incretins and Diabetic-Neuropathies

Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular andmicrovascular complications. Macrovascular complications include coronary artery diseaseand cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications.

Topics: Animals; Cardiovascular Diseases; Cerebrovascular Circulation; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Inflammation; Kidney; Oxidative Stress; Protein Kinase C

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Neuropathies; Evidence-Based Medicine; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Receptors, Glucagon; Venoms

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

Topics: Alzheimer Disease; Brain Ischemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liver Diseases; Parkinson Disease; Patient Care Planning

Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function.. The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing.. Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02).. Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

Topics: Adult; Autonomic Nervous System; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Double-Blind Method; Electric Stimulation; Electroencephalography; Evoked Potentials, Somatosensory; Female; Humans; Incretins; Interleukin-6; Liraglutide; Male; Median Nerve; Middle Aged; Polyneuropathies; Prospective Studies; Treatment Failure; Weight Loss

The aim of this study was to determine the effect of diabetic autonomic neuropathy (AN) on the incretin effect in patients with type 2 diabetes mellitus (DM2).. Forty patients with DM2 (20 with and 20 without AN) and 10 healthy controls were studied. The subjects underwent an oral glucose tolerance test (OGTT) and 7-14 days later an intravenous infusion of 25 g glucose. Blood samples were drawn for glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) determination during the tests. The incretin effect was calculated from the total integrated amount of insulin or C-peptide during OGTT (A) and intravenous glucose infusion (B) according to the formula (A-B)/Ax100.. Total insulin and C-peptide responses during OGTT were significantly higher than those after IV glucose infusion in the group of normal subjects, but not in the groups of diabetic patients. After the oral glucose load, GIP levels presented a significant increase in normal subjects and patients without AN, whereas GLP-1 levels increased only in normal subjects. Calculated either with the insulin or C-peptide responses, the incretin effect presented no significant difference between the two diabetic groups. However, using insulin responses, only the patients with AN had significantly lower incretin effect than controls, whereas when using C-peptide responses, both diabetic groups did.. The incretin effect was impaired in both groups of diabetic patients. Autonomic neuropathy may further impair the incretin effect in DM2 through interference with GIP secretion or hepatic insulin extraction.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Health; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male

Diabetic neuropathy is one of the major three diabetic complications, together with diabetic retinopathy and nephropathy. It develops early and with a high incidence after the onset of diabetes mellitus and influences the QOL and prognosis of patients with diabetes mellitus. Although the exact mechanism by which hyperglycemia causes nerve damage remains a subject of debate, metabolic and vascular disturbances due to hyperglycemia are assumed to cause nerve damage. The treatments of diabetic neuropathy aim at both the inhibition of its onset and progression (causative treatment) and the care for symptoms due to neuropathy such as pain(symptomatic treatment). In this paper, we describe the outlines of these two kinds of treatment for diabetic neuropathy.

Topics: Blood Glucose; Diabetic Neuropathies; Humans; Incretins

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incretins; Obesity; Postprandial Period; Prevalence