peptide-yy and Diabetes-Mellitus

The antiobesity effects of activation of hypothalamic neuropeptide Y2 receptors (NPYR2) by the gut-derived hormone, peptide YY (PYY), are established. However, more recent insight into the biology of PYY has demonstrated remarkable benefits of sustained activation of pancreatic beta-cell NPYR1, that promises to open a new therapeutic avenue in diabetes.. The therapeutic applicability of NPYR2 agonists for obesity has been considered for many years. An alternative pathway for the clinical realisation of PYY-based drugs could be related to the development of NPYR1 agonists for treatment of diabetes. Thus, although stimulation of NPYR1 on pancreatic beta-cells has immediate insulinostatic effects, prolonged activation of these receptors leads to well defined beta-cell protective effects, with obvious positive implications for the treatment of diabetes. In this regard, NPYR1-specific, long-acting enzyme resistant PYY analogues, have been recently developed with encouraging preclinical effects observed on pancreatic islet architecture in diabetes. In agreement, the benefits of certain types of bariatric surgeries on beta-cell function and responsiveness have also been linked to elevated PYY secretion and NPY1 receptor activation.. Enzymatically stable forms of PYY, that selectively activate NPYR1, may have significant potential for preservation of beta-cell mass and the treatment of diabetes.

Topics: Diabetes Mellitus; Humans; Insulin-Secreting Cells; Islets of Langerhans; Obesity; Peptide YY

The vast majority of research to date on the gut hormone Peptide YY (PYY) has focused on appetite suppression and body weight regulation effects. These biological actions are believed to occur through interaction of PYY with hypothalamic Y

Topics: Appetite Regulation; Diabetes Mellitus; Humans; Hypothalamus; Obesity; Peptide Fragments; Peptide YY; Receptors, Neuropeptide Y

The antidiabetic mechanism of dipeptidyl peptidase 4 (DPP4) inhibitors is attributed to attenuation of incretin metabolism. Because DPP4 has at least 45 substrates, context-dependent off-target effects of DPP4 inhibitors are likely. Here, we consider the clinical ramifications of the context-dependent effects of DPP4 inhibitors.. Although incretins protect organs from diabetic injury, nonincretin DPP4 substrates also accumulate when DPP4 is inhibited. Neuropeptide Y(1-36), peptide YY(1-36), and CXCL12α(1-68) are DPP4 substrates, and emerging results suggest that these peptides promote heart and kidney damage or increase blood pressure. Because levels of, and cellular responses to, these peptides vary depending on context, likely the harmful effects of DPP4 inhibitors are context-dependent. This conclusion is supported by the contrasting results of preclinical studies, some showing cardiorenal protection and others demonstrating harmful effects on the heart and kidneys. Likewise, some preclinical studies report antihypertensive and others prohypertensive effects of DPP4 inhibitors. Several randomized clinical trials, observational studies, and meta-analyses describe detrimental effects of DPP4 inhibitors on outcomes, although others do not (context-dependence).. The beneficial effects of DPP4 inhibitors might be optimized by careful patient selection or by coadministration of Y1 or CXCR4 receptor antagonists to eliminate the off-target effects of DPP4 inhibition.

Topics: Animals; Blood Pressure; Chemokine CXCL12; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Peptide YY

Replenishment of beta cell mass is a key aim of novel therapeutic interventions for diabetes, and the implementation of new strategies will be aided by understanding the mechanisms employed to regulate beta cell mass under normal physiological conditions. We have recently identified a new role for the gut hormone peptide YY (PYY) and the neuropeptide Y (NPY) receptor systems in the control of beta cell survival. PYY is perhaps best known for its role in regulating appetite and body weight, but its production by islet cells, the presence of NPY receptors on islets and the demonstration that Y1 activation causes proliferation of beta cells and protects them from apoptosis, suggest a role for this peptide in modulating beta cell mass. This review introduces PYY and its potential role in glucose homeostasis, then focuses on evidence supporting the concept that PYY and NPY receptors are exciting new targets for the preservation of beta cells.

Topics: Animals; Apoptosis; Appetite Regulation; Cell Proliferation; Diabetes Mellitus; Glucose; Homeostasis; Humans; Peptide YY

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

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

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Topics: Animals; Behavior, Animal; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Synergism; Eating; Energy Intake; Feeding Behavior; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Peptide Fragments; Peptide YY; Rats

Topics: Animals; Bariatric Surgery; Diabetes Mellitus; Humans; Peptide YY

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Insulin; Obesity; Overweight; Peptide YY; Postprandial Period

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity.

Topics: Animals; Cell Lineage; Cell Separation; Cholecystokinin; Diabetes Mellitus; Enteroendocrine Cells; Flow Cytometry; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Green Fluorescent Proteins; Humans; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Transgenic; Neurotensin; Obesity; Peptide YY; Promoter Regions, Genetic