vasoactive-intestinal-peptide and Diabetes-Mellitus--Type-1

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Humans; Inflammation; Inflammatory Bowel Diseases; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Rheumatic Diseases; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Type 1 diabetes (T1DM) is an autoimmune condition in which the immune system attacks and destroys insulin-producing beta cells in the pancreas leading to hyperglycemia. Vasoactive intestinal peptide (VIP) manifests insulinotropic and anti-inflammatory properties, which are useful for the treatment of diabetes. Because of its limited half-life due to DPP-4-mediated degradation, constant infusions or multiple injections are needed to observe any therapeutic benefit. Since gene therapy has the potential to treat genetic diseases, an HIV-based lentiviral vector carrying VIP gene (LentiVIP) was generated to provide a stable VIP gene expression in vivo. The therapeutic efficacy of LentiVIP was tested in a multiple low-dose STZ-induced animal model of T1DM. LentiVIP delivery into diabetic animals reduced hyperglycemia, improved glucose tolerance, and prevented weight loss. Also, a decrease in serum CRP levels, and serum oxidant capacity, but an increase in antioxidant capacity were observed in LentiVIP-treated animals. Restoration of islet cell mass was correlated with an increase in pancreatic beta-cell proliferation. These beneficial results suggest the therapeutic effect of LentiVIP is due to the repression of diabetes-induced inflammation, its insulinotropic properties, and VIP-induced beta-cell proliferation.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 1; Genetic Therapy; Inflammation; Insulin; Vasoactive Intestinal Peptide

Cardiovascular autonomic neuropathy (CAN) is a relatively common and detrimental complication of diabetes mellitus (DM). Dysregulation of neuropeptides, such as calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP), are thought to play significant roles in diabetes-related cardiovascular disease. Accumulating evidence indicates the neuroprotective effects of granulocyte-colony stimulating factor (G-CSF) in different neurological disorders. The purpose of the study is to investigate the role of CGRP and VIP and possible effects of G-CSF on CAN in type I DM model in rats.. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) for 14 rats. Seven rats served as controls and 6 rats were administered G-CSF alone. DM group was randomly divided into 2 groups and received either 1mL/kg saline (DM+saline group) or 100 μg/kg/day G-CSF (DM+G-CSF group) for 4 weeks. Following electrocardiography (ECG), GCRP and VIP levels were measured in plasma samples.. Diabetes promoted a significant prolongation in the corrected QT interval (cQT) (P<0.001) whereas G-CSF administration significantly shortened cQT interval (P<0.05). Plasma VIP and CGRP levels of saline treated DM group were significantly lower than those of control group (P<0.05). G-CSF treatment significantly prevented the reduction in plasma VIP and CGRP levels (P<0.01 and P<0.05, respectively). Also, correlation analysis showed a significant negative correlation between the cQT and neuropeptide levels.. This study suggests that G-CSF can be effective in CAN by means of neuroprotection, and plasma VIP and CGRP levels can be used for the assessment of autonomic and sensory functions in diabetes.

Topics: Animals; Calcitonin Gene-Related Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Granulocyte Colony-Stimulating Factor; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Streptozocin; Vasoactive Intestinal Peptide

The pathogenetic mechanisms underlying gastrointestinal dysmotility in diabetic patients remain poorly understood, although enteric neuropathy, damage to interstitial cells of Cajal (ICC) and smooth muscle cell injury are believed to play a role. The aim of this study was to investigate the morphological and functional changes underlying intestinal dysmotility in RIP-I/hIFNβ transgenic mice treated with multiple very low doses of streptozotocin (20 mg/kg, i.p., 5 days). Compared with vehicle-treated mice, streptozotocin-treated animals developed type 1 diabetes mellitus, with sustained hyperglycaemia for 3.5 months, polyphagia, polydipsia and increased faecal output without changes in faecal water content (metabolic cages). Diabetic mice had a longer intestine, longer ileal villi and wider colonic crypts (conventional microscopy) and displayed faster gastric emptying and intestinal transit. Contractility studies showed selective impaired neurotransmission in the ileum and mid-colon of diabetic mice. Compared with controls, the ileal and colonic myenteric plexus of diabetic mice revealed ultrastructural features of neuronal degeneration and HuD immunohistochemistry on whole-mount preparations showed 15% reduction in neuronal numbers. However, no immunohistochemical changes in apoptosis-related markers were noted. Lower absolute numbers of neuronal nitric oxide synthase- and choline acetyltransferase-immunopositive neurons and enhanced vasoactive intestinal polypeptide and substance P immunopositivity were observed. Ultrastructural and immunohistochemical analyses did not reveal changes in the enteric glial or ICC networks. In conclusion, this model of diabetic enteropathy shows enhanced intestinal transit associated with intestinal remodelling, including neuroplastic changes, and overt myenteric neuropathy. Such abnormalities are likely to reflect neuroadaptive and neuropathological changes occurring in this diabetic model.

Topics: Animals; Choline O-Acetyltransferase; Colon; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Gastric Emptying; Gastrointestinal Motility; Ileum; Interferon-beta; Male; Mice; Mice, Transgenic; Myenteric Plexus; Nitric Oxide Synthase Type I; Receptor-Interacting Protein Serine-Threonine Kinases; Streptozocin; Substance P; Vasoactive Intestinal Peptide

Type I diabetes is an autoimmune T-cell-mediated disease associated with overexpression of inflammatory mediators and the disturbance of different T-cell subsets. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent with regulatory effects on activated T cells. As the equilibrium between different T-cell subsets is involved in the final outcome, leading to tolerance or autoimmunity, we studied the evolution of markers for T cells in nonobese diabetic (NOD) mice. The study of different transcription factors, cytokines or cytokine receptors, shows that VIP interferes with functional phase of T helper 17 (Th17) cells and prevents the increase in the proportion of Th1 to Th17 cells. On the other hand, VIP-treated NOD mice show an increase in the proportion of CD4(+)CD25(+) cells in the spleen. Thus, VIP switches the Tregs/Th17 ratio leading to tolerance in NOD mice. Similarly, VIP reverses the ratio of Th1-/Th2-cell subsets associated with autoimmune pathology. All these effects on the ratio of T-cell subsets and the anti-inflammatory effect of VIP in decreasing proinflammatory mediators result in a reduction of β-cell destruction in pancreas. Taken together, these results show that VIP provides significant protection against spontaneous diabetes by modulating T-cell subsets and counterbalancing tolerance and immunity.

Topics: Animals; Autoimmunity; Cell Proliferation; Cytokines; Diabetes Mellitus, Type 1; Female; Forkhead Transcription Factors; Humans; Mice; Mice, Inbred NOD; Nuclear Receptor Subfamily 1, Group F, Member 3; Pancreas; Spleen; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells; Vasoactive Intestinal Peptide

A functional interaction between progesterone, Th2 cytokines and a suitable balance between nitric oxide and prostaglandins in the uterus is considered to have a major role in the success of embryo implantation and pregnancy. Non-obese diabetic (NOD) mice offer a suitable model to study the modulatory role of Th1 cytokines on uterus signalling and function, since at the prediabetic stage they develop a spontaneous Th1 autoimmune response against exocrine glands similar to Sjögren's syndrome. Vasoactive intestinal peptide (VIP) is a vasoactive neuro- and immunopeptide that promotes Th2 profiles and contributes to the smooth muscle relaxation and vasodilation. The aim of the present study was to investigate the activities of nitric oxide synthase and cyclo-oxygenase and the effect of VIP in the uterus of NOD mice with an emerging Th1 cytokine response. We present evidence of a reduced basal and VIP-stimulated activity of both enzymes in the uterus of NOD mice compared with normal BALB/c mice in proestrus. An altered functional interaction between both enzymes is also present in NOD mice at the time when increased levels of serum interleukin (IL)-12 and tumour necrosis factor-alpha but not interferon (IFN)-gamma or IL-10 were detected. We conclude that signalling alterations in uteri of NOD mice are simultaneous to the onset of a systemic Th1 cytokine response.

Topics: Animals; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 1; Dinoprostone; Enzyme Activation; Female; Immunohistochemistry; Indomethacin; Interferon-gamma; Interleukin-10; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Models, Animal; Nitric Oxide Synthase; omega-N-Methylarginine; Pregnancy; Prostaglandin-Endoperoxide Synthases; Sjogren's Syndrome; Th1 Cells; Tumor Necrosis Factor-alpha; Uterus; Vasoactive Intestinal Peptide

The spontaneous non-obese diabetic (NOD) mouse model of Sjögren's syndrome provides a valuable tool to study the onset and progression of both the autoimmune response and secretory dysfunction. Our purpose was to analyse the temporal decline of salivary secretion in NOD mice in relation to the autoimmune response and alterations in various signalling pathways involved in saliva secretion within each salivary gland. A progressive loss of nitric oxide synthase activity in submandibular and parotid glands started at 12 weeks of age and paralleled the decline in salivary secretion. This defect was associated with a lower response to vasoactive intestinal peptide in salivary flow rate, cAMP and nitric oxide/cGMP production. No signs of mononuclear infiltrates or local cytokine production were detectable in salivary glands in the time period studied (10-16 weeks of age). Our data support a disease model for sialadenitis in NOD mice in which the early stages are characterized by defective neurotransmitter-mediated signalling in major salivary glands that precedes the autoimmune response.

Topics: Animals; Autoantibodies; Autoimmunity; Cyclic GMP; Cytokines; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Nitric Oxide Synthase; Parotid Gland; Salivary Glands; Sialadenitis; Signal Transduction; Submandibular Gland; Vasoactive Intestinal Peptide

Diabetic neuropathy affects both sensory and autonomic peripheral nerve fibres. Vasoactive intestinal polypeptide (VIP) is present in autonomic fibres which modulate sweat secretion, while calcitonin gene-related peptide (CGRP) is localized to cutaneous sensory fibres. In this study, immunohistochemistry and image analysis were used to assess changes of VIP and CGRP, and of the pan-neuronal marker protein gene-product (PGP)-9.5, in skin biopsies of 18 patients affected by type 1 diabetes (age range 18-46 years) and from seven aged-matched controls. Patients were divided into three groups: group 1 (n = 6), with diabetes for 6 months to 3 years; group 2 (n = 5), with the disease for 5-10 years; and group 3 (n = 7), with diabetes for more than 10 years. VIP immunoreactivity (IR) and PGP-9.5-IR were significantly reduced around sweat glands (P < 0.005) in groups 2 and 3. Epidermal CGRP-IR and PGP-9.5-IR were significantly reduced in group 3 (P < 0.05). Twenty-eight per cent (5/18) of all patients showed high VIP-IR around sweat glands (> 95 per cent confidence limits of controls) and all of these patients had diabetes for less than 3 years. Conversely, 55 per cent (10/18) of patients had low VIP-IR (< 5 per cent confidence limit of controls). The latter, compared with the former, showed a significantly longer duration of diabetes (Fisher exact test P = 0.002), presence of clinical autonomic neuropathy (Fisher exact test P = 0.04), and a reduced sural nerve conduction velocity (Fisher exact test P = 0.04). These results suggest that quantitative immunohistochemical analysis of peptide-containing cutaneous nerves allows an objective evaluation of nerve fibre alterations at early stages of diabetes than is currently possible with neurophysiological functional tests.

Topics: Adolescent; Adult; Calcitonin Gene-Related Peptide; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Humans; Immunohistochemistry; Male; Middle Aged; Skin; Sweat Glands; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Plasma pancreatic polypeptide (PP), vasoactive intestinal polypeptide (VIP), substance P (SP), neurotensin (NT) and noradrenaline (NA) were measured in eight healthy subjects and 12 long-term insulin-dependent diabetic patients with and without autonomic neuropathy, before and after intravenous infusion of the ganglionic blocking agent trimethaphan camsylate, in order to determine the influence of the autonomic nervous system on the baseline values of the substances. The basal levels of the measured substances were not significantly different in healthy subjects and patients with or without diabetic autonomic neuropathy. In healthy subjects, the ganglionic blockade induced a significant decrease in PP (80%) (P less than 0.02), NA (58%) (P less than 0.05), NT (27%) (P less than 0.05) and a significant increase in SP (30%) (P less than 0.05), while the VIP concentration remained unchanged. The diabetic patients had nearly the same significant decrease in PP (68%) (P less than 0.01), NA (50%) (P less than 0.01), NT (22%) (P less than 0.02), VIP (21%) (P less than 0.05) and increase in SP (73%) (P less than 0.01). No relationship was found between the autonomic neuropathy and changes of the substances during ganglionic blockade. The results indicate that the postganglionic part of the autonomic nervous system participates in the maintenance of a normal baseline level of PP, NT and NA, but not of VIP. The regulation of VIP may be disturbed in long-term diabetic subjects.

Topics: Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Female; Humans; Male; Neurotensin; Norepinephrine; Pancreatic Polypeptide; Peptides; Substance P; Trimethaphan; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Alloxan; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; DNA Repair; Humans; Insulin; Islets of Langerhans; Molecular Weight; Pancreatic Neoplasms; Rats; Streptozocin; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) has been demonstrated by immunofluorescence histochemistry in nerves in human and rat penile tissue. A reduction in VIP-like immunoreactivity in nerves was revealed in tissue from streptozotocin-diabetic rats and a human diabetic with impotence. These results suggest that an impairment in the VIP-ergic innervation in penile tissue may be an important factor in the development of impotence in diabetes. They also support the view that the streptozotocin-treated rat is a useful experimental model for diabetic autonomic neuropathy.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Erectile Dysfunction; Fluorescent Antibody Technique; Humans; Male; Penis; Rats; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Aged; Diabetes Mellitus, Type 1; Humans; Hypokalemia; Liver Neoplasms; Male; Pancreatic Neoplasms; Streptozocin; Syndrome; Vasoactive Intestinal Peptide; Vipoma