Peptide-1 Levels Research Articles

Mulberry leaf extract exhibits multiple anti-diabetic activities and alleviates dysglycemia, systemic inflammation, hepatic steatosis, and xenobiotic metabolism abnormalities in type 2 diabetic mice

Mulberry leaves can be processed into a tea rich in polyphenols and gamma-aminobutyric acid (GABA) with health benefits. This study aimed to investigate the anti-diabetic effects of mulberry leaf extracts. Potential hypoglycemic and anti-glycation activities were evaluated in vitro. The in vivo therapeutic efficacy was assessed in type 2 diabetic mice, with GABA and exendin-4 serving as reference anti-diabetic agents. The ethanol extract of mulberry leaves was found to contain higher levels of GABA and polyphenols than the water extract. Both extracts exhibited multiple anti-diabetic biological activities. Regarding in vivo therapeutic effects, incorporating 3% (g/g) mulberry leaf extract into the diet for 8 weeks improved glycemic control, insulin sensitivity, serum glucagon like peptide-1 levels, hepatic steatosis and xenobiotic metabolism abnormalities. Additionally, the ethanol extract had a more pronounced effect on immunity. In conclusion, mulberry leaves could be considered a sustainable dietary material to alleviate symptoms of type 2 diabetes.

Study on the Mechanism of the Blood-Glucose-Lowering Effect of Collagen Peptides from Sturgeon By-Products

In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.

MicroRNA-194: a novel regulator of glucagon-like peptide-1 synthesis in intestinal L cells

In the status of obesity, the glucagon-like peptide-1 (GLP-1) level usually declines and results in metabolic syndrome. This study aimed to investigate the intracellular mechanism of GLP-1 synthesis in L cells from the perspective of microRNA (miRNA). In the present study, we found that GLP-1 level was down-regulated in the plasma and ileum tissues of obese mice, while the ileac miR-194 expression was up-regulated. In vitro experiments indicated that miR-194 overexpression down-regulated GLP-1 level, mRNA levels of proglucagon gene (gcg) and prohormone convertase 1/3 gene (pcsk1), and the nuclear protein level of beta-catenin (β-catenin). Further investigation confirmed that β-catenin could promote gcg transcription through binding to transcription factor 7-like 2 (TCF7L2). miR-194 suppressed gcg mRNA level via negatively regulating TCF7L2 expression. What’s more, forkhead box a1 (Foxa1) could bind to the promoter of pcsk1 and enhanced its transcription. miR-194 suppressed pcsk1 transcription through targeting Foxa1. Besides, the interference of miR-194 reduced palmitate (PA)-induced cell apoptosis and the anti-apoptosis effect of miR-194 inhibitor was abolished by TCF7L2 knockdown. Finally, in HFD-induced obese mice, the silence of miR-194 significantly elevated GLP-1 level and improved the metabolic symptoms caused by GLP-1 deficiency. To sum up, our study found that miR-194 suppressed GLP-1 synthesis in L cells via inhibiting TCF7L2-mediated gcg transcription and Foxa1-mediated pcsk1 transcription. Meanwhile, miR-194 took part in the PA-induced apoptosis of L cells.

Evaluation of glucagon-like peptide-1, adropin, and desnutrin levels, and related factors in patients with bipolar disorder

Objective: It is known that impaired energy metabolism contributes to the neuropathology of bipolar disorder (BD). Our aim in this study was to compare the levels of glucagon-like peptide-1 (GLP-1), adropin and desnutrin, which have many metabolic functions after the regulation of energy metabolism in patients with bipolar disorder and those in healthy controls, and to investigate the related factors. Methods: To the study group of the research, 73 age- and sex-matched people were included. Of them, 35 were patients diagnosed with BD, and 38 were healthy individuals. In the blood samples, in addition to routine biochemistry lipid parameters, the levels of adropin, desnutrin and GLP-1 were determined. Results: Adropin, desnutrin and GLP-1 levels were significantly lower in the patients with bipolar disorder than were those in the healthy controls. On the other hand, Body mass index, total cholesterol, triglyceride, low density lipoprotein values were significantly higher in the patients with BD than were those in the healthy controls (p

Conservation of glucagon like peptide-1 level with liraglutide and linagilptin protects the kidney against angiotensin II-induced tissue fibrosis in rats

This study tested the hypothesis that the enhancement of glucagon-like peptide-1 (GLP-1) level through either exogenous supply of GLP-1 agonist, liraglutide or prevention of endogenous GLP-1 degradation with dipeptidyl peptidease-4 inhibitor, lingaliptin ameliorates angiotensin II (Ang II)-induced renal fibrosis. Sprague-Dawley rats were randomly divided into four groups: 0.9% saline or Ang II (500 ng/kg/min) was infused with osmotic minipumps for 4 weeks, defined as sham and Ang II groups. In drug treated groups, liraglutide (0.3 mg/kg) was injected subcutaneously twice daily or linagliptin (8 mg/kg) was administered daily via oral gavage during Ang II infusion. Compared with Ang II stimulation, liraglutide or linagliptin comparatively down-regulated the protein level of the AT1 receptor, and up-regulated the AT2 receptor, as identified by a reduced AT1/AT2 ratio (all p < 0.05), consistent with less locally-expressed AT1 receptor and enhanced AT2 receptor in the glomerular capillaries and proximal tubules of the renal cortex. Furthermore, both drugs significantly increased the expression of GLP-1 receptor and attenuated the protein levels of TLR4, NOX4 and IL-6. The populations of macrophages and α-SMA expressing myofibroblasts decreased with treatment of liraglutide and linagliptin, in coincidence with the reduced expression of phosphor-Smad2/3, Smad4, TGFβ1, and up-regulated Smad7. Along with these modulations, renal morphology was preserved and synthesis of fibronectin/collagen I was down-regulated, as identified by small collagen-rich area in the renal cortex. These results suggest that the preservation of GLP-1 level using liraglutide or linagliptin might be considered as an add-on therapeutic option for inhibiting Ang II induced renal fibrosis and failure.

The Effect of Different Types of Bariatric Surgery on Metabolic and Hormonal Parameters in Rats with a Decompensated Form of Type II Diabetes Mellitus

Bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB), and ileal transposition (IT), is one of the approaches currently used for the correction of metabolic disturbances in type 2 diabetes mellitus (DM2) with obesity. However, the efficiency of these approaches and their impact on hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain poorly characterized. The aim of this work is to study the effect of IT, SG, and GB on insulin, leptin, ghrelin, and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with a decompensated form of DM2 induced by a high-fat diet (three months) and a single low dose of streptozotocin (25 mg/kg, two months after the start of the diet). Pronounced hyperglycemia, impaired glucose tolerance, a decrease in the glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels, and a slight increase in the ghrelin level are detected in diabetic rats. Expression of genes encoding the GLP-1 receptor, the orexigenic agouti-related peptide (AgRP), and phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways, is increased in the hypothalamus. IT in diabetic rats leads to a reduction of glucose levels 120 min after glucose loading, an increase of basal and glucose-stimulated GLP-1 levels, and normalization of the expression levels of the phosphotyrosine phosphatase 1B, SOCS3, AgRP, and GLP-1 receptor genes, which is indicative of restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. Glucose tolerance is improved in the case of SG and GB, and an increase in the basal and glucose-stimulated GLP-1 levels is demonstrated in the case of SG, but no significant effects on the expression of the hypothalamic genes are observed in SG and GB. Thus, IT is the most efficient bariatric surgical intervention among those studied for the treatment of severe DM2 forms without obesity.

HYPOGLYCEMIC EFFECT OF HIGH-RESISTANT STARCH ANALOG RICE THROUGH GLP-1 AND INSULIN OR HIGH-RESISTANT STARCH ANALOG RICE ATTENUATES BLOOD GLUCOSE LEVEL THROUGH ENHANCEMENT OF GLP-1 AND INSULIN

Objective: This study was to investigate the effect of analog rice (AR) on glucagon-like peptide-1 (GLP-1) and insulin serum levels, glucose transporter-2 (GLUT-2) expression, and fasting blood glucose (FBG) level in diabetic rats.&#x0D; Methods: Fifty male Wistar rats divided into the control group (n=10) and the experimental group. High-fat diet and streptozotocin were administered in experimental groups, which then divided into four equal groups (n=10, each) (negative control group, rice group, AR1 and AR2 group, given standard pellet, rice pellet, AR1 and AR2 pellet, respectively, for 6 weeks). GLP-1 and insulin serum levels were measured by enzyme-linked immunosorbent assay. The expression of GLUT-2 and the number of pancreatic β-cells observed using an immunohistochemistry method.&#x0D; Results: FBG levels in the AR1 and AR2 groups decreased, while the rice group remained. GLP-1 serum levels of the negative control and rice groups were not significantly different from the control group, while the AR1 and AR2 groups higher than the control group (p≤0.05). All the treatment groups had insulin serum levels significantly lower than control group (p≤0.05), except the AR1 group. The expression of GLUT-2 and the number of pancreatic β-cells in the treatment groups were less than the control group, but between treatment groups were not significantly different.&#x0D; Conclusion: AR significantly effective in reducing FBG level in diabetic rats through stimulation of increased GLP-1 and insulin serum levels serum levels but AR did not affect on the expression of GLUT-2.

187-OR: Gut Microbiota Regulate Pancreatic Growth, Exocrine Function, and Gut Hormones

Growing evidence suggests a link between alterations in gut microbiota, diabetes, and metabolic syndrome. We recently showed that treatment with antibiotics to alter gut microbiota could improve insulin signaling and glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on high-fat diet (HFD). This occurred in part through changing metabolite composition in plasma and decreasing adipose tissue inflammation. We also showed that these changes could be induced in germ-free mice by transferring the gut microbiota. It is known that diabetes is associated with exocrine pancreatic dysfunction, and diseases of the exocrine pancreas can be associated with diabetes. To explore the role of gut microbiota on host pancreatic exocrine function and its crosstalk with the endocrine system, mice were given either normal chow or HFD, or HFD and treatment with vancomycin or metronidazole. As expected, HFD alone produced signs of metabolic syndrome but also increased total pancreas weight by ~20%, an amount that could not be explained by islet hyperplasia. Analysis of the fecal proteome of these mice identified 138 host proteins of which 32 changed with either HFD or antibiotic treatment. Notably, the most significantly changed proteins by diet and altered microbiome were pancreatic enzymes: amylase, lipase and elastase. Furthermore, the plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) levels were decreased, while glucose-dependent insulinotropic peptide (GIP) was increased by the HFD. These alterations of pancreas growth, acinar cell hyperplasia, exocrine pancreas function, and hormone secretion were reversed by antibiotic treatment of the host. These changes could also be reproduced in germ free mice by transfer of gut microbiota. Together, these data indicate that gut microbiota can regulate pancreatic growth and both exocrine and endocrine function. Better understanding pancreas-gut microbiome crosstalk can help us develop probiotics to cure pancreas dysfunction in diabetes. Disclosure E. Altindis: None. M. Soto: Employee; Self; LNC Therapeutics. Other Relationship; Self; biomeostasis. L. Orliaguet: None. Q. Huang: None. C. Cederquist: None. E. Dirice: None. S. Fujisaka: None. J. Hu: None. R. Kulkarni: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam. Funding National Institutes of Health

1973-P: Deficiency of Protein Deacetylase Sirt3 Enhances Acetylation of Histone H3 and H4 as to Affect Glucose Metabolism through Regulation of Dipeptidyl Peptidase-4 in Mice

Background: Sirt3 is a NAD-dependent deacetylase that regulates lipid metabolism in mice and is related to longevity through modification of epigenome. Sirt3-deficient knockout (KO) mice fed a high-fat diet have been shown to develop obesity and metabolic syndrome-like phenotype. However, the precise mechanism by which they cause glucose intolerance has not been known. To reveal the regulatory mechanism of glucose metabolism through Sirt3, the metabolic parameters in the Sirt3-KO mice were examined. Objective and Methods: The histone acetylation levels in various organs of the Sirt3-KO mice were examined by immunostaining of acetylated histone H3 (H3Ac) and H4 (H4Ac). Blood glucose levels in the Sirt3-KO mice after glucose loading were examined, associated with blood glucagon-like peptide-1 (GLP-1) levels and dipeptidyl peptidase-4 (DPP-4) activity. Gene expressions which were associated with the expressions and functions of GLP-1 and DPP-4 were quantified by qPCR. Results: The Sirt3-KO mice were subjected to an oral glucose tolerance test (OGTT), together with an intraperitoneal glucose tolerance test (ipGTT). OGTT revealed an increase in the blood glucose levels in the KO mice, although ipGTT did not show the increase after the glucose loading. The blood GLP-1 and insulin levels decreased, and the DPP-4 activity increased significantly in the KO mice. qPCR analysis revealed a predominance of Sirt3 expression in the intestinal tract in the wild type mice. The immunostaining of H3Ac and H4Ac showed enhanced intensity in the small intestine and colon, and in the vascular endothelial cells in the KO mice. Conclusion: These results suggest that Sirt3 deficiency impairs the incretin effect by a suppression of the blood GLP-1 levels and causes glucose intolerance. Enhanced acetylation of histone H3 and H4 in the KO mice might relate to the increase in the DPP-4 activity, which lead to the decrease in the GLP-1 levels. Disclosure A. Uto: None. K. Miyashita: Research Support; Self; Johnson &amp; Johnson, Merck &amp; Co., Inc., Novo Nordisk Inc.

1162-P: DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion via Stimulation of GLP-1 Secretion

Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control. Disclosure J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.

316-LB: Medically Reproducing Bariatric Surgery (MRB): A Proof-of-Concept Study

Introduction: Roux-en-Y gastric bypass (RYGB) leads to durable type 2 diabetes (DM2) remission. Increased glucagon-like peptide-1 (GLP-1) levels and caloric restriction are known sequela of RYGB and independently improve DM2 control. Hypothesis: Since Liraglutide increases GLP-1 levels and the OPTIFAST program induces caloric restriction, we hypothesize that Liraglutide + OPTIFAST will medically reproduce RYGB and lead to DM2 remission, weight loss, decreased medication intensity and improved health related quality of life (HRQL). Methods: The Medically Reproducing Bariatric surgery (MRB) study is a pilot study that tested whether poorly controlled DM2 subjects on Liraglutide ± other diabetic medicines experienced DM2 remission after completing the 24 week OPTIFAST program. Primary outcome: glycemic control. Secondary outcome: weight, medication intensity and HRQL measured by Problem Areas In Diabetes (PAID) score. Results: Conclusion: Responders (yellow) vis-a-vis Non-responders (plain) experienced significant improvements in glycemic control, weight, medication intensity and HRQL. Responders vis-a-vis Non-responders had much better compliance during the OPTIFAST weight loss phase (week 1-12) when 800 calories per day were being consumed. Non-responders still experienced modest improvement in weight loss and HRQL. No serious adverse events occurred. The MRB approach merits further study. Disclosure M. Dar: None. K.F. Smythe: None. N.K. Leggett-Frazier: None. W.S. Yancy: None. Funding Nestl?

773-P: The Study of Metabolic Improvement by Nutritional Intervention Controlling Endogenous GIP (Mini Egg Study): A Randomized, Double-Blinded, Crossover Study

Objective: Given the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions. Research Design and Methods: Overweight/obese men (n=21; mean age: 41 ± 9 y; mean BMI: 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU (protein/fat=1.0, fiber/carb ratio≥0.063, and omega-3 PUFA/fat ratio ≥0.054) or isocaloric control meal for two weeks, in a randomized, double-blind, cross-over setup with a four-week washout period. For the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 minutes post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Results: Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4, P &amp;lt; 0.05); however, between meals, there was no significant difference in the levels of GLP-1, PYY, and ghrelin. Relative to control meal, a SMART WASHOKU intervention produced a modest but significant reduction of VFA in our participants (-3.4 ± 12.3 vs. -13.0 ± 9.3 cm2, P &amp;lt; 0.05). Compared with the control meal, SMART WASHOKU meal did not modify the concentrations of AST, ALT, GGT, and hs-CRP; however, we did observe a significantly reduced in the levels of LDL-cholesterol, triglyceride, and HbA1c. Conclusions: Based on our findings, we conclude that in overweight/obese men, a SMART WASHOKU meal would be helpful in decreasing VFA and improving metabolic parameters, possibly via suppressing GIP secretion. Disclosure N. Sakane: Board Member; Spouse/Partner; Kao Corporation. H. Takase: Employee; Self; Kao Corporation. J. Suzuki: Employee; Self; Kao Corporation. C. Suzukamo: Employee; Self; Kao Corporation. S. Nirengi: None. A. Suganuma: None. N. Osaki: Employee; Self; Kao Corporation. Funding Kao Corporation; Japan Society for the Promotion of Science (18K01988); Strategic Innovation Project of Japan (14533567); Bio-oriented Technology Research Advancement Institution, NARO

Correction: The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin.

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases’ different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors’ effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists’ neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

Comparative assessment of metabolic, hormonal and psychological characteristics of young obese men

Aim. To study metabolic-hormonal status and psychological characteristics of young obese men. Material and methods. The study included 87 young obese men (BMI ≥30 kg/m2) aged 16-25 yr given medication or non-medication treatment for 12 weeks. Blood glucagon-like peptide-1 (GLP-1), insulin, and glucose levels were measured after orlistat intake. Final screening included biochemical and hormonal studies. 48 patients underwent psychological testing. Results. Orlistat therapy resulted in clinically significant reduction of body mass (by more than 5% in 50% of the patients). Cortisol level also decreased while testosterone level increased. Meal test revealed elevated baseline GLP-1 level in 77,7% of the patients. There was correlation between baseline GLP-1 and insulin levels (r=0,61; р=0,001). Orlistat therapy decreased anxiety and depression (p&lt;0,05) as well as manifestations of external eating behaviour but increased those of restrictive eating behaviour.

Nesfatin-1 and glucagon-like peptide-1(GLP-1) levels in Parkinson’s disease and their effect on oxidative processes

Nesfatin-1 and glucagon-like peptide-1(GLP-1) levels in Parkinson’s disease and their effect on oxidative processes

The Effect of Pumpkin on GLP-1 and HOMA-β in Hypercholesterolemic Rats

Abstract Background and aim: High fat and fructose diet may impair β cell function through oxidative stress that is induced by subsequent hypercholesterolemia. The β cell function is usually quantified by homeostatic model assessment beta-cell function (HOMA-β). Oxidative stress may be decreased by β-carotene from pumpkin (Cucurbita maxima). This study aimed to evaluate the effects of pumpkin powder on glucagon-like peptide-1 (GLP-1) level and HOMA-β in rats with high fat and fructose diet. Material and method: A total 25 rats were administered a high fat and fructose diet during 25 days. They were divided into five groups 1) normal, 2) hypercholesterolemic rats 3) hypercholesterolemic rats with 0.16 g pumpkin/200g bodyweight (BW); 4) hypercholesterolemic rats with 0.32 g pumpkin/200 g BW, and 5) hypercholesterolemic rats with 0.64 g of pumpkin/200 g BW. The lipid levels were measured before and after administration of pumpkin for 4 weeks, and at the end of the study, GLP-1 level and HOMA-β were analyzed. Results: Administration of pumpkin to the rats on a high fat and fructose diet reduced total cholesterol, triglyceride, and increased HDL levels. Changes were positively correlated with the amount of pumpkin intake. The decrease of cholesterol levels was positively associated with GLP-1 level, and negatively correlated with HOMA-β Conclusions: This study suggested that pumpkin can improve the HOMA-β and decrease GLP-1 levels, possibly by reducing cholesterol levels.

Autoimmune diabetes is suppressed by treatment with recombinant human tissue Kallikrein-1.

The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.

DPP4 Deficiency Preserved Cardiac Function in Abdominal Aortic Banding Rats

Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. A prominent GLP-1 level in DPP4-deficient rats contributed to the resistance of endotoxemia and myocardial infarction. DPP4 deficiency also increased the capability against H2O2-induced stress in cardiomyocyte. However, long term effect of loss DPP4 activity on cardiac performance remained unclear. We used abdominal aortic banding (AAB) to induce pressure overload in wild-type and DPP4-deficient rats, and investigated the progression of heart failure. Cardiac histology and function were determined. Blood sample was collected for the plasma biochemical marker measurement. Heart weight to body weight ratio increased 1.2-fold after 6 weeks of AAB surgery. Cardiac function was compensated against pressure overload after 6 weeks of AAB surgery, but progressed to deterioration after 10 weeks of AAB surgery. AAB induced cardiac dysfunction was alleviated in DPP4-deficient rats. DPP4 activity increased significantly in wild-type rats after 10 weeks of AAB surgery, but remained unchanged in DPP4-deficient rats. In contrast, GLP-1 concentration was elevated by AAB after 6 weeks of surgery in DPP4-deficient rats, and remained high after 10 weeks of surgery. Ang II level markedly increased after 6 weeks of AAB surgery, but were less in DPP4-deficient rats. Massive collagen deposits in wild-type rat hearts appeared after 10 weeks of AAB surgery, which were alleviated in DPP4-deficient rats. Long term deficiency of DPP4 activity improved cardiac performance against pressure overload in rat, which may be attributed to a great quantity of GLP-1 accumulation during AAB.

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, improves hyperglycemia and dyslipidemia independent of suppression of food intake in diabetic rats.

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group. Results. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment. Conclusions. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.