xenin-25 and Insulin-Resistance

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Gastrointestinal Hormones; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Neurotensin; Sitagliptin Phosphate

To demarcate pathological events in the brain as a result of short-term to chronic high-fat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and to assess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.. C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and the Morris water maze. Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry, quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage.. Recognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer. HFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Biomarkers; Brain; Cognition Disorders; Diet, High-Fat; Disease Models, Animal; Encephalitis; Exploratory Behavior; Gene Expression Regulation, Developmental; Immunohistochemistry; Insulin Resistance; Male; Maze Learning; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Neurotensin; Nootropic Agents; Oxidative Stress; Peptides; Random Allocation

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Intake; Gastrointestinal Hormones; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Molecular Sequence Data; Neurotensin

Xenin is a peptide of the neurotensin/xenopsin/xenin family secreted from gastric cells and other tissues. The first aim of this study was to investigate the serum xenin and ghrelin levels in obese children and compare the patients with healthy controls. The second aim was to compare the xenin levels in patients with nonalcoholic fatty liver disease (NAFLD) and also with insulin resistance with the patients without these complications.. 62 obese adolescents (27 with NAFLD) and 32 healthy controls were enrolled in the study. Obesity was defined as a body mass index exceeding the 95th percentile for the patients' age and sex. NAFLD was diagnosed via ultrasonographic examination. The insulin resistance was calculated by a homeostasis model assessment (HOMA-IR) index. Serum xenin and ghrelin levels were assessed by enzyme-linked immunosorbent assay.. The mean serum xenin concentration was significantly higher in obese adolescents than the healthy peers (68.15 ± 0.63 vs 16.54 ± 0.07 pg/mL, p = 0.000). Serum xenin levels were not different between the patients with and without NAFLD and also between the patients with and without IR (p > 0.05). There was a positive correlation between xenin levels and relative weight (r = 0.663, p < 0.001) and HOMA-IR (r = 0.612, p < 0.001). Ghrelin was negatively correlated with relative weight (r = -0.283, p < 0.05).. In this study, serum xenin levels of both groups of obese patients were found higher than controls. On the other hand, xenin levels were not different in patients with and without NAFLD. High levels of xenin may be in relation with obesity.

Topics: Adolescent; Biomarkers; Child; Female; Ghrelin; Humans; Insulin Resistance; Male; Neurotensin; Non-alcoholic Fatty Liver Disease; Obesity

Shift work is associated with circadian rhythm disorder, impaired sleep and behavioural changes, including eating habits, predisposing to obesity and metabolic dysfunctions. It involves a neuro-hormonal dysregulation of appetite towards positive energy balance, including increased ghrelin and decreased leptin, but little is known about other hormones, such as xenin, derived from the upper gut (like ghrelin), and lower gut hormones. Our objective was to compare night workers with day workers in relation to appetite-regulating hormones and other metabolic parameters.. Cross-sectional, observational study.. Twenty-four overweight women, divided into night shift workers (n = 12) and day shift workers (n = 12).. BMI, waist circumference, fat mass percentage; diet composition; Pittsburgh Sleep Quality Index; lipids; adipokines; meal tolerance test curves of glucose, insulin, ghrelin, PYY3-36, oxyntomodulin, xenin, GLP-1; insulin sensitivity (Stumvoll index).. Night workers, as compared with day workers, had greater body fat mass percentage and tendency to greater waist circumference despite similar BMI; greater energy intake; impaired sleep; lower insulin sensitivity; increased triglycerides and tendency to increased C-reactive protein; similar levels of leptin and other adipokines. Night workers had a blunted post-meal suppression of ghrelin (AUCi(0-60 min) 19·4 ± 139·9 vs -141·9 ± 9·0 ng/ml·60 min, P < 0·01); blunted rise of xenin (AUC(0-180 min) 8690·9 ± 2988·2 vs 28 504·4 ± 20 308·3 pg/ml·180 min, P < 0·01) and similar curves of PYY3-36, oxyntomodulin and GPL-1.. Compared with day workers within the same BMI range, night workers presented a disrupted control of ghrelin and xenin, associated with behavioural changes in diet and sleep and increased adiposity and related metabolic alterations.

Topics: Adiposity; Adult; Appetite Regulation; Cross-Sectional Studies; Digestive System; Energy Intake; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Neurotensin; Overweight; Oxyntomodulin; Peptide Fragments; Peptide YY; Sleep Disorders, Circadian Rhythm; Work Schedule Tolerance