial therapy was better (dipeptidyl peptidase-4 inhibitors, 59.6% and 47.6%; sodium-glucose co-transporter-2 inhibitors, 61.9% and 47.0%) than that of initial monotherapy with metformin (47.0% and 39.1%) or sulfonylureas (52.4% and 41.8%) at years 1 and 2, respectively.Conclusion: Analysis of persistence of treatment with novel glucose-lowering medications revealed differences between drug classes, favoring dipeptidyl peptidase-4 inhibitors vs. sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Persistence data of novel antihyperglycemic agents may be useful for guiding the decision at initiation of antidiabetic treatment.Funding: Hungarian Diabetes Association.Plain Language Summary: Plain language summary available for this article. [ABSTRACT FROM AUTHOR]

Background: One of the new current treatment options for Diabetes Mellitus is about increasing glucagon-like peptide-1 (GLP-1) activity. GLP-1 with its incretin effect showed major role in glucose homeostasis. Gastroileostomy can increase GLP-1 secretion by rapid delivery of undigested food to the terminal ileum. We studied the early effects of a gastroileostomy on serum levels of GLP-1, glucose, and insulin in rats.Methods: Gastroileostomies with side-to-side anastomosis were performed on 15 male New Zealand rats. Blood samples were obtained before and 1 week after the gastroileostomy.Results: Our results showed that the rats lost a lot of weight from start (330 ± 15 g) to the end (240 ± 25 g) of the experiment (p = 0.048). The data analysis showed that the gastroileostomy surgery elevates the level of GLP-1in plasma significantly (89.1852 vs. 177.440 respectively; p < 0.001) and caused a significant decrease in plasma glucose as well (92.00 and 66.29 mg/dL respectively; p < 0.001). However, the insulin state elevated after the surgery significantly (8.03 vs. 9.89; p < 0.001).Conclusion: In this study, we showed the effectiveness of gastroileostomy treatment to decrease body weight and plasma glucose with increased GLP-1 in rats. This small rat model suggests the potential of this surgery to treat type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear.Methods: The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism.Results: GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet.Conclusion: RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM. [ABSTRACT FROM AUTHOR]

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications. [ABSTRACT FROM AUTHOR]

The relationship between the rs2302382, rs8111428 and Glu354Gln (rs1800437) polymorphisms in the GIPR (glucose-dependent insulinotropic polypeptide receptor) gene and plasma levels of mediators involved in the regulation of carbohydrate metabolism has been investigated in obese patients with type 2 diabetes mellitus (T2DM) before and after test breakfast. The contribution of the polymorphic variants of rs2302382, rs8111428 in the GIPR gene contributed to T2DM genetic predisposition in Russian individuals belonging to the Slavic population. Polymorphisms rs2302382 and rs8111428 in the GIPR gene were characterized by the linkage disequilibrium. The decrease in the expression level of the GIPR gene in mesenteric adipose tissue of the small intestine in the carriers of the CC genotype rs2302382 and AA rs8111428 was associated with the increase in the plasma leptin level, whereas during its normal expression, the plasma content of insulin, and GIP (in persons with the CA genotype of the polymorphism rs2302382 and AG polymorphism rs8111428), resistin and ghrelin (in individuals with the CA genotype of the polymorphism rs2302382) increased. We propose the stimulating effect of GIP on the secretion of resistin, leptin and ghrelin, with an increase in insulin production in obese patients with T2DM. [ABSTRACT FROM AUTHOR]

Purpose: Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants.Method: In a randomised, single-dose, open-label, three-treatment, three-period, three-sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions. PK parameters (Cmax, Tmax, AUC0-∞ and t1/2) were determined using Phoenix WinNonlin software. PD parameters [DPP-IV inhibition, active glucagon-like peptide-1 (GLP-1) and insulin] were determined using established methods.Results: PK parameters expressed in mean (SD) were Cmax 491.7 (135.9) ng/mL; AUC0-∞ 4256.1 (509.9) ng· hr/mL, Tmax 2.9 (1.0) hr and t1/2 10.4 (3.0) hr. The weighted average (WA) plasma DPP-4 inhibition over 24 h was 89.6% and WA of plasma active GLP-1 over 2 h after standardised meal (geometric mean ratio) was 11.1 (9.9) pM/L which is two- to- four fold higher compared to that reported in other populations. The mean average (SD) AUC of plasma insulin over 2 h of standardised meal was 47.9 (24.9) μIU/mL.Conclusion: Although, there are differences in pharmacokinetic parameters, no clinically meaningful differences were observed with respect to DPP-IV inhibition between Indian and non-Indian population. [ABSTRACT FROM AUTHOR]

Therapies to prevent diabetes in particular the progressive loss of β-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the β-cells; it normalizes β-cell sensitivity to glucose, has an antiapoptotic role, stimulates β-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post-secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP-1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non-invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Human physiology provides an integral description for mechanisms of the entire spectrum of functions in the human body. Successful work of the mechanisms requires a highly stabilized internal environment, which is continuously created by visceral organs under the influence of nerve impulses, hormones, incretins, and autacoids. The review discusses the physicochemical parameters of the human internal environment and new possibilities of clearance methods with the involvement of kidneys in homeostatic processes. [ABSTRACT FROM AUTHOR]