glucagon-like-peptide-1 and Diabetic-Neuropathies

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 presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.

Topics: Antihypertensive Agents; Autonomic Nervous System Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Drug Therapy, Combination; Exenatide; Exercise Therapy; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Insulin; Oxidative Stress; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic β-cells, but also suppresses glucagon secretion from pancreatic α-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, Glucagon

Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs' dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN.

Topics: Antioxidants; Cytokines; Diabetic Neuropathies; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Inflammation; Insulin; Liraglutide; Nerve Growth Factors; Schwann Cells

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.

Topics: Animals; Cell Movement; Cell Survival; Chromones; Coculture Techniques; Diabetic Neuropathies; Exenatide; Ganglia, Spinal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin-Secreting Cells; Morpholines; Myelin Sheath; Neurons; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Schwann Cells; Sciatic Nerve

Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.

Topics: Animals; Diabetic Neuropathies; Disease Models, Animal; Ganglia, Spinal; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Fibers, Myelinated; Neural Conduction; Neuronal Outgrowth; Receptors, Glucagon; RNA, Messenger

1-[(2-adamantyl)amino]acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride (PKF275-055), a vildagliptin analog, is a novel, selective, potent, orally bioavailable, and long-acting dipeptidyl peptidase IV inhibitor. We studied the effect of PKF275-055 administration on the prevention, protection, and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. PKF275-055 improved body and muscle weight. Oral glucose tolerance tests showed a marked improvement in glucose metabolism under all treatment schedules. When tested in prevention and protection experiments, PKF275-055 completely averted the decrease of Na⁺/K⁺-ATPase activity and partially counteracted the nerve conduction velocity (NCV) deficit observed in untreated diabetic rats but had no effects on abnormal mechanical and thermal sensitivity. When used in a therapeutic setting, PKF275-055 induced a significant correction in the alteration in Na⁺,K⁺-ATPase activity and NCV present in untreated diabetics. Diabetic rats developed mechanical hyperalgesia within 2 weeks after streptozotocin injection and exhibited significantly longer thermal response latencies. It is noteworthy that PKF275-055 treatment restored mechanical sensitivity thresholds by approximately 50% (p < 0.01) and progressively improved the alteration in thermal responsiveness. In conclusion, PKF275-055 showed an anabolic effect, improved oral glucose tolerance, and counteracted the alterations in Na⁺,K⁺-ATPase activity, NCV, and nociceptive thresholds in diabetic rats. The present data support a potential therapeutic effect of PKF275-055 in the treatment of rodent diabetic neuropathy.

Topics: Adamantane; Animals; Behavior, Animal; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Dose-Response Relationship, Drug; Drinking; Eating; Glucagon-Like Peptide 1; Glucose Tolerance Test; Male; Neural Conduction; Nitriles; Pain Threshold; Peripheral Nervous System Diseases; Pyrrolidines; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Vildagliptin

Like insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months' diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

Topics: Animals; Axons; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Immunohistochemistry; Insulin; Male; Mice; Motor Neurons; Neural Conduction; Peptides; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Sensory Receptor Cells; Signal Transduction; Venoms

A 22 year old obese woman with type 1 diabetes for 17 years and poor metabolic control despite continuous insulin infusion (case 1). Case 2 was a 16 year-old girl of normal weight in whom diabetes mellitus type 1 was diagnosed accidentally. Her 54 year old father was and had been treated for diabetes mellitus type 1 for 10 years. He was poorly controlled and associated with polyneuropathy and history of myocardial infarction (case 3).. In Case 1 the C-peptide test was negative, glutamic acid decarboxylase- and IA2-antibodies were not demonstrated. Cases 2 and 3 showed normal C-peptide, tests for GAD-, IA2- and ICA antibodies were negative. A nucleotid substitution in intron 1 of the HNF-4α gene was demonstrated.. All three patients were treated with liraglutide. There was a reduction in HbA(1c), glucose fluctuations, hypoglycaemia, daily insulin dose and body weight, as well as an improvement of well-being and quality of life.. These case reports indicate that GLP-1 analogs may reduce postprandial and fasting glucose levels in non-type 2 diabetic patients, independently or residual beta cell function. Further studies are needed to evaluate the benefits of treatment with liraglutide in patients with type 1 or type 3 diabetes.

Topics: Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidental Findings; Insulin; Insulin Resistance; Liraglutide; Male; Middle Aged; Young Adult

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces glucose-dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP-1 receptors (GLP-1Rs) in peripheral nerve and to assess the impact of GLP-1R agonists on diabetes-induced nerve disorders.. Tissues were collected from streptozotocin-diabetic rats. GLP-1R function was assessed by incubating tissues from normal and diabetic rats with GLP-1R agonists and antagonists and measuring induction of ERK1/2 phosphorylation by Western blot. Streptozotocin-diabetic mice were also treated with the GLP-1R agonist exenatide for 8 weeks to assess the impact of GLP-1R signalling on peripheral nerve function and structure.. GLP-1R protein was detected in rat dorsal root ganglia and the neurons and Schwann cells of the sciatic nerve. Protein levels were not affected by streptozotocin-induced diabetes. GLP-1R agonists did not signal via ERK1/2 in sciatic nerve of normal rats. However, GLP-1R agonists significantly increased pERK1/2 levels in sciatic nerves from diabetic rats, indicating that GLP-1Rs are functional in this tissue. Exenatide treatment did not affect blood sugar, insulin levels or paw thermal response latencies in either control or diabetic mice. However, the reductions of motor nerve conduction velocity and paw intraepidermal fibre density seen in diabetic mice were attenuated by exenatide treatment.. These data show that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; MAP Kinase Signaling System; Mice; Neural Conduction; Rats; Receptors, Glucagon; Sciatic Nerve; Signal Transduction

GLP-1 lowers blood glucose in fasting type 2 diabetic patients. To clarify the relation of the effect of GLP-1 to obesity, blood glucose, beta-cell function, and insulin sensitivity, GLP-1 (1.2 pmol/kg.min) was infused iv for 4-6 h into 50 fasting type 2 diabetic patients with a wide range of age, body mass index, HbA1c, and fasting plasma glucose. The effectiveness of GLP-1 was evaluated by calculation of a glucose disappearance constant for each individual (Kg, linear slope of log-transformed plasma glucose), and by the lowest stable glucose level (Nadir plasma glucose) obtained during the infusion. Grouped according to fasting plasma glucose (<10, 10-15, >15 mmol/liter), Kg values were 0.45 +/- 0.03, 0.38 +/- 0.04, and 0.28 +/- 0.04%/min (P = 0.005), and Nadir plasma glucose values were 4.7 +/- 0.1 (3.9-5.9), 5.8 +/- 0.4 (4.3-8.4), and 8.7 +/- 1.4 (6.2-18.7) mmol/liter (P = 0.0003). Nonresponders were not identified. Multiple regression analysis with Kg or Nadir plasma glucose as the dependent parameter and body mass index, age, gender, diabetes duration, and significantly correlated parameters (in multiple regression for Kg: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, peak insulin, and the logarithm of beta-cell function; and for Nadir plasma glucose: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, delta glucagon decrement, F-GLP-1 total, logarithm of beta-cell function, and Kg) as independent parameters resulted in fasting plasma glucose as the only significant predictor of Kg, and fasting plasma glucose and Kg as predictors of Nadir plasma glucose. Kg and Nadir plasma glucose were neither influenced by treatment nor by neuropathy per se. In conclusion, GLP-1 lowers plasma glucose in type 2 diabetes regardless of severity, but glucose elimination is faster and obtained glycemic level lower in patients with the lower fasting plasma glucose. Not all patients can be expected to reach normoglycemia.

Topics: Area Under Curve; Autoantibodies; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dipeptidyl Peptidase 4; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Infusions, Intravenous; Insulin; Islets of Langerhans; Isoenzymes; Male; Middle Aged; Peptide Fragments; Protein Precursors; Regression Analysis