vasoactive-intestinal-peptide and Insulin-Resistance

To review and discuss the available international literature regarding the indirect and direct biochemical mechanisms that occur after exercise, which could positively, or negatively, influence oncogenic pathways.. The PubMed, MEDLINE, Embase and Cochrane libraries were searched for papers up to July 2016 addressing biochemical changes after exercise with a particular reference to cancer. The three authors independently assessed their appropriateness for inclusion in this review based on their scientific quality and relevance.. 168 papers were selected and categorised into indirect and direct biochemical pathways. The indirect effects included changes in vitamin D, weight reduction, sunlight exposure and improved mood. The direct effects included insulin-like growth factor, epigenetic effects on gene expression and DNA repair, vasoactive intestinal peptide, oxidative stress and antioxidant pathways, heat shock proteins, testosterone, irisin, immunity, chronic inflammation and prostaglandins, energy metabolism and insulin resistance.. Exercise is one of several lifestyle factors known to lower the risk of developing cancer and is associated with lower relapse rates and better survival. This review highlights the numerous biochemical processes, which explain these potential anticancer benefits.

Topics: Carcinogenesis; Energy Metabolism; Epigenesis, Genetic; Exercise; Fibronectins; Heat-Shock Proteins; Humans; Inflammation; Insulin Resistance; Life Style; Neoplasms; Oxidative Stress; Prostaglandins; Somatomedins; Testosterone; Vasoactive Intestinal Peptide

Reciprocal interactions closely connect energy metabolism with circadian rhythmicity. Altered clockwork and circadian desynchronization are often linked with impaired energy regulation. Conversely, metabolic disturbances have been associated with altered autonomic and hormonal rhythms. The effects of high-energy (HE) diet on the master clock in the suprachiasmatic nuclei (SCN) remain unclear.This question was addressed in the Sand rat (Psammomys obesus), a non-insulin-dependent diabetes mellitus (NIDDM) animal model. The aim of this work was to determine whether enriched diet in Psammomys affects locomotor activity rhythm, as well as daily oscillations in the master clock of the SCN and in an extra-SCN brain oscillator, the piriform cortex. Sand rats were fed during 3 months with either low or HE diet. Vasoactive intestinal peptide (VIP), vasopressin (AVP) and CLOCK protein cycling were studied by immunohistochemistry and running wheel protocol was used for behavioral analysis. High energy feeding dietary triggered hyperinsulinemia, impaired insulin/glucose ratio and disruption in pancreatic hormonal rhythms. Circadian disturbances in hyper-insulinemic animals include a lengthened rest/activity rhythm in constant darkness, as well as disappearance of daily rhythmicity of VIP, AVP and the circadian transcription factor CLOCK within the suprachiasmatic clock. In addition, daily rhythmicity of VIP and CLOCK was abolished by HE diet in a secondary brain oscillator, the piriform cortex. Our findings highlight a major impact of diabetogenic diet on central and peripheral rhythmicity. The Psammomys model will be instrumental to better understand the functional links between circadian clocks, glucose intolerance and insulin resistance state.

Topics: Animals; Biological Clocks; Body Weight; Brain; CLOCK Proteins; Diet; Dietary Fats; Dietary Fiber; Eating; Gene Expression Regulation; Gerbillinae; Insulin Resistance; Somatostatin; Vasoactive Intestinal Peptide; Vasopressins

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ-induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Gene Transfer Techniques; Glucose; Glucose Intolerance; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lentivirus; Mice; Mice, Inbred C57BL; Obesity; Vasoactive Intestinal Peptide

Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver-brain-pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote β-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in β-cells selectively, thereby efficiently promoting β-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic β-cells.

Topics: Animals; Blood Glucose; Brain; Carbachol; Cell Proliferation; Cholinergic Agonists; Forkhead Box Protein M1; Gastrointestinal Agents; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Liver; Mice; Neurons; Neurotransmitter Agents; Obesity; Pituitary Adenylate Cyclase-Activating Polypeptide; Signal Transduction; Vagotomy; Vagus Nerve; Vasoactive Intestinal Peptide

Islet beta cell adaptation to dexamethasone-induced insulin resistance was characterized with respect to glucose-stimulated insulin secretion and islet innervation. Male Sprague-Dawley rats were injected daily with dexamethasone (2 mg/kg for 12 days), which resulted in hyperinsulinemia and hyperglycemia compared with controls (which were injected with sodium chloride). Insulin secretion was characterized in collagenase-isolated islets. Islet innervation was examined by immunocytochemical analysis of tyrosine hydroxylase, neuropeptide Y (sympathetic nerves), and vasoactive intestinal polypeptide (cholinergic nerves). In islets isolated from the insulin-resistant animals, the insulin response to 3.3 or 8.3 mM glucose was three times greater during perifusion compared with controls (p < 0.001). Incubation of islets at 0 to 20 mM glucose revealed a marked leftward shift of the glucose dose-response relation after dexamethasone treatment (potency ratio, 1.78; p < 0.01), with no difference at 0 or 20 mM glucose. Thus, the potency but not the efficacy of glucose was increased. The number of islet nerves did not differ between dexamethasone-treated rats and controls. Dexamethasone-induced insulin resistance leads to adaptively increased glucose responsiveness of the islet beta cells, with increased potency, but not increased efficacy, of glucose to stimulate insulin secretion without any evidence of altered islet innervation.

Topics: Adaptation, Physiological; Animals; Blood Glucose; Dexamethasone; Female; Insulin Resistance; Islets of Langerhans; Neuropeptide Y; Perfusion; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

To study islet function following reduced insulin sensitivity, we examined mice of the C57BL/6J strain, the genotype of which carries an increased propensity to develop insulin resistance when metabolically challenged. The mice received either a high-fat diet (58% fat on an energy basis) or a control diet (11% fat) for 12 weeks. The body weight of mice on the high-fat diet increased significantly more than that of mice on the control diet (25.8 +/- 0.4 v 21.3 +/- 0.2 g, P < .001). Already after 1 week on the high-fat diet, a significant hyperglycemia accompanied by hyperinsulinemia had evolved, indicative of insulin resistance. After 12 weeks, plasma glucose levels for high-fat diet-treated mice were 7.5 +/- 0.1 mmol/L, versus 6.5 +/- 0.1 mmol/L in controls (P < .001); corresponding values for plasma insulin were 248 +/- 17 and 104 +/- 7 pmol/L, respectively (P < .001). Mice given a high-fat diet also had elevated levels of total cholesterol, triglycerides, and free fatty acids (FFAs) compared with controls. After 4, 8, and 12 weeks, glucose (2.8, 8.3, or 16.7 mmol/kg) or the cholinergic agonist carbachol (0.16 or 0.53 micromol/kg) was injected intraperitoneally. The insulinotropic response to glucose was not different between the two groups after 4 or 8 weeks, whereas after 12 weeks, glucose-induced insulin secretion was markedly impaired in high-fat diet-treated mice (P < .001). In contrast, after 8 and 12 weeks on a high-fat diet, carbachol-stimulated insulin secretion was potentiated (P < .01), whereas carbachol-stimulated glucagon secretion was not significantly altered. Furthermore, after 12 weeks on the high-fat diet, insulin secretion from isolated islets was impaired at glucose levels of 8.3, 11.1, and 16.7 mmol/L (P < or = .05). Moreover, islet morphology as examined by immunocytochemistry using insulin antibodies and islet innervation, as revealed by immunostaining of tyrosine hydroxylase (TH), neuropeptide Y (NPY), galanin, vasoactive intestinal polypeptide (VIP), and substance P (SP) were unaffected by the high-fat diet for 12 weeks. However, quantitative in situ hybridization showed a 3.5-fold upregulation of insulin gene expression in response to the high-fat diet (P < .001) despite unaltered B-cell mass and pancreatic insulin content. We conclude that as little as 1 week of treatment with a high-fat diet induces insulin resistance in C57BL/6J mice. This is accompanied later by hyperlipemia, potentiated carbachol-stimulated insulin secretio

Topics: Animals; Blood Glucose; Body Weight; Carbachol; Cholesterol; Dietary Fats; Eating; Fatty Acids, Nonesterified; Female; Fluorescent Antibody Technique, Indirect; Galanin; Gene Expression; Genotype; Glucagon; Glucose; Immunohistochemistry; In Situ Hybridization; Insulin; Insulin Resistance; Islets of Langerhans; Mice; Mice, Inbred C57BL; Muscarinic Agonists; Neuropeptide Y; Substance P; Triglycerides; Vasoactive Intestinal Peptide