peptide-yy and Diabetes-Mellitus--Type-2

Glucagon-like peptide-1 (GLP-1)-based medication is now widely employed in the treatment of type 2 diabetes and obesity. Like other gut hormones, GLP-1 is released from eneteroendocrine cells after a meal and in this review, based on the Dorothy Hodgkin lecture delivered during the annual meeting of Diabetes UK in 2023, I argue that there is sufficient spare capacity of GLP-1 and other gut hormone expressing cells that could be recruited therapeutically. Years of research has revealed several receptors expressed in enteroendocrine cells that could be targeted to stimulate hormone release: although from this research it seems unlikely to find agents that selectively boost GLP-1, release of a mixture of hormones might be the more desirable outcome anyway, given the recent promising results of new peptides combining GLP1-receptor with other gut hormone receptor activation. Alternatively, the fact that GLP-1 and peptideYY (PYY) expressing cells are found in greater density in the ileum might be exploited by increasing the delivery of chyme to the distal small intestine.

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Ileum; Peptide YY

Peptide YY (PYY) is a gastrointestinal hormone consisting of 36 amino acids, that is predominantly secreted by intestinal l-cells. Originally extracted from pig intestines, it belongs to the pancreatic polypeptide (PP) family, but has functions distinct from those of PP and neuropeptide Y (NPY). PYY is a potential treatment for type 2 diabetes mellitus (T2DM) because of its ability to delay gastric emptying, reduce appetite, decrease weight, and lower blood glucose. However, the clinical use of PYY is limited because it is rapidly cleared by the kidneys and degraded by enzymes. In recent years, researchers have conducted various structural modifications, including amino acid substitution, PEGylation, lipidation, and fusion of PYY with other proteins to prolong its half-life and enhance its biological activity. This study presents an overview of the recent progress on PYY, including its physiological functions, metabolites and structure-activity relationships.

Topics: Amino Acid Substitution; Amino Acids; Animals; Diabetes Mellitus, Type 2; Obesity; Peptide YY; Swine

Obesity is one of the major global threats to human health and risk factors for cardiometabolic diseases and certain cancers. Glucagon-like peptide-1 (GLP-1) plays a major role in appetite and glucose homeostasis and recently the USFDA approved GLP-1 agonists for the treatment of obesity and type 2 diabetes. GLP-1 is secreted from enteroendocrine L-cells in the distal part of the gastrointestinal (GI) tract in response to nutrient ingestion. Endogenously released GLP-1 has a very short half-life of <2 min and most of the nutrients are absorbed before reaching the distal GI tract and colon, which hinders the use of nutritional compounds for appetite regulation. The review article focuses on nutrients that endogenously stimulate GLP-1 and peptide YY (PYY) secretion via their receptors in order to decrease appetite as preventive action. In addition, various delivery technologies such as pH-sensitive, mucoadhesive, time-dependent, and enzyme-sensitive systems for colonic targeting of nutrients delivery are described. Sustained colonic delivery of nutritional compounds could be one of the most promising approaches to prevent obesity and associated metabolic diseases by, e.g., sustained GLP-1 release.

Topics: Appetite; Colon; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Nutrients; Obesity; Peptide YY

In this review, authors have selected from literature the most recent and suggestive studies on therapy of nonalcoholic fatty liver disease (NAFLD). The selected interventions regulate the action of gastrointestinal peptides, such as gastric inhibitory polypeptide (GIP), nesfatin, peptide YY, cholecystokinin, and glucagon-like peptide 1 (GLP-1). These hormones have been found frequently modified in obesity and/or type 2 diabetes mellitus, morbidities mostly associated with NAFLD. This disease has a very high prevalence worldwide and could evolve in a more severe form, that is, nonalcoholic steatohepatitis, characterized by inflammation and fibrosis. The findings shown by this article describe the metabolic effects of new drugs, mainly but not only, as well of some old substances.. Recent approaches, in animal models or in humans, use synthetic GLP-1 receptor agonists, a centrally administered antibody neutralizing GIP receptor, curcumin, compound being active on nesfatin, resveratrol (antiinflammatory agent), and Ginseg, both of them acting on nesfatin, a cholecystokinin receptor analogue, and finally coffee functioning on YY peptide.. The implications of the presented findings, if they are confirmed in larger clinical trials, likely open the door to future application in clinical practice. In fact, nowadays, patients have only diet and article (incl abstract and keywords) exercise as well accepted recommendations. Thus, there are unmet needs to find substances that could really improve the progression of nonalcoholic steatohepatitis toward liver cirrhosis and hepatocellular carcinoma.

Topics: Animals; Diabetes Mellitus, Type 2; Drugs, Investigational; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Peptide YY; Phytochemicals; Phytotherapy

Obesity represents an important public health challenge for the twenty-first century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy, and as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1's therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY

A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Food-Drug Interactions; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Obesity; Peptide YY; Secretagogues

Bariatric surgery in obese individuals leads to rapid and lasting remission of type 2 diabetes (T2D). This phenomenon occurs independently of weight loss possibly via a combination of factors. The incretin hormone GLP-1 has so far been recognised as a critical factor. However, recent data have indicated that elevation in another gut hormone, peptide tyrosine tyrosine (PYY), may drive the beneficial effects of surgery. Here we discuss recent findings on PYY-mediated control of glucose homeostasis and its role in diabetes, in the context of what is known for GLP-1. Identification of factors that increase the expression of PYY following bariatric surgery and elucidation of its role in diabetes reversal may have clinical relevance as a nonsurgical therapy for T2D.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucose; Homeostasis; Humans; Islets of Langerhans; Peptide YY

Gut hormones have long been understood to regulate food intake and metabolism. Bariatric surgery significantly elevates circulating gut hormone levels and is proven to affect acute remission of type 2 diabetes before any weight loss is observed. Subsequent weight loss is accrued over weeks to months but is sustained into the long term. Hence, there exists great enthusiasm to recapitulate these changes in gut hormones in the form of novel combination drugs for type 2 diabetes and obesity.

Topics: Animals; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Peptide YY

The effects of non-nutritive sweeteners (NNS) on glucose metabolism and appetite regulating hormones are not clear. There is an ongoing debate concerning NNS use and deleterious changes in metabolism.. The aim of this review is to analyze the scientific available evidence regarding the effects of NNS on glucose metabolism and appetite regulating hormones.. We identified human observational studies evaluating the relation between NNS consumption and obesity, diabetes, and metabolic syndrome, in addition to clinical trials evaluating the effects of NNS in glucose metabolism and appetite regulating hormones.. Fourteen observational studies evaluating the association between NNS consumption and the development of metabolic diseases and twenty-eight clinical trials studying the effects of NNS on metabolism were included. Finally, two meta-analyses evaluating the association between the consumption of NNS-containing beverages and the development of type 2 diabetes were identified.. Some observational studies suggest an association between NNS consumption and development of metabolic diseases; however, adiposity is a confounder frequently found in observational studies. The effects of the NNS on glucose metabolism are not clear. The results of the identified clinical trials are contradictory and are not comparable because of the major existing differences between them. Studies evaluating specific NNS, with an adequate sample size, including a homogeneous study group, identifying significant comorbidities, with an appropriate control group, with an appropriate exposure time, and considering adjustment for confounder variables such as adiposity are needed.

Topics: Carbonated Beverages; Cholecystokinin; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Ghrelin; Glucose; Humans; Non-Nutritive Sweeteners; Observational Studies as Topic; Peptide YY; Prospective Studies

Obesity is a disease that develops as a result of long-term positive energy balance. In recent years, the influence of gut microflora composition, as a potential factor affecting the energy balance and contributing to fat accumulation, has been studied. It seems that bacteria can affect host energy balance through several mechanisms, such as increased fermentation of undigested polysaccharides and obtaining extra energy from the portion of food, reduced expression of FIAF (fasting-induced adipocyte factor) in the enterocytes with inhibitory activity towards intestinal lipoprotein lipase, and the increased release of peptide YY that slows the intestinal motility. It is also believed that changes in the composition of gut microflora may be one of the factors that induce systemic microinflammation in the obese, an important link in the pathogenesis of obesity related complications, including dyslipidaemia, hypertension and type 2 diabetes. However, the results of previous studies are inconclusive. Many of them have been carried out in an animal model and were not confirmed in studies involving humans. These discrepancies may be due to different composition of the diet, distinct physiological gut microflora and the methodology used in these studies. The present article reviews the current literature on the potential role of gut microflora in the pathogenesis of obesity.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Dyslipidemias; Energy Metabolism; Enterocytes; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Hypertension; Intestines; Lipase; Microbiota; Obesity; Peptide YY

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Topics: Bariatric Surgery; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Homeostasis; Humans; Incretins; Insulin Resistance; Male; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Weight Loss

Obesity continues to be a major public health problem in the United States and worldwide. While recent statistics have demonstrated that obesity rates have begun to plateau, more severe classes of obesity are accelerating at a faster pace with important implications in regards to treatment. Bariatric surgery has a profound and durable effect on weight loss, being to date one of the most successful interventions for obesity.. To provide updates to the possible role of gut hormones in post bariatric surgery weight loss and weight loss maintenance.. The current review examines the changes in gastro-intestinal hormones with bariatric surgery and the potential mechanisms by which these changes could result in decreased weight and adiposity.. The mechanism by which bariatric surgery results in body weight changes is incompletely elucidated, but it clearly goes beyond caloric restriction and malabsorption.. Changes in gastro-intestinal hormones, including increases in GLP-1, PYY, and oxyntomodulin, decreases in GIP and ghrelin, or the combined action of all these hormones might play a role in induction and long-term maintenance of weight loss.

Topics: Bariatric Surgery; Bile Acids and Salts; Caloric Restriction; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Oxyntomodulin; Peptide YY; Postoperative Period; United States; Weight Loss

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Topics: Appetite; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Milk Proteins; Obesity; Peptide YY; Thermogenesis; Whey Proteins

Bariatric surgery managing/preventing complications of severe overweight is nowadays widely accepted as a mainstay in the treatment of morbid obesity. Its role is particularly important in type 2 diabetes developing on the base of long-standing significant overweight. The glycemic control improves within days-weeks after these surgeries, when weight loss and reduction of the visceral fat mass is barely detectable. This short term effect is probably due to an increased secretion of glucagon-like peptide and, as a consequence, an improvement in hepatic insulin sensitivity as well as the whole body glucose uptake. Besides the prolonged glucagon-like peptide effects, the favourable long term effect of these operations - lasting for 10 years even after surgery - is the decrease of visceral fat mass and elimination of harmful influence of cytokines produced by the fatty tissue. The article overviews the metabolic effects of these procedures, their undoubted advantages and potential risks.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Hungary; Insulin; Insulin Resistance; Intra-Abdominal Fat; Male; Obesity, Morbid; Peptide YY; United States; Weight Loss

Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Digestive System; Energy Metabolism; Food; Ghrelin; Glucagon-Like Peptides; Homeostasis; Humans; Obesity; Oxyntomodulin; Peptide YY

The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin Resistance; Metabolic Diseases; Metagenome; Obesity; Peptide YY

Behavioral and pharmaceutical intervention to treat obesity and its comorbidities typically results in only a 5-10% weight loss. Thus, bariatric surgery is the most effective obesity treatment with some surgeries resulting in 30% sustained weight loss. Although this degree of weight loss has profound metabolic impact, these surgeries seem to have metabolic effects that are independent of weight loss. In support of this is the clinical literature showing rapid resolution of Type 2 diabetes mellitus (T2DM) that occurs before significant weight loss. To gain a complete understanding of the weight loss-independent effects of bariatric surgery, animal models have been developed. These are becoming more widely implemented and allow the use of pair-fed or weight-matched sham-operated controls in order to gain mechanistic insights into the mode of action of bariatric surgery. Increases in anorectic gut hormones, such as glucagon-like peptide-1 and peptide YY, or decreases in the orexigenic hormone ghrelin have been seen and are implicated as mediators of weight loss-independent actions of bariatric surgery. Changes in nutrient processing and sensing may also have a mechanistic role that is independent of, or that regulates, gut hormone responses to these surgeries. Ultimately, the hope is that understanding the mechanisms of bariatric surgeries will aid in the development of less invasive surgeries or pharmacological therapies that are more specifically, and perhaps individually, targeted at weight loss and/or resolution of T2DM.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Malabsorption Syndromes; Peptide YY; Weight Loss

The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Peptide YY; Weight Loss

Bariatric surgery is the most effective treatment modality for obesity, resulting in durable weight loss and amelioration of obesity-associated comorbidities, particularly type 2 diabetes mellitus (T2DM). Moreover, the metabolic benefits of bariatric surgery occur independently of weight loss. There is increasing evidence that surgically induced alterations in circulating gut hormones mediate these beneficial effects of bariatric surgery. Here, we summarise current knowledge on the effects of different bariatric procedures on circulating gut hormone levels. We also discuss the theories that have been put forward to explain the weight loss and T2DM resolution following bariatric surgery. Understanding the mechanisms mediating these beneficial outcomes of bariatric surgery could result in new non-surgical treatment strategies for obesity and T2DM.

Topics: Bariatric Surgery; Caloric Restriction; Diabetes Mellitus, Type 2; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Weight Loss

This review analyzes the literature concerning gut peptides and bariatric surgery, from 2005 to July 2009. In particular, we are interested in whether, and how, gastrointestinal peptide alterations following surgery interfere with appetite/satiety, and what role they might play in the resolution of comorbidities.. PubMed/MEDLINE and ISI Web of Knowledge were used to search for human studies concerning gut peptides profiles after any bariatric operation technique.. Most of the studies reviewed had longitudinal design, short follow-up, and low statistical power. The diversity of study results may be partially explained by methodological aspects. Glucagon-like peptide-1, gastric inhibitory peptide, and peptide YY alterations may contribute to the excellent results in glycemic control of diabetics. Results do vary depending on bariatric operation technique; this is particularly evident in the case of ghrelin, which has been much studied in recent years. Ghrelin suppression has been linked to increased satiety, alterations in energy homeostasis, and better glucose metabolism.. There is a lack of long-term data on gastrointestinal hormone profiles after bariatric surgery and the studies have many methodological pitfalls. We still need prospective, long-term, good methodological studies in this area.

Topics: Appetite Regulation; Bariatric Surgery; Diabetes Mellitus, Type 2; Energy Metabolism; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Obesity, Morbid; Peptide Hormones; Peptide YY; Satiation

Metabolic pathologies such as Type 2 Diabetes have become a major health problem for worldwide populations. Unfortunately, efforts to cure and especially to prevent these significant global problems have so far been met with disappointment. Recently, the involvement of the gut-derived hormonal dysregulation in the development of obesity-related disturbances has been intensively studied. For instance, studies of gut-derived peptides such as peptide YY 3-36, glucagon-like peptide-1, oxyntomodulin and, more recently, ghrelin have significantly improved our understanding of mechanisms underlying weight and metabolic regulation. Even though early reports of the existence of secretin, the first peptide hormone to be described, date back as far as 1825, so much and yet so little is still known about its physiological role in mammals, including humans. However, recent years have provided a better understanding of how the release of secretin is regulated by enteral secretagogues. On the other hand, most basic questions about its role in the post-prandial regulation of metabolic functions in normal and pathophysiological conditions remain to be elucidated. The present work intends to review the physiology of secretin along with its central and peripheral outcomes on metabolic functions.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Type 2; Humans; Peptide Fragments; Peptide YY; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Secretin; Tissue Distribution

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

Topics: Animals; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Bypass; Gastric Emptying; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose; Homeostasis; Humans; Incretins; Intestine, Small; Leptin; Liver; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Weight Loss

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Since adipose tissue was shown to be more than a storage organ, the many cytokines it produces have been identified, along with their roles in energy homeostasis, appetite, and insulin resistance. Concurrently, numerous gut hormones with a diversity of effects have been discovered. They include, amongst many others, peptide YY, ghrelin and oxyntomodulin. As these peptides have been investigated, the potential for their use as novel anti-obesity and antidiabetic therapies has been realized. In this chapter we describe the actions of four of the peptides that have been proposed as the basis for promising new therapies for diabetes: leptin, adiponectin, obestatin and peptide YY. They each have an effect on appetite and, directly or indirectly, on glucose metabolism. We synthesize available data for these peptides and consider the therapeutic potential of each.

Topics: Adiponectin; Animals; Appetite; Diabetes Mellitus, Type 2; Ghrelin; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Leptin; Oxyntomodulin; Peptide YY

Morbid obesity is a serious health problem associated with disease and mortality. One such disease is non-insulin-dependent diabetes mellitus (NIDDM). Approximately 95% of American diabetics have NIDDM. One of the major causes for type 2 diabetes is obesity. The improvement of diabetes with weight control is not in the earliest description of the disease. However, dietary control of NIDDM is often disappointing. Diet can improve glucose metabolism in obesity, but the improvement usually represents only a portion or a brief return to euglycemia, even when patients appear to be compliant. In contrast, reversal of NIDDM has been much more successfully achieved after bariatric surgery. Intra-abdominal fat deposition is associated with increased plasma concentration of free fatty acids, which reduce insulin sensitivity at both muscular and hepatic sites. The progression of diabetes is heralded by the inability of the beta-cells to maintain their previously high rate of insulin secretion in response to glucose, in the face of insulin resistance. The propensity to develop type 2 diabetes may be genetically determined or triggered by environmental factors. The connection between diabetes and obesity represents a continuum that progresses through different phases in which defective insulin action is the principal problem. At this point, we are unable to correlate the different findings of the many questions that arise, such as: 1) Does the decrease in sensitivity to insulin result from rearrangement of the insulin receptor? 2) Is weight loss the trigger for decrease of insulin resistance? 3) Is rearrangement of part of the intestine a mechanism to trigger the secretion of hormones (incretins) that help in insulin response? 4) Which mechanism controls the insulin resistance? The goal of this paper is to review literature on incretins and address the role of incretins after bariatric surgery. We know very little about the action of incretins in diabetes. We will assess the interaction between the secretion of incretins and bariatric surgery for the cure of diabetes.

Topics: Acyl Coenzyme A; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Lipolysis; Obesity, Morbid; Peptide Fragments; Peptide Hormones; Peptide YY; Protein Precursors

Glycemic control, after metabolic surgery, is achieved in two stages, initially with neuroendocrine alterations and in the long-term with sustainable weight loss. The resection of the gastric fundus, as the major site of ghrelin production, is probably related with optimized glucose regulation. The aim of the present study is to investigate whether the modification of laparoscopic Roux-en-Y gastric bypass (LRYGBP) with fundus resection offers superior glycemic control, compared to typical LRYGBP.. Participants were 24 patients with body mass index (BMI) ≥40kg/m. Ninety-five percent of patients showed complete remission of T2DM after 12 months. LRYGBP+FR was not related with improved glycemic control, compared to LRYGBP. Ghrelin levels were not significantly reduced at 6 and 12 months after LRYGBP+FR. GLP-1 and PYY levels were remarkably increased postprandially in both groups at 6 and 12 months postoperatively (p<0.01). Patients who underwent LRYGBP+FR achieved a significantly lower BMI at 12 months in comparison to LRYGBP (p<0.05).. Fundus resection is not associated with improved glycemic regulation, compared to typical LRYGBP and the significant decrease in BMI after LRYGBP+FR has to be further confirmed with longer follow-up.

Topics: Diabetes Mellitus, Type 2; Gastric Bypass; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Laparoscopy; Obesity, Morbid; Peptide YY

The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery.. To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD).. Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups.. Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery.. Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention.. Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB.. Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.

Topics: Adult; Aged; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Infusions, Subcutaneous; Male; Metabolomics; Middle Aged; Obesity, Morbid; Oxyntomodulin; Peptide YY; Single-Blind Method; Treatment Outcome; Weight Loss; Young Adult

To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity.. The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: -8.6 [-28.6 to 11.4], 13.4 [-6.1 to 33.0] and 1.0 [-18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions.. In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy.. NCT02798744, www.. gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.

Topics: Adult; Aged; Appetite; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Double-Blind Method; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucosides; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Overweight; Peptide YY; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

The consumption of blueberries, as well as the phenolic compounds they contain, may alter metabolic processes related to type 2 diabetes. The study investigated the effects of adding 140 g of blueberries to a higher-carbohydrate breakfast meal on postprandial glucose metabolism, gastrointestinal hormone response, and perceived appetite. As part of a randomized crossover design study, 17 healthy adults consumed a standardized higher-carbohydrate breakfast along with 2 treatments: (1) 140 g (1 cup) of whole blueberries and (2) a placebo gel (matched for calories, sugars, and fiber of the whole blueberries). Each subject participated in two 2-h meal tests on separate visits ≥8 days apart. Venous blood samples and perceived appetite ratings using visual analog scales were obtained prior to and at 30, 60, 90, and 120 min after consuming the breakfast meals. Results show that glucose metabolism, several gastrointestinal hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) concentrations and perceived appetite did not change significantly with blueberry consumption. However, pancreatic polypeptide (PP) concentrations were statistically significantly higher (

Topics: Adult; Appetite; Blood Glucose; Blueberry Plants; Breakfast; Cross-Over Studies; Diabetes Mellitus, Type 2; Energy Intake; Female; Fruit; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Pancreas; Pancreatic Polypeptide; Peptide YY; Polyphenols; Postprandial Period; Reference Values; Young Adult

Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity.. In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (. GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Male; Meals; Middle Aged; Obesity; Oxyntomodulin; Peptide YY; Postprandial Period; Prediabetic State; Single-Blind Method; Weight Loss

Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.

Topics: Adult; Aged; Body Weight; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Pancreatic Polypeptide; Peptide YY; Time Factors; Treatment Outcome

The purpose of this study is to compare the effect of diabetes control induced by Roux-en-Y gastrojejunostomy(RY) vs Billroth-I reconstruction(BI) after distal gastrectomy in patients with early gastric cancer(EGC) and type 2 diabetes(T2DM). Forty EGC patients with T2DM, aged 20-80 years, who were expected to undergo curative distal gastrectomy were randomized 1:1 to RY(n = 20) or BI(n = 20). Diabetes medication status, biochemical and hormonal data including blood glucose, HbA1c, insulin, C-peptide, HOMA-IR, ghrelin, leptin, GLP-1, PYY, and GIP were evaluated for 12 months after surgery. Although pre- and postoperative 12-month fasting and postprandial glucose levels did not show a significant difference, HbA1c, C-peptide, and HOMA-IR levels were significantly improved at 12 months after surgery in both BI and RY groups. Sixty percent of RY patients and 20% of BI patients decreased their medication satisfying FBS<126 mg/dL and HbA1c<6.5% and 5% of BI patients stopped their medication satisfying the criteria of FBS<126 mg/dL and HbA1c<6.0%. The improvement patterns were more sustainable with less fluctuation in RY than in BI. On hormonal analysis, ghrelin and leptin levels were decreased and PYY and GIP levels were increased at 12 months after surgery in both groups without significant difference according to the reconstruction type and diabetic improvement status except ghrelin. In gastric cancer surgery, RY reconstruction showed better and more durable diabetes control compared to BI during the first year after surgery. Gastric cancer surgery led to decreased ghrelin and leptin and increased PYY and GIP, which might have a role in improving insulin resistance and glucose homeostasis.

Topics: Aged; Diabetes Mellitus, Type 2; Duodenum; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Male; Middle Aged; Peptide YY; Prospective Studies; Stomach; Stomach Neoplasms; Treatment Outcome

GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics.. Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues.. By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA.. We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

Topics: Attention; Brain; Cross-Over Studies; Cues; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Functional Neuroimaging; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Hypoglycemic Agents; Image Processing, Computer-Assisted; Leptin; Liraglutide; Magnetic Resonance Imaging; Male; Middle Aged; Peptide YY; Reward

Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY. In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY. Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY

Topics: Appetite; Appetite Regulation; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Eating; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Obesity, Morbid; Peptide Fragments; Peptide YY; Treatment Outcome; Weight Loss

Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.. Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.. Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.. Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Topics: Acetates; Adult; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diacylglycerol O-Acyltransferase; Diarrhea; Dose-Response Relationship, Drug; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Intestinal Absorption; Male; Middle Aged; Obesity; Peptide YY; Pyrazines; Treatment Outcome; Weight Loss

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.. Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Mesylates; Metformin; Middle Aged; Oxadiazoles; Peptide YY; Prognosis; Pyrazines; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Triazoles

Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.. www.ClinicalTrials.gov NCT01357876.

Topics: Adolescent; Adult; Aged; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Intestinal Mucosa; Intestines; Male; Metformin; Microbiota; Middle Aged; Peptide YY

Rosiglitazone often results in weight gain. We hypothesized that rosiglitazone may modulate circulating levels of ghrelin and peptide YY(3-36) and this modulation may be related to weight-gaining effect of this agent. This study was designed as an open-label, randomized, controlled trial of 3-month duration. Women with newly diagnosed type 2 diabetes were studied. Twenty-eight of the 55 eligible participants were randomly assigned to receive rosiglitazone (4 mg/d). Twenty-seven patients with diabetes matched for age and body mass index served as controls on diet alone. We evaluated the effects of 3 months of rosiglitazone treatment on fasting peptide YY(3-36) and ghrelin levels, and anthropometric measurements. The 3-month administration of rosiglitazone reduced fasting plasma peptide YY(3-36) levels by 25%, the between-group difference was statistically significant. No effect of this thiazolidinedione compound on fasting ghrelin concentrations was observed at the end of study. The ghrelin/body mass index ratio also did not change significantly after treatment. Seventy-five percent of the women with diabetes complained of increased hunger at the end of study. Nevertheless, all subjects exhibited a decrease in fasting PYY levels after 3 months of rosiglitazone therapy, irrespective of the levels of hunger. There was no significant correlation between changes in peptide YY(3-36) and those in anthropometric parameters and insulin sensitivity at the end of the study. Rosiglitazone-induced decrease in fasting peptide YY(3-36) levels may in part contribute to orexigenic and weight-gaining effect of this thiazolidinedione derivative.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Down-Regulation; Fasting; Female; Humans; Middle Aged; Peptide YY; Rosiglitazone; Thiazolidinediones; Weight Gain

In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes.. Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects.. GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group.. Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Carbonated Beverages; Child; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Humans; Male; Peptide YY; Young Adult

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Topics: Administration, Oral; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Glycosides; Humans; Hypoglycemic Agents; Intestinal Absorption; Male; Middle Aged; Peptide YY; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

Laparoscopic Roux-en Y-Gastric bypass (LRYGBP) is the commonest available option for the surgical treatment of morbid obesity. Weight loss following bariatric surgery has been linked to changes of gastrointestinal peptides, shown to be implicated also in metabolic effects and appetite control. The purpose of this study was to evaluate whether gastric fundus resection in patients undergoing LRYGBP enhances the efficacy of the procedure in terms of weight loss, glucose levels, and hormonal secretion.. Twelve patients underwent LRYGBP and 12 patients LRYGBP plus gastric fundus resection (LRYGBP+FR). All patients were evaluated before and at 3, 6, and 12 months postoperatively. Blood samples were collected after an overnight fast and 30, 60, and 120 min after a standard 300-kcal mixed meal.. Body weight and body mass index decreased markedly and comparably after both procedures. Fasting ghrelin decreased 3 months after LRYGBP, but increased at 12 months to levels higher than baseline while after LRYGBP+FR was markedly and persistently decreased. Postprandial GLP-1, PYY, and insulin responses were enhanced more and postprandial glucose levels were lower after LRYGBP+FR compared to LRYGBP. Postoperatively, ghrelin changes correlated negatively with GLP-1 changes.. Resection of the gastric fundus in patients undergoing LRYGBP was associated with persistently lower fasting ghrelin levels; higher postprandial PYY, GLP-1, and insulin responses; and lower postprandial glucose levels compared to LRYGBP. These findings suggest that fundus resection in the setting of LRYGBP may be more effective than RYGBP for the management of morbid obesity and diabetes type 2.

Topics: Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Gastric Fundus; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Obesity, Morbid; Peptide YY; Postprandial Period; Weight Loss

To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes.. A double-blinded, placebo-controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add-on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90-min 20 mM hyperglycaemic clamp with 5 g of l-arginine infusion. Main outcome measure was postprandial total glucagon-like peptide 1 (GLP-1) concentration. Additional measures were insulin and C-peptide, glycaemic control, intact and total peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP), and intact glucagon-like peptide 2 (GLP-2) and GLP-1.. All patients [sitagliptin n = 12, age: 59.5 (39-64) years, HbA1c: 8.0 (7.3-10.0)%, BMI: 33.2 (29.3-39.4); placebo n = 12, age: 60 (31-72) years, HbA1c: 7.7 (7.1-9.8)%, BMI: 30.7 (25.7-40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP-1, GIP or intact GLP-2, but reduced total PYY and PYY(3- 36), and increased PYY(1- 36) and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group.. The postprandial responses of total GLP-1 and GIP and intact GLP-2 were unaltered. PYY degradation was prevented. Glucose and non-glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Metformin; Middle Aged; Peptide YY; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Triazoles

To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3-36 (PYY3-36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3-36 levels.. The increased PYY3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery.. Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10).. : PYY3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 +/- 34.4 pg/mL vs. 39.9 +/- 21.1 pg/mL; P < 0.05). PYY3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 +/- 20.5 pg/mL-132.7 +/- 49.7 pg/mL; P < 0.001; AUC0-180: 51.5 +/- 23.3 pg/mL x min-91.1 +/- 32.2 pg/mL x min P < 0.001), but not after diet (peak: 85.5 +/- 51.9 pg/mL-84.8 +/- 41.13 pg/mL; P = NS; AUC0-180: 68.3 +/- 38.5 pg/mL x min-61.1 +/- 42.2 pg/mL.min P = NS). Fasting ghrelin levels increased after diet (425 +/- 91 pg/mL-519 +/- 105 pg/mL; P < 0.05), but did not change after GBP (506 +/- 121 pg/mL-482 +/- 196 pg/mL; P = NS).. Diabetes status seems to be a determinant of PYY3-36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3-36 levels. The increase in stimulated PYY3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.

Topics: Adult; Body Mass Index; Caloric Restriction; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Ghrelin; Humans; Leptin; Middle Aged; Obesity, Morbid; Peptide Fragments; Peptide YY; Weight Loss

We tested the hypothesis that variants in the gene encoding the prepropeptide YY (PYY) associate with type 2 diabetes and/or obesity. Mutation analyses of DNA from 84 patients with obesity and familial type 2 diabetes identified two polymorphisms, IVS3 + 68C>T and Arg72Thr, and one rare variant, +151C>A of PYY. The common allele of the Arg72Thr variant associated with type 2 diabetes with an allele frequency of the Arg allele of 0.667 (95% CI 0.658-0.677) among 4,639 glucose-tolerant subjects and 0.692 (0.674-0.710) among 1,326 patients with type 2 diabetes (P = 0.005, odds ratio 1.19 [95% CI 1.05-1.35]). The same polymorphism associated with overweight (25 < or = BMI < 30 kg/m2) (P = 0.018, 1.15 [1.02-1.28]). In quantitative trait analyses of a population-based sample of 6,022 subjects, the Arg allele was associated with an increased plasma glucose level 2 h after an oral glucose tolerance test (OGTT) (P = 0.03), an increased area under the curve for the post-OGTT plasma glucose level (P = 0.03), and a lower insulinogenic index (P = 0.01). In conclusion, the common Arg allele of the PYY Arg72Thr variant modestly associates with type 2 diabetes and with type 2 diabetes-related quantitative traits.

Topics: Arginine; Body Mass Index; Diabetes Mellitus, Type 2; DNA; DNA Mutational Analysis; Female; Humans; Male; Obesity; Odds Ratio; Pedigree; Peptide YY; Polymorphism, Genetic; Risk Factors; Sequence Deletion

Peptide YY (PYY) is a recently discovered peptide found in the distal ileum and colon. It circulates in plasma and concentrations rise in malabsorptive conditions. The potential of PYY as an indicator of impaired carbohydrate digestion was studied in a pharmacological model of intestinal glucosidase inhibition. Thirteen type-2 diabetics on long-term treatment with the alpha-glucosidase inhibitor acarbose (3 x 100 mg per day) had test meals with and without acarbose 100 mg before and after the treatment period (mean 46 weeks), a test meal with acarbose after 20 weeks of continuous treatment and a final test meal without acarbose 6 weeks after cessation of treatment. Without acarbose mean plasma PYY concentrations rose from a mean basal value of 11.5 +/- 2.9 pmol/l to 19.5 +/- 3.9 pmol/l 120 min postprandially (P less than 0.01). Acarbose treatment did not effect basal plasma PYY concentrations but significantly enhanced food stimulated PYY concentrations acutely, at 20 weeks and at the final treatment test meal. Mean incremental integrated plasma responses (area under curve) rose by 183%, 184% and 169%, respectively (P less than 0.05). After cessation of treatment postprandial responses returned to pretreatment values within 6 weeks. Conversely, the integrated incremetal postprandial plasma responses of glucose and insulin were reversibly reduced by acarbose to 58% +/- 9% and 60% +/- 10% of controls, respectively. Self-assesed side effects of flatulence and more frequent bowel action showed no regular relationship to the PYY response. PYY seems to act as an indicator of the increased carbohydrate load to the distal intestine even in the absence of clinical symptoms. It may contribute to the hypoglycaemic effect of alpha-glucosidase inhibitors by slowing down intestinal transit.

Topics: Acarbose; Adult; Aged; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Middle Aged; Peptide YY; Peptides; Time Factors; Trisaccharides

More than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls.. Sixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed.. Participants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower.. Patients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Pancreatitis, Chronic; Peptide YY

The disturbance of intestinal microorganisms and the exacerbation of type 2 diabetes (T2D) are mutually influenced. In this study, the effect of exopolysaccharides (EPS) from

Topics: Animals; Bacterial Adhesion; Blood Glucose; Caco-2 Cells; Diabetes Mellitus, Type 2; Energy Metabolism; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Inflammation; Interleukin-10; Interleukin-6; Intestines; Lacticaseibacillus paracasei; Lactobacillus plantarum; Liver; Male; Mice; Mice, Inbred C57BL; Pancreas; Peptide YY; Polysaccharides, Bacterial; Random Allocation; Synbiotics; Tumor Necrosis Factor-alpha

Diabetes is expected to increase up to 700 million people worldwide with type 2 diabetes being the most frequent. The use of nutritional interventions is one of the most natural approaches for managing the disease. Minerals are of paramount importance in order to preserve and obtain good health and among them molybdenum is an essential component. There are no studies about the consumption of biofortified food with molybdenum on glucose homeostasis but recent studies in humans suggest that molybdenum could exert hypoglycemic effects. The present study aims to assess if consumption of lettuce biofortified with molybdenum influences glucose homeostasis and whether the effects would be due to changes in gastrointestinal hormone levels and specifically Peptide YY (PYY), Glucagon-Like Peptide 1 (GLP-1), Glucagon-Like Peptide 2 (GLP-2), and Gastric Inhibitory Polypeptide (GIP). A cohort of 24 people was supplemented with biofortified lettuce for 12 days. Blood and urine samples were obtained at baseline (T0) and after 12 days (T2) of supplementation. Blood was analyzed for glucose, insulin, insulin resistance, β-cell function, and insulin sensitivity, PYY, GLP-1, GLP-2 and GIP. Urine samples were tested for molybdenum concentration. The results showed that consumption of lettuce biofortified with molybdenum for 12 days did not affect beta cell function but significantly reduced fasting glucose, insulin, insulin resistance and increased insulin sensitivity in healthy people. Consumption of biofortified lettuce did not show any modification in urine concentration of molybdenum among the groups. These data suggest that consumption of lettuce biofortified with molybdenum improves glucose homeostasis and PYY and GIP are involved in the action mechanism.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Food, Fortified; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Lactuca; Molybdenum; Peptide YY

Reproduction and metabolism are intricately linked. Gut hormones play key roles in the regulation of body weight and glucose homeostasis, factors that influence the functioning of the hypothalamic-pituitary-gonadal axis and reproductive outcomes. Data from rodent models suggest gut hormones may have direct stimulatory effects on reproductive hormone release. However, the effects of gut hormones on reproductive function in humans are more complex, with possible involvement of direct (e.g. via gut hormone receptor agonism) as well as indirect (e.g. via weight reduction in people with obesity) mechanisms. The use of gut hormone receptor agonists has become an integral part of the management of metabolic diseases (including obesity and type 2 diabetes), with additional indications for their use on the horizon. Future work may identify specific roles for gut hormone receptor agonists in the treatment of reproductive co-morbidities that are increasingly being recognised in people with metabolic diseases.

Topics: Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Obesity; Peptide YY; Reproduction

Type 2 diabetes is a high-profile global public health problem, particularly in Asia. The young age of onset, low body mass index, and early appearance of pancreatic islet dysfunction are characteristics of Asian patients with T2DM. Metabolic surgery has become the standard treatment for T2DM patients and can significantly improve T2DM through a variety of mechanisms including modulation of energy homeostasis and reduction of body fat mass. Indeed, restoration of islet function also plays an integral role in the remission of T2DM. After metabolic surgery, islet function in Asian T2DM patients has improved significantly, with proven short-term and long-term effects. In addition, islet function is an important criterion and reference for patient selection prior to metabolic surgery. The mechanism of islet function improvement after metabolic surgery is not clear, but postoperative anatomical changes in the gastrointestinal tract leading to a number of hormonal changes seem to be the potential cause, including glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, ghrelin, and cholecystokinin. The authors analyzed the current retrospective and prospective studies on the effect of metabolic surgery on the islet function of Asian T2DM patients with a low BMI and its mechanism, summarized the clinical evidence that metabolic surgery improved islet function in Asian T2DM patients with a low BMI, and discussed its underlying mechanism. It is of great significance for realizing personalized and precise treatment of metabolic surgery and further improving its clinical benefits.. 2型糖尿病（T2DM）是当前备受瞩目的全球性公共卫生问题，在亚洲地区尤为突出。发病年龄小、体质指数（BMI）低以及早期出现胰岛功能缺陷是亚洲T2DM患者的特征。代谢手术已经成为T2DM的标准治疗手段，其可通过调节能量稳态和降低体脂质量等多种机制显著改善T2DM。事实上，胰岛功能的恢复在T2DM的缓解过程中同样发挥着不可或缺的作用。代谢手术后，亚洲T2DM患者的胰岛功能显著改善，其短期及长期效果均已获得验证。不仅如此，胰岛功能还是代谢手术前进行患者选择的重要依据和参考指标。代谢手术后胰岛功能改善的机制尚不明确，但术后胃肠道的解剖改变所致的胰高血糖素样肽-1、抑胃肽、酪酪肽、胃饥饿素及胆囊收缩素等激素的变化可能参与其中。笔者分析了目前针对代谢手术对亚洲低BMI T2DM患者胰岛功能的影响及其机制的回顾性和前瞻性研究，总结了关于代谢手术改善亚洲低BMI T2DM患者胰岛功能的临床证据，并探讨其内在机制。这对于实现代谢手术的个性化、精准化治疗，进一步提高其临床效益具有重要意义。.

Topics: Bariatric Surgery; Body Mass Index; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Peptide YY; Prospective Studies; Retrospective Studies; Treatment Outcome

Glycosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to weight loss and improved diabetes control, but a significant disparity exists between observed and expected weight loss with these medications, hindering clinical effects. This study investigated whether this discrepancy could be explained by compensatory increases in appetite and associated alterations in appetite-regulating hormones.. This was a prospective single-center observational pilot study. Adults 18-70 years old newly prescribed an SGLT2 inhibitor through usual care were invited to participate. Fasting and postprandial appetite was assessed immediately before, 1 week after, and 12 weeks after SGLT2 inhibitor initiation. Serum samples were collected at corresponding time points to measure ghrelin, leptin, and peptide tyrosine-tyrosine (PYY). Seven patients were included. At 1 and 12 weeks after SGLT2 inhibitor initiation, self-reported appetite did not change significantly and trended toward a decrease in appetite. There were no significant differences in fasting or postprandial ghrelin, leptin, or PYY.. Results suggest the discrepancy between expected and observed weight loss with SGLT2 inhibitors cannot be explained by increases in appetite or changes in appetite-regulating hormones. Further studies are needed to investigate alternative metabolic compensatory mechanisms to optimize weight loss with SGLT2 inhibitor use.

Topics: Aged; Appetite Regulation; Biomarkers; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Peptide YY; Pilot Projects; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Weight Loss

To investigate the antidiabetic efficacy of enzymatically stable Peptide YY (PYY) peptides from phylogenetically ancient fish.. N-terminally stabilized, PYY (1-36) sequences from Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesized, and both biological actions and antidiabetic therapeutic efficacy were assessed.. All fish PYY (1-36) peptides were resistant to dipeptidyl peptidase-4 (DPP-4) degradation and inhibited glucose- and alanine-induced (P < 0.05 to P < 0.001) insulin secretion. In addition, PYY (1-36) peptides imparted significant (P < 0.05 to P < 0.001) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β cells with CRISPR-Cas9-induced knockout of Npyr1. In contrast to human PYY (1-36), the piscine-derived peptides lacked appetite-suppressive actions. Twice-daily administration of sea lamprey PYY (1-36), the superior bioactive peptide, for 21 days significantly (P < 0.05 to P < 0.001) decreased fluid intake, non-fasting glucose and glucagon in streptozotocin (STZ)-induced diabetic mice. In addition, glucose tolerance, insulin sensitivity, pancreatic insulin and glucagon content were significantly improved. Metabolic benefits were linked to positive changes in pancreatic islet morphology as a result of augmented (P < 0.001) proliferation and decreased apoptosis of β cells. Sturgeon PYY (1-36) exerted similar but less impressive effects in STZ mice.. These observations reveal, for the first time, that PYY (1-36) peptide sequences from phylogenetically ancient fish replicate the pancreatic β-cell benefits of human PYY (1-36) and have clear potential for the treatment of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Mice; Neuropeptides; Peptide YY

Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs-Glucerna (GL) and Ultra Glucose Control (UGC)-versus oatmeal on selected satiety and hunger hormones.. After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC. iAUC. Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.

Topics: Aged; Blood Glucose; Cholecystokinin; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Food, Formulated; Ghrelin; Glucagon; Humans; Hunger; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Peptide YY; Postprandial Period; Satiation

The study was aimed to investigate gut hormone responses to mixed meal test in individuals with new-onset prediabetes or diabetes after acute pancreatitis (cases) compared with healthy controls, and the effect of body fat parameters. A total of 29 cases and 29 age- and sex-matched healthy controls were recruited. All participants were given standard mixed meal drink and blood samples were collected to measure dipeptidyl peptidase IV, gastric inhibitory peptide, glucagon like peptide-1, insulin, oxyntomodulin, and peptide YY. Body fat parameters were measured using magnetic resonance imaging. Repeated measures and linear regression analyses were conducted in unadjusted and adjusted models. Gastric inhibitory peptide levels were significantly higher whereas oxyntomodulin levels were significantly lower in cases compared with controls in both the unadjusted (p<0.001 and p<0.001, respectively) and adjusted (p<0.001 and p<0.001, respectively) models. In cases, liver fat % contributed up to 13.4% (vs. 2.9% in controls) to variance in circulating levels of gastric inhibitory peptide whereas body mass index - up to 20.8% (vs. 9.9% in controls) in circulating levels of oxyntomodulin. New-onset prediabetes/diabetes after acute pancreatitis is characterised by increased levels of gastric inhibitory peptide and decreased levels of oxyntomodulin. Further, liver fat % and body mass index appear to be the body fat parameters that contribute most significantly to gastric inhibitory peptide and oxyntomodulin levels, respectively.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Magnetic Resonance Imaging; Male; Meals; Middle Aged; Oxyntomodulin; Pancreatitis; Peptide YY; Postprandial Period; Prediabetic State; Subcutaneous Fat

Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied.. Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22.. We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release.. This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.

Topics: Animals; Bariatric Surgery; Biomarkers; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Female; Gene Expression; Glucagon-Like Peptide 1; Humans; Interleukin-22; Interleukins; Islets of Langerhans; Male; Mice; Peptide YY; Rats

The antidiabetic drug metformin causes weight loss, but the underlying mechanisms are unclear. Recent clinical studies show that metformin increases plasma levels of the anorectic gut hormone, peptide YY (PYY), but whether this is through a direct effect on the gut is unknown.. We hypothesized that exposure of human gut mucosal tissue to metformin would acutely trigger PYY secretion.. Mucosal tissue was prepared from 46 human colonic and 9 ileal samples obtained after surgical resection and ex vivo secretion assays were performed. Tissue was exposed to metformin, as well as a series of other compounds as part of our mechanistic studies, in static incubations. Supernatant was sampled after 15 minutes.. PYY levels in supernatant, measured using ELISA.. Metformin increased PYY secretion from both ileal (P < 0.05) and colonic (P < 0.001) epithelia. Both basal and metformin-induced PYY secretion were unchanged across body mass index or in tissues obtained from individuals with type 2 diabetes. Metformin-dependent PYY secretion was blocked by inhibitors of the plasma membrane monoamine transporter (PMAT) and the serotonin reuptake transporter (SERT), as well as by an inhibitor of AMP kinase (AMPK).. This is a report of a direct action of metformin on the gut epithelium to trigger PYY secretion in humans, occurring via cell internalization through PMAT and SERT and intracellular activation of AMPK. Our results provide further support that the role of metformin in the treatment of metabolic syndrome has a gut-based component.

Topics: Adult; Aged; AMP-Activated Protein Kinases; Colon; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Equilibrative Nucleoside Transport Proteins; Female; Humans; Hypoglycemic Agents; Ileum; Intestinal Mucosa; Male; Metformin; Middle Aged; Peptide YY; Serotonin Plasma Membrane Transport Proteins; Weight Loss

Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants.. In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine.. Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine.. Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants.. NCT03044860.

Topics: Adult; Aged; Chromogranin A; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Immunohistochemistry; Male; Middle Aged; Peptide YY; Proprotein Convertase 1; Proprotein Convertase 2; Proprotein Convertases

To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism.. In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6-hour mixed-meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention.. Similar improvements in glucose levels, β-cell function, insulin sensitivity and post-meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet-only intervention induced greater improvements in basal hepatic glucose output and post-meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post-meal glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glucagon levels.. Strict peri-operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB-induced changes in the incretin hormones GLP-1 and PYY probably play a major role in long-term compliance with such major dietary restrictions through central and peripheral mechanisms.

Topics: Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Remission Induction

Gastric bypass surgery leads to profound changes in the secretion of gut hormones with effects on metabolism, appetite, and food intake. Here, we discuss their contributions to the improvement in glucose tolerance and the weight loss that results from the operations. We find that the improved glucose tolerance is due the following events: a negative energy balance and resulting weight loss, which improve first hepatic and later peripheral insulin sensitivity, in combination with increased postprandial insulin secretion elicited particularly by exaggerated glucagon-like peptide-1 responses. The weight loss is due to loss of appetite resulting in reduced energy intake, and we find it probable that this process is driven by exaggerated secretion of appetite-regulating gut hormones including, but probably not limited to, glucagon-like peptide-1 and peptide-YY. The increased secretion is due to an accelerated exposure to and absorption of nutrients in the small intestine. This places the weight loss and the gut hormones in key positions with respect to the metabolic improvements after bypass surgery.

Topics: Appetite; Bariatric Surgery; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Proteins; Digestion; Eating; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Absorption; Nutrients; Obesity, Morbid; Peptide YY; Weight Loss

The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion.. Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and β cell function were measured before and following each stimulus.. Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of β cell function.. Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/β cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.

Topics: Administration, Intravenous; Arginine; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Secreting Cells; Peptide YY; Postprandial Period; Prediabetic State; Time Factors; United States

The duodenal-jejunal bypass sleeve ((DJBS) or EndoBarrier Gastrointestinal Liner) induces weight loss in obese subjects and may improve glucose homeostasis in patients with type 2 diabetes (T2D). To explore the underlying mechanisms, we evaluated postprandial physiology including glucose metabolism, gut hormone secretion, gallbladder emptying, appetite and food intake in patients undergoing DJBS treatment.. A total of 10 normal glucose-tolerant (NGT) obese subjects and 9 age-, body weight- and body mass index-matched metformin-treated T2D patients underwent a liquid mixed meal test and a subsequent ad libitum meal test before implantation with DJBS and 1 week (1w) and 26 weeks (26w) after implantation.. At 26w, both groups had achieved a weight loss of 6 to 7 kg. Postprandial glucagon-like peptide-1 (GLP-1) and peptide YY responses increased at 1w and 26w, but only in T2D subjects. In contrast, glucose-dependent insulinotropic polypeptide responses were reduced only by DJBS in the NGT group. Postprandial glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin responses were unaffected by DJBS in both groups. Satiety and fullness sensations were stronger and food intake was reduced at 1w in NGT subjects; no changes in appetite measures or food intake were observed in the T2D group. No effect of DJBS on postprandial gallbladder emptying was observed, and gastric emptying was not delayed.. DJBS-induced weight loss was associated with only marginal changes in postprandial physiology, which may explain the absence of effect on postprandial glucose metabolism.

Topics: Adult; Appetite; Bariatric Surgery; Blood Glucose; Body Composition; C-Peptide; Case-Control Studies; Cholecystokinin; Comorbidity; Diabetes Mellitus, Type 2; Eating; Female; Gallbladder Emptying; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Prospective Studies; Satiety Response; Treatment Outcome

Apolipoprotein A-IV (ApoA-IV) has been shown to be involved in obesity and diabetes pathogenesis in animal studies, but its role in humans is uncertain.. The objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery.. University Hospital.. The patients (n = 49) included lean controls (n = 8) and patients before and after a mean of 7 months after laparoscopic adjustable gastric banding (LAGB, n = 12), laparoscopic Roux-en-Y gastric bypass (RYGB, n = 22), or laparoscopic sleeve gastrectomy (SG, n = 11). ApoA-IV and other hormone assays were performed in the fasting and the postprandial state. Pearson's correlation analyses controlled for baseline BMI and percent excess weight loss (EWL) were used to determine relationships between ApoA-IV levels and insulin resistance (HOMA-IR).. With all bariatric procedures combined, the change in ApoA-IV [533 versus 518 microg/L, P = .813] or ApoA-IV area under the curve (AUC - 1072 versus 1042, P = .939) was not significant. None of the surgeries individually affected levels of fasting or ApoA-IV AUC. Bariatric surgery resulted in a decrease in HOMA-IR (5.3 versus 2.0, P<.001). In the RYGB group, higher baseline ApoA-IV levels correlated with decrease in HOMA-IR [r = -.6, P = .008]. This relationship was independent of EWL and was not observed in the LAGB or SG group. There was no association of ApoA-IV levels with EWL, insulin secretion, Peptide-YY, or leptin levels.. Preoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB.

Topics: Adult; Apolipoproteins A; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Gastrectomy; Gastric Bypass; Gastroplasty; Humans; Insulin Resistance; Laparoscopy; Male; Obesity; Peptide YY; Postoperative Care; Postprandial Period; Preoperative Care; Weight Loss

Duodenal-jejunal bypass (DJB) has been proven effective in glycemic control in various type 2 diabetes (T2DM) rat models. "Hindgut hypothesis" and "foregut hypothesis" are two prevailing theories to elucidate the weight-independent anti-diabetic mechanisms of DJB, however, which mechanism plays the dominant role that has not been illuminated.. This paper aims to verify that exclusion of the foregut leads to loss of weight and remission of type 2 diabetes without expedited delivery of nutrients to the distal bowel.. Thirty-five diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ) were randomly assigned to the control, sham-DJB (S-DJB), DJB, ileal bypass (ILB), and DJB combined with ILB (DJB-ILB) groups. Effects of surgeries on body weight, food intake, blood glucose, glucose-stimulated insulin, and gastrointestinal hormones secretion were evaluated at indicated time points.. Compared to the control and S-DJB groups, the DJB group had significant and sustained glycemic control independent of weight loss. Excluding part of the distal ileum did not reverse the diabetic control that followed DJB surgery. The glucagon-like peptide 1 (GLP-1) and PYY levels were significantly increased after DJB. Although GLP-1 and PYY are mainly secreted by L cells in the distal ileum, excluding part of the ileum did not decrease the levels of GLP-1 and PYY after DJB.. The beneficial effects of DJB in glycemic control could not be reversed by excluding the distal ileum.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Duodenum; Glucagon-Like Peptide 1; Ileum; Jejunum; Male; Obesity, Morbid; Peptide YY; Rats; Rats, Wistar

Bariatric procedures that exclude the proximal small intestine lead to significant weight loss which is probably mediated by changes in hormones that alter appetite, such as peptide YY (PYY), ghrelin, cholecystokinin (CCK), and leptin. Here, the effect of the non-surgical duodenal-jejunal bypass liner (DJBL) on concentrations of hormones implicated in appetite control was investigated.. A two-center prospective study was conducted between January and December 2010. Seventeen obese subjects with type 2 diabetes were treated with the DJBL for 24 weeks. Fasting concentrations of leptin and meal responses of plasma PYY, CCK, and ghrelin were determined prior to and after implantation of the DJBL.. At baseline, subjects had an average body weight of 116.0 ± 5.8 kg. One week after implantation, subjects had lost 4.3 ± 0.6 kg (p < 0.01), which progressed to 12.7 ± 1.3 kg at week 24 (p < 0.01). Postprandial concentrations of PYY and ghrelin increased (baseline vs. week 1 vs. week 24 PYY: 2.6 ± 0.2 vs. 4.1 ± 0.4 vs. 4.1 ± 0.7 nmol/L/min and ghrelin: 7.8 ± 1.8 vs. 11.0 ± 1.8 vs. 10.6 ± 1.8 ng/mL/min, all p < 0.05). In parallel, the CCK response decreased (baseline vs. week 1 vs. week 24: 434 ± 51 vs. 229 ± 52 vs. 256 ± 51 pmol/L/min, p < 0.01). Fasting leptin concentrations also decreased (baseline vs. week 24: 98 ± 17 vs. 53 ± 10 ng/mL, p < 0.01).. DJBL treatment induces weight loss paralleled by changes in concentrations of hormones involved in appetite control.

Topics: Bariatrics; Cholecystokinin; Diabetes Mellitus, Type 2; Duodenum; Female; Ghrelin; Humans; Jejunum; Leptin; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postprandial Period; Prospective Studies; Treatment Outcome

Obesity and type 2 diabetes mellitus are increasing worldwide, reaching pandemic proportions. The understanding of the role of functional restriction and gut hormones can be a beneficial tool in treating obesity and diabetes. However, the exact hormonal profiles in different metabolic states and surgical models are not known.. The HIPER-1 Study is a single-centre cross-sectional study in which 240 patients (in different metabolic states and surgical models) will receive an oral mixed-meal tolerance test (OMTT). At baseline and after 30, 60 and 120 min, peptide YY and glucagon-like peptide 1 levels and glucose and insulin sensitivity will be measured. The primary end point of the study will be the area under the glucagon-like peptide 1 and peptide YY curves after the OMTT. Secondary study end points will include examination of the difference in plasma levels of the distal ileal hormones in subjects with various health statuses and in patients who have been treated with different surgical techniques.. An independent ethics committee, the Institutional Review Board of Istanbul Sisli Kolan International Hospital, Turkey, has approved the study protocol. Dissemination will occur via publication, national and international conference presentations, and exchanges with regional, provincial and national stakeholders.. NCT02532829; Pre-results.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Models, Anatomic; Obesity; Peptide YY; Prospective Studies; Research Design; Turkey

Roux-en-Y gastric bypass (RYGB) is a weight-reduction procedure resulting in rapid resolution of type 2 diabetes (T2D). The role of pancreatic islet function in this restoration of normoglycemia has not been fully elucidated. Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrate that RYGB restores normal glucose regulation of glucagon and insulin secretion and normalizes islet morphology. Culture of isolated islets with serum from RYGB animals mimicked these effects, implicating a humoral factor. These latter effects were reversed following neutralization of the gut hormone peptide tyrosine tyrosine (PYY) but persisted in the presence of a glucagon-like peptide-1 (GLP-1) receptor antagonist. The effects of RYGB on secretion were replicated by chronic exposure of diabetic rat islets to PYY in vitro. These findings indicate that the mechanism underlying T2D remission may be mediated by PYY and suggest that drugs promoting PYY release or action may restore pancreatic islet function in T2D.

Topics: Adult; Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Peptide YY; Rats, Wistar; Transcription, Genetic

Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM.. Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM.. A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found.. This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.

Topics: Adult; Bile Acids and Salts; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Humans; Hydroxylation; Middle Aged; Obesity, Morbid; Peptide YY; Postoperative Period; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome; Weight Loss

We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.. Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated.. The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups.. Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

Topics: Adult; Cholecystokinin; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity, Morbid; Peptide YY; Proprotein Convertase 2; Treatment Outcome

To elucidate the specific role of gastric vs. intestinal manipulations in the regulation of body weight and glucose homeostasis.. The effects of intestinal bypass alone (duodenal-jejunal bypass -DJB) and gastric resection alone (SG) in Zucker Diabetic Fatty (ZDF) rats were compared. Additional animals underwent a combination procedure (SG + DJB). Outcome measures included changes in weight, food intake (FI), oral glucose tolerance (GT) and gut hormones.. DJB did not substantially affect weight and FI, whereas SG significantly reduced weight gain and food consumption. DJB rats showed weight-independent improvement in GT, which improved less after SG. Furthermore, SG significantly suppressed plasma ghrelin and increased insulin, glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide and peptide YY response to oral glucose whereas DJB had no effects on postprandial levels of these hormones. DJB restored postprandial glucagon suppression in diabetic rats whereas SG did not affect glucagon response. The combination procedure (SG + DJB) induced greater weight loss and better GT than SG alone without reducing food intake further.. These findings reveal a dominant role of the stomach in the regulation of body weight and incretin response to oral glucose whereas intestinal bypass primarily affects glucose homeostasis by a weight-, insulin- and incretin-independent mechanism.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Gastrectomy; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Insulin; Jejunoileal Bypass; Jejunum; Male; Obesity; Peptide YY; Postoperative Care; Rats

Both glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are gut hormones involved in energy homoeostasis. Obesity, insulin resistance and hyperglycaemia are significant confounders when GLP-1 and PYY secretion is assessed. Thus, we evaluated GLP-1 and PYY response after fat load in morbidly obese patients with different degrees of insulin resistance and glycemic status.. We studied 40 morbidly obese subjects (mean age, 40·6 ± 1·3 years; mean BMI, 53·1 ± 1·2 kg/m(2) ) divided into groups according to their glycemic status: normal fasting glucose (NFG) group, impaired fasting glucose (IFG) group and type 2 diabetes mellitus (T2D) group. NFG patients were additionally subclassified, according to the homoeostasis model assessment of insulin resistance (HOMAIR ), into a low insulin-resistance (LIR) group (HOMAIR <3·9) or a high insulin-resistance (HIR) group (HOMAIR ≥3·9).. Lipid emulsion was administered orally and measurements made at baseline and 180 min postprandially of levels of GLP-1, PYY, insulin, glucose, free fatty acids, triglycerides and leptin.. At the 180-minute postprandial reading, GLP-1 and PYY had increased in LIR-NFG subjects (41·84%, P = 0·01; 35·7%, P = 0·05; respectively), whereas no changes were observed in HIR-NFG, IFG or T2D subjects.. These results suggest that in morbidly obese subjects, both insulin resistance and abnormal glucose metabolism (IFG or T2D) impair the GLP-1 and PYY response to fat load. The implications of this attenuated enteroendocrine response should be elucidated by further studies.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Peptide YY

To evaluate the foregut and hindgut hypotheses for metabolic surgery in obese rats with diabetes.. Otsuka Long-Evans Tokushima fatty rats were divided into a sham operation group, a partial duodeno-jejunal bypass (P-DJB) group, and a complete DJB (C-DJB) group. P-DJB is a model to test foregut hypothesis, whereas C-DJB is a model to test both hypotheses. We performed oral glucose tolerance tests (OGTT) on all groups at baseline, and then 4 and 8 weeks postoperatively. The rats were killed thereafter and the plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured. A separate sub-group of C-DJB rats underwent OGTT after treatment with the GLP-1 antagonist, the PYY antagonist, or saline.. Marked improvement of the blood glucose control during the OGTT was noted 8 weeks after C-DJB, but not 8 weeks after P-DJB or the sham operation. The serum GLP-1 and PYY levels were higher in the C-DJB group than in the other two groups. Pretreatment with the GLP-1 antagonist increased the blood glucose levels 30 min after the OGTT in the C-DJB rats.. Improvement in glucose metabolism after DJB was associated with the inflow of bile and pancreatic juice into the ileum, supporting validity of the hindgut hypothesis. GLP-1 appears to play a role in this improvement.

Topics: Animals; Bariatric Surgery; Bile; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Ileum; Jejunum; Male; Obesity; Pancreatic Juice; Peptide YY; Rats; Rats, Inbred OLETF

To assess the rapid improvement of insulin sensitivity and β-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes.. Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS.. Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants.. Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and β-cell function after BPD-DS in type 2 diabetes.

Topics: Adult; Biliopancreatic Diversion; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Duodenum; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Obesity, Morbid; Peptide YY; Pilot Projects

Changes in gastrointestinal peptide release may play an important role in improving glucose control and reducing body weight following Roux-en-Y gastric bypass (RYGB), but the impact of low caloric intake on gut peptide release post-surgery has not been well characterized. The purpose of this study was to assess the relationships between low caloric intake and gut peptide release and how they were altered by RYGB. Obese females including ten normoglycemic (ON) and ten with type 2 diabetes mellitus (T2DM) (OD) were studied before, 1 week, and 3 months after RYGB. Nine lean, normoglycemic women were studied for comparison. Subjects were given three separate mixed meal challenges (MMCs; 75, 150, and 300 kcal). Plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were analyzed. Prior to surgery, only minimal increases in GLP-1 and PYY were observed in response to the MMCs. After surgery, the peak GLP-1 concentration was progressively elevated in response to increasing meal sizes. The meal sizes had a statistically significant impact on elevation of GLP-1 incremental areas under the curve (ΔAUC) in both ON and OD at 1 week and 3 months post-surgery visits (p < 0.05 for all comparisons). The PYY ∆AUC was also significantly increased in a meal size-dependent manner in both ON and OD at both post-surgery visits (p < 0.05 for all comparisons). Meal sizes as small as 75-300 kcal, which cause minimal stimulation in GLP-1 or PYY release in the subjects before RYGB, are sufficient to provide statistically significant, meal size-dependent increases in the peptides post-RYGB both acutely and after meaningful weight loss occurred.

Topics: Adult; Anastomosis, Roux-en-Y; Diabetes Mellitus, Type 2; Female; Food; Glucagon-Like Peptide 1; Humans; Middle Aged; Obesity, Morbid; Peptide YY; Postoperative Period

Incretins are hormones produced by the intestine and can stimulate the secretion of insulin, helping to diminish the post-prandial glycemia. The administration of an emulsion of palm oil can help in the maintenance of the weight, and can increase circulating incretins levels. Glutamine increases the concentration of incretins in diabetic people. Both can help in metabolic syndrome.. To analyze the effects of ingestion of palm oil and glutamine in glycemia and in incretins in patients with diabetes submitted to surgical duodenojejunal exclusion with ileal interposition without gastrectomy.. Eleven diabetic type 2 patients were included and were operated. They were called to laboratory follow-up without eating anything between eight and 12 hours. They had there blood collected after the stimulus of the palm oil and glutamine taken in different days. For the hormonal doses were used ELISA kits.. The glycemia showed a meaningful fall between the fast and two hours after the stimulus of the palm oil (p=0,018). With the glutamine the GLP-1 showed an increase between the fast and one hour (p=0,32), the PYY showed an important increase between the fast and one hour after the stimulus (p=0,06), the glycemia showed a meaningful fall after two hours of the administration of the stimulus (p=0,03).. Palm oil and glutamine can influence intestinal peptides and glucose.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Eating; Female; Glucagon-Like Peptide 1; Glutamine; Humans; Male; Middle Aged; Palm Oil; Peptide YY; Plant Oils; Young Adult

Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the BA receptor G protein-coupled bile acid receptor 1 (GPBAR1).. A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration.. GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys.. Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.

Topics: Animals; Cell Line; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Isonipecotic Acids; Macaca fascicularis; Male; Metabolic Detoxication, Phase II; Mice; Mice, Mutant Strains; Mice, Transgenic; Oximes; Peptide YY; Piperidines; Receptors, G-Protein-Coupled; Recombinant Proteins; Taurine

Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance.. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery.. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients.. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Obesity; Peptide YY; Postoperative Period; Stomach Neoplasms; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Male; Peptide YY

In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control.. The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG).. Insulin sensitivity, β-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured.. T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, β-cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery β-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission.. RYGB and SLG have a similar impact on diabetes remission, of which baseline β-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glycemic Index; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Male; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Remission Induction

To study the changes of plasma glucagon-like peptide-1 (GLP-1), serum peptide-YY (PYY) and Ghrelin and their secretion functions in patients with newly diagnosed type 2 diabetes mellitus (T2DM).. A total of 102 subjects were enrolled, including 32 normal-glucose-tolerance controls (NGT) and 70 patients with newly diagnosed T2DM. Height, body mass, waist circumference (WC) and hip circumference were measured. The plasma lipids and 0 h, 1/2 h, 2 h plasma glucose, insulin (INS), GLP-1, serum PYY and Ghrelin in a standard meal test in each subject were detected, and body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI), homeostasis model assessment of beta cell function (HOMA-B) and early insulin secretion function index (DeltaI30/DeltaG30) were calculated. All these variables were compared between the two groups.. Compared with those in NGT group, the WC, fasting plasma glucose (FPG), postprandial plasma glucose (2 h-PG), triglyceride (TG), HOMA-IR were significantly higher (P 0.05), while INS(30), HOMA-B, ISI, DeltaI30/DeltaG30 were significantly lower in T2DM group (P<0. 05). In addition, in T2DM group, 0 h, 1/2 h, 2 h plasma GLP-1 and serum PYY and the area under the curve (AUC) of GLP-1 (GLP-lAuc ) and PYY (PYYAc) in standard meal test were significantly lower (P<0. 05), but the serum Ghrelin and GhrelinA, were significantly higher (P<0. 05). Meanwhile, the secretory peak of GLP-1 and PYY after standard meal in T2DM patients all disappeared. In T2DM group, PYYAUC and TG were negatively correlated (P<0.05), the fasting serum Ghrelin level was negatively associated with total cholesterol (TC), and GhrelinAuc was positively associated with HOMA-B, but negatively with the low-density lipoprotein cholesterol (LDL-C) and FPG (P(<0. 05).. Patients with newly diagnosed T2DM have decreased fasting and postprandial GLP-1 and PYY levels, along with changes of their secretion mode and increased levels of Ghrelin.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Peptide YY

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.

Topics: Administration, Rectal; Adult; Appetite Regulation; Blood Glucose; Body Mass Index; Cholagogues and Choleretics; Diabetes Mellitus, Type 2; Enema; Glucagon-Like Peptide 1; Humans; Male; Obesity; Peptide YY; Taurocholic Acid; Treatment Outcome

The effects of gastric bypass surgery on the secretion of the anorexigenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet.. Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6 ± 3.3 days after gastric bypass (GBP, n = 10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (control, n = 10).. Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0 ± 28.6-323 ± 51 pg/ml, P < 0.01; high-fat peak: 81.8 ± 9.6-278 ± 49 pg/ml, P < 0.01), but not after diet (mixed-nutrient peak: 104.4 ± 9.4-114.9 ± 15.8 pg/ml, P = NS; high-fat peak: 118.1 ± 16.4-104.4 ± 10.8 pg/ml, P = NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8 ± 26.0-220.7 ± 52.9 pg/ml, P = 0.09; GBP high-fat peak: 142.1 ± 34.6-197.9 ± 12.7 pg/ml, P = 0.07; diet mixed-nutrient peak: 99.8 ± 8.0-101.1 ± 13.3 pg/ml, P = NS; diet high-fat peak: 105.0 ± 8.8-103.1 ± 11.8 pg/ml, P = NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY total area under the curve (AUC(0-120)) was significantly greater than the high-fat PYY AUC(0-120) (22,081 ± 5,662 pg/ml min vs. 18,711 ± 1,811 pg/ml min, P = 0.04).. Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent of caloric restriction. The phenomenon of "bariatric surgery-induced anorexia" may be linked to the increased levels after GBP.

Topics: Adolescent; Adult; Aged; Appetite; Body Mass Index; Caloric Restriction; Case-Control Studies; Diabetes Mellitus, Type 2; Diet, High-Fat; Fasting; Female; Food; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postprandial Period; Prospective Studies; Weight Loss; Young Adult

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Obesity; Peptide YY; Weight Loss

Gastric bypass leads to the remission of type 2 diabetes independently of weight loss. Our hypothesis is that changes in bile flow due to the altered anatomy may partly explain the metabolic outcomes of the operation. We prospectively studied 12 patients undergoing gastric bypass and six patients undergoing gastric banding over a 6-wk period. Plasma fibroblast growth factor (FGF)19, stimulated by bile acid absorption in the terminal ileum, and plasma bile acids were measured. In canine and rodent models, we investigated changes in the gut hormone response after altered bile flow. FGF19 and total plasma bile acids levels increased after gastric bypass compared with no change after gastric banding. In the canine model, both food and bile, on their own, stimulated satiety gut hormone responses. However, when combined, the response was doubled. In rats, drainage of endogenous bile into the terminal ileum was associated with an enhanced satiety gut hormone response, reduced food intake, and lower body weight. In conclusion, after gastric bypass, bile flow is altered, leading to increased plasma bile acids, FGF19, incretin. and satiety gut hormone concentrations. Elucidating the mechanism of action of gastric bypass surgery may lead to novel treatments for type 2 diabetes.

Topics: Adult; Animals; Bile; Bile Acids and Salts; Blood Glucose; C-Reactive Protein; Calorimetry; Diabetes Mellitus, Type 2; Dogs; Female; Fibroblast Growth Factors; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Peptide YY; Rats; Rats, Wistar; Weight Loss

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are secreted from enteroendocrine L cells in response to numerous stimuli, including bile salts. Both have multiple effects that are potentially useful in treating diabetes and obesity. L cell number and hormone content in the intestine are highest in the rectum in humans. We investigated the effects of intrarectal sodium taurocholate on plasma GLP-1, PYY, insulin and glucose concentrations, and on food intake of a subsequent meal.. Ten obese type 2 diabetic volunteers were each studied on five separate occasions after an overnight fast and oral administration of 100 mg sitagliptin 10 h before the study. They then received an intrarectal infusion of either one of four doses of taurocholate (0.66, 2, 6.66 or 20 mmol, each in 20 ml of vehicle) or vehicle alone (1% carboxymethyl cellulose) single-blind over 1 min. Hormone and glucose measurements were made prior to, and for 1 h following, the infusion. The consumption of a previously selected favourite meal eaten to satiety was measured 75 min after the infusion.. Taurocholate dose-dependently increased GLP-1, PYY and insulin, with 20 mmol doses resulting in peak concentrations 7.2-, 4.2- and 2.6-fold higher, respectively, than those achieved with placebo (p < 0.0001 for each). Plasma glucose decreased by up to 3.8 mmol/l (p < 0.001). Energy intake was decreased dose-dependently by up to 47% (p < 0.0001). The ED(50) values for effects on integrated GLP-1, insulin, PYY, food intake and glucose-lowering responses were 8.1, 10.5, 18.5, 24.2 and 25.1 mmol, respectively.. Therapies that increase bile salts (or their mimics) in the distal bowel may be valuable in the treatment of type 2 diabetes and obesity.

Topics: Adult; Blood Glucose; Body Mass Index; Cholagogues and Choleretics; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Peptide YY; Rectum; Taurocholic Acid; United Arab Emirates

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Topics: Adiponectin; Adult; Blood Glucose; C-Peptide; Caloric Restriction; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity; Peptide YY; Weight Loss

We studied whether serum fasting levels of active form of peptide YY (PYY), PYY(3-36), are associated with obesity and related phenotypes. The study population consisted of 428 patients with coronary artery disease and diagnosed type 2 diabetes and 440 patients with coronary artery disease but without evidence of diabetes from the ARTEMIS study. The patients were recruited from the consecutive series of patients undergoing coronary angiography in the Oulu University Hospital. The patients without diabetes underwent a 2-hour oral glucose tolerance test. PYY(3-36) levels were analyzed by human PYY(3-36) specific radioimmunoassay. Result suggested that when PYY(3-36) tertiles were considered, high serum fasting PYY(3-36) concentration was associated with high body mass index, waist circumference, hemoglobin A1c, fasting blood glucose, leptin, triglyceride (p for all p ≤ 0.001), serum insulin (p=0.013) and with a low high-density lipoprotein cholesterol (p=0.004) concentrations in the analyses adjusted for age, sex and study group. The link high PYY(3-36)-high insulin level was evident in subjects with normal glucose tolerance (p<0.05). The prevalence of diabetes was 72%, 46% and 30% in the highest, medium and lowest PYY(3-36) tertile (p<0.001). The PYY(3-36) concentrations (after adjustment for age, sex and body mass index) were higher in type 2 diabetics compared to subjects with impaired fasting glucose, impaired glucose tolerance and normal glucose tolerance (p<0.001 for trend). In conclusion, fasting PYY(3-36) concentrations in type 2 diabetic subjects are high. Although high PYY(3-36) is strongly linked to obesity and associated insulin resistance, the relation between PYY(3-36) and type 2 diabetes is independent of body fatness.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Coronary Artery Disease; Diabetes Mellitus, Type 2; Fasting; Humans; Insulin; Insulin Resistance; Obesity; Peptide YY

The aim of this study was to evaluate the possible role of sleeve gastrectomy (SG) per se in the reversibility of diabetes.. Insulin secretion and peripheral insulin sensitivity using the intravenous glucose tolerance test (IVGTT) were assessed in 18 obese type 2 diabetic patients and in 10 nondiabetic obese patients before and 3 days after SG, before any food intake and any weight change occurrence. At the same time, ghrelin, GLP-1, and PYY levels were determined.. In diabetic patients who had the disease less than 10.5 years, the first phase of insulin secretion promptly improved after SG. The early insulin area under the curve (AUC) significantly increased at the postoperative IVGTT, indicating an increased glucose-induced insulin secretion. The second phase of insulin secretion (late AUC) significantly decreased after SG in all groups, indicating an improved insulin peripheral sensitivity. In all groups, pre- and postoperatively, intravenous glucose stimulation determined a decrease in ghrelin values and an increase in GLP-1 and PYY values. However, in the group of patients with disease duration >10.5 years, the differences were not significant except for the late insulin AUC. Postoperative basal and intravenous glucose-stimulated ghrelin levels were lower than preoperative levels in all groups of patients. Basal and intravenous stimulated GLP-1 and PYY postoperative values were higher than preoperative levels in all groups.. Restoration of the first phase of insulin secretion and improved insulin sensitivity in diabetic obese patients immediately after SG, before any food passage through the gastrointestinal tract and before any weight loss, seem to be related to ghrelin, GLP-1, and PYY hormonal changes of possible gastric origin and was neither meal- nor weight-change-related. Duration of the disease up to 10.5 years seems to be a major cut off in the pathophysiological changes induced by SG. A "gastric" hypothesis may be put forward to explain the antidiabetes effect of SG.

Topics: Diabetes Mellitus, Type 2; Female; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Peptide YY

Various digestive tract procedures effectively improve metabolic syndrome, especially the control of type 2 diabetes mellitus. Very good metabolic results have been shown with vertical gastrectomy and entero-omentectomy; however, the metabolic effects of an isolated entero-omentectomy have not been previously studied.. Nine patients with type 2 diabetes mellitus and a body mass index ranging from 29 to 34.8 kg/m² underwent an entero-omentectomy procedure that consisted of an enterectomy of the middle jejunum and exeresis of the major part of the omentum performed through a mini-laparotomy. Glucagon-like peptide-1 and peptide YY were measured preoperatively and three months following the operation. Fasting and postprandial variations in glycemia, insulinemia, triglyceridemia, hemoglobin A1c, and body mass index were determined in the preoperative period and 3, 18 and, 36 months after the operation.. All patients significantly improved the control of their type 2 diabetes mellitus. Postprandial secretion of peptide YY and Glucagon-like peptide-1 were enhanced, whereas hemoglobin A1c, fasting and postprandial glucose, insulin, and triglyceride levels were significantly reduced. Mean body mass index was reduced from 31.1 to 27.3 kg/m². No major surgical or nutritional complications occurred.. Entero-omentectomy is easy and safe to perform. A simple reduction in jejunal extension and visceral fat causes important improvements in the metabolic profile.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Jejunum; Male; Metabolic Syndrome; Middle Aged; Nutritional Status; Omentum; Peptide YY; Postoperative Period; Time Factors; Treatment Outcome

To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism.. A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured.. Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (iAUC) (0.33 vs. 0.49 mmol . l(-1) . min(-1)) compared with gastroduodenal feeding. beta-Cell function (iAUC(Cpeptide/Glu)) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold.. Improvement in postprandial glucose metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight loss, and caloric restriction.

Topics: Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Enteral Nutrition; Fatty Acids, Nonesterified; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postoperative Period; Postprandial Period

Bariatric surgery has been shown to reverse type 2 diabetes; however, mechanisms by which this occurs remain undefined. Ileal interposition (IT) is a surgical model that isolates the effects of increasing delivery of unabsorbed nutrients to the lower gastrointestinal tract. In this study we investigated effects of IT surgery on glucose tolerance and diabetes onset in UCD-T2DM (University of California at Davis type 2 diabetes mellitus) rats, a polygenic obese animal model of type 2 diabetes.. IT or sham surgery was performed on 4-month-old male UCD-T2DM rats. All animals underwent oral glucose tolerance testing (OGTT). A subset was killed 2 months after surgery for tissue analyses. The remainder was followed until diabetes onset and underwent oral fat tolerance testing (OFTT).. IT surgery delayed diabetes onset by 120 +/- 49 days compared with sham surgery (P < .05) without a difference in body weight. During OGTT, IT-operated animals exhibited lower plasma glucose excursions (P < .05), improved early insulin secretion (P < .01), and 3-fold larger plasma glucagon-like peptide-1(7-36) (GLP-1(7-36)) excursions (P < .001), and no difference in glucose-dependent insulinotropic polypeptide responses compared with sham-operated animals. Total plasma peptide YY (PYY) excursions during OFTT were 3-fold larger in IT-operated animals (P < .01). IT-operated animals exhibited lower adiposity (P < .05), smaller adipocyte size (P < .05), 25% less ectopic lipid deposition, lower circulating lipids, and greater pancreatic insulin content compared with sham-operated animals (P < .05).. IT surgery delays the onset of diabetes in UCD-T2DM rats which may be related to increased nutrient-stimulated secretion of GLP-1(7-36) and PYY and improvements of insulin sensitivity, beta-cell function, and lipid metabolism.

Topics: Adipocytes; Adiponectin; Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin; Lipid Metabolism; Male; Peptide YY; Rats; Weight Loss

Topics: Appetite Regulation; Biomedical Research; Diabetes Mellitus, Type 2; Drug Design; Energy Metabolism; Forecasting; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Pancreatic Polypeptide; Peptide YY

To investigate the response of serum ghrelin and PYY to oral glucose and steamed-bread load and their relationships to insulin and glucose in nonobese and obese patients with type 2 diabetes.. Ten obese subjects (Male: waist > or =90 cm, Female: waist > or =80 cm) and eleven nonobese subjects with type 2 diabetes were given oral glucose load and steamed-bread challenge in 2 consecutive days after blood glucose was controlled. The serum levels of ghrelin, PYY, insulin and glucose were measured with routine methods.. (1) Either in oral glucose or steamed-bread load tests, both fasting serum PYY and ghrelin levels of obese subjects were significantly lower than those of nonobese subjects. After taking glucose or steamed-bread, all subjects were observed the increase of PYY and ghrelin levels, which reached the peak at 30 min and 60 min respectively. However, there were no significant difference found between nonobese and obese group at 30 min, 60 min and 120 min (P=NS). (2) In all subjects, fasting serum PYY, ghrelin concentrations were inversely associated with waist circumferences and BMI but not WHR. (3) No correlations were observed between serum PYY and insulin, glucose at any time points. The ghrelin and insulin levels showed a correlation at 0 min (r = -0.591, P = 0.005), however, no correlations were found at any other time points. When comparing PYY, ghrelin AUC with the AUC of insulin and glucose, no correlations were found. (4) Ghrelin level was positively correlated with QUICKI, however, no correlation between PYY concentrations and QUICKI was noted.. In the subjects with type 2 diabetes, both PYY and ghrelin respond differently to glucose and bread, athough the calories are similar. PYY and ghrelin levels are inversely related to waist and BMI but not WHR. It is fasting ghrelin not PYY negatively associated with fasting insulin and positively with QUICKI.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY

Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content.. Prospective cross-sectional cohort study.. Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON).. Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content.. Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance.. Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05).. A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.

Topics: Adult; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Disease Progression; Enteroendocrine Cells; Epidemiologic Studies; Family Health; Female; Genetic Predisposition to Disease; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Triglycerides

Weight loss is difficult to achieve in type 2 diabetes and many therapies are associated with weight gain, an effect attenuated by metformin. We studied the effects of metformin on energy expenditure, appetite and the regulation of PYY and ghrelin in type 2 diabetes.. Plasma peptide YY (PYY), ghrelin, resting metabolic rate (RMR), postprandial thermogenesis (PPTG), and appetite ratings were measured at baseline and following a mixed meal in 11 type 2 diabetic subjects treated with diet alone (T2D) and 10 treated with metformin monotherapy (T2MF). The groups were similar in age, gender and adiposity.. There were no differences in baseline anthropometric, or metabolic variables between the groups. Postprandially, plasma ghrelin fell equally in both groups (23% versus 24.5%, p < 0.05 versus baseline, p = NS between groups) but were reduced for longer in T2MF (below baseline 60-240 min T2MF versus 60-180 min T2D) coincidentally with a prolonged sensation of fullness and suppression of hunger in the metformin-treated group. There were no differences in PYY concentrations, RMR or PPTG.. Metformin prolongs the postprandial fall in ghrelin concentrations. These effects may prolong the inter-meal interval, thereby decreasing snack intake and daily energy intake, promoting weight loss.

Topics: Adult; Appetite; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Ghrelin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Osmolar Concentration; Peptide Hormones; Peptide YY; Postprandial Period; Satiety Response; Thermogenesis

Topics: Adult; Diabetes Mellitus, Type 2; Fasting; Ghrelin; Humans; Middle Aged; Peptide Hormones; Peptide YY; Postprandial Period

Low circulating peptide YY (PYY) levels are reported in obese and type II diabetic subjects and results from PYY knockout animals suggests that PYY deficiency may have a causative role in the etiology of obesity and type 2 diabetes. Here, our aims were to determine whether people with a genetic predisposition to developing type 2 diabetes and obesity differ from otherwise similar subjects without such family history, in fasting or meal-related PYY levels, fasting insulin, insulin secretion (HOMA-B) and insulin sensitivity. We also investigated whether PYY ablation affects the intrinsic ability of islets to secrete insulin, which may be a contributing factor to the hyperinsulinemia observed in PYY knockout mice. Healthy female first-degree relatives of people with type 2 diabetes were matched for age, gender and BMI to control subjects but had significantly lower insulin sensitivity (p<0.05). Relatives also had significantly lower fasting serum PYY levels than controls (p<0.05), but their PYY response to a high fat meal (4250 kJ, 73% fat) was not significantly different. Fasting PYY level correlated positively with glucose infusion rate (r=0.713, p=0.002) and fasting adiponectin (r=0.5, p=0.02). Islets of Langerhans from PYY knockout mice were found to hypersecrete insulin in response to 25 mM glucose (p<0.05). These data demonstrate that lack of PYY enhances insulin secretion from the Islets of Langerhans and that low fasting PYY levels are associated with insulin resistance in humans. Together, these findings suggest that low circulating levels of PYY could contribute to hyperinsulinemia and insulin resistance, and possibly contribute to subsequent development of obesity and type 2 diabetes.

Topics: Adiponectin; Adiposity; Adult; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Female; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Mice; Mice, Knockout; Middle Aged; Peptide YY; Radioimmunoassay

Topics: Diabetes Mellitus, Type 2; Exenatide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Peptide Fragments; Peptide Hormones; Peptide YY; Peptides; Protein Precursors; United States; Venoms

Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration.. To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices.. Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[3-36] acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day).. Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[3-36].

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Implants; Eating; Energy Intake; Female; Infusions, Intravenous; Injections, Intraperitoneal; Male; Mice; Mice, Mutant Strains; Models, Animal; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Inbred Strains; Rats, Zucker

Topics: Adult; Animals; Appetite; Child; Congresses as Topic; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Fragments; Peptide YY; Pharmacology, Clinical; Protein Precursors; Receptors, Glucocorticoid

Gastrointestinal transit was measured in non-obese diabetic (NOD) mice, as an animal model of human diabetes type 1, and in obese diabetic mice, as an animal model of human diabetes type 2. The endocrine cells known to correlate to gastrointestinal transit, namely secretin, serotonin, Peptide YY (PYY) and enteroglucagon cells, were identified by immunocytochemistry and quantified by computer image analysis in different segments of the gut. Gastrointestinal transit was significantly accelerated in NOD mice and slower in obese diabetic mice than in controls. The density of duodenal secretin and serotonin as well as colonic PYY and enteroglucagon cells in NOD mice was significantly higher than that of control mice. On the other hand, the density of duodenal secretin and serotonin cells was significantly lower in obese diabetic mice than in controls. It was concluded that changes in duodenal secretin and colonic serotonin, PYY and enteroglucagon cells may play a role in accelerated gastrointestinal transit in NOD mice and delayed gastrointestinal transit in obese diabetic mice.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Enteroendocrine Cells; Gastrointestinal Transit; Glucagon-Like Peptides; Humans; Image Processing, Computer-Assisted; Mice; Mice, Inbred BALB C; Mice, Obese; Peptide YY; Secretin; Serotonin

Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, notably energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in genetically obese ob/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate these effects. Here, we show that crossing the Y2 receptor knockout mouse (Y2(-/-)) onto the ob/ob background attenuates the increased adiposity, hyperinsulinemia, hyperglycemia, and increased hypothalamo-pituitary-adrenal (HPA) axis activity of ob/ob mice. Compared with lean controls, ob/ob mice had elevated expression of NPY and agouti-related protein (AgRP) mRNA in the arcuate nucleus and decreased expression of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. Y2 deletion in ob/ob mice significantly increased the hypothalamic POMC mRNA expression, with no effect on NPY, AgRP, or CART expression. [Y2(-/-)ob/ob] mice were no different from ob/ob littermates with respect to food intake and body weight, and Y2 receptor deficiency had no beneficial effect on the infertility or the reduced hypothalamo-pituitary-gonadotropic function of ob/ob mice. These data demonstrate that Y2 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice, possibly via alterations in melanocortin tonus in the arcuate nucleus and/or effects on the HPA axis.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gene Deletion; Gonadotropins; Hypothalamo-Hypophyseal System; Insulin; Male; Mice; Mice, Knockout; Neuropeptides; Obesity; Peptide Fragments; Peptide YY; Pituitary-Adrenal System; Receptors, Neuropeptide Y; Syndrome; Thermogenesis; Thyrotropin

This study examined the relationship between islet neurohormonal characteristics and the defective glucose-stimulated insulin secretion in genetic type 2 diabetic Chinese hamsters. Two different sublines were studied: diabetes-prone CHIG hamsters and control CHIA hamsters. The CHIG hamsters were divided into three subgroups, depending on severity of hyperglycemia. Compared to normoglycemic CHIG hamsters and control CHIA hamsters, severely hyperglycemic CHIG hamsters (glucose > 15 mmol/l) showed marked glucose intolerance during i.p. glucose tolerance test and 75% impairment of glucose-stimulated insulin secretion from isolated islets. Mildly hyperglycemic CHIG animals (glucose 7.2-15 mmol/l) showed only moderate glucose intolerance and a 60% impairment of glucose-stimulated insulin secretion from the islets. Immunostaining for neuropeptide Y and tyrosine hydroxylase (markers for adrenergic nerves) and for vasoactive intestinal peptide (marker for cholinergic nerves) revealed significant reduction in immunostaining of islets in the severely but not in the mildly hyperglycemic animals, compared to control CHIA hamsters. The study therefore provides evidence that in this model of type 2 diabetes in Chinese hamsters, severe hyperglycemia is accompanied not only by marked glucose intolerance and islet dysfunction but also by reduced islet innervation. This suggests that islet neuronal alterations may contribute to islet dysfunction in severe but not in mild diabetes.

Topics: Animals; Animals, Inbred Strains; Blood Glucose; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Immunohistochemistry; Insulin; Insulin Secretion; Islets of Langerhans; Male; Nerve Fibers; Neuropeptides; Pancreas; Pancreatic Hormones; Peptide YY