exenatide 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

This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy.. This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy.. A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05).. Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control.

Topics: Cornea; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Exenatide; Female; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Microscopy, Confocal; Middle Aged; Nerve Fibers; Nerve Regeneration; Pioglitazone; Treatment Outcome

To assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D).. This is a substudy of the Qatar Study, an open-label, randomized controlled trial. 38 subjects with poorly controlled T2D were studied at baseline and 1-year follow-up and 18 control subjects were assessed at baseline only. A combination of exenatide (2 mg/week) and pioglitazone (30 mg/day) or glargine with aspart insulin were randomly assigned to patients to achieve an HbA1c <53 mmol/mol (<7%). DPN was assessed with corneal confocal microscopy (CCM), DN4, vibration perception and sudomotor function.. Subjects with T2D had reduced corneal nerves, but other DPN measures were comparable with the control group. In the combination treatment arm (n=21), HbA1c decreased by 35.2 mmol/mol (3.8 %) (p<0.0001), body weight increased by 5.6 kg (p<0.0001), corneal nerve branch density increased (p<0.05), vibration perception worsened (p<0.05), and DN4 and sudomotor function showed no change. In the insulin treatment arm, HbA1c decreased by 28.7 mmol/mol (2.7 %) (p<0.0001), body weight increased by 4.6 kg (p<0.01), corneal nerve branch density and fiber length increased (p≤0.01), vibration perception improved (p<0.01), and DN4 and sudomotor function showed no change. There was no association between the change in CCM measures with change in HbA1c, weight or lipids.. Treatment with exenatide and pioglitazone or basal-bolus insulin results in corneal nerve regeneration, but no change in neuropathic symptoms or sudomotor function over 1 year.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Peptides; Pioglitazone; Qatar; Venoms

Mitochondrial dysfunction under diabetic condition leads to the development and progression of neurodegenerative complications. Recently, the beneficial effects of glucagon-like peptide-1 (GLP-1) receptor agonists on diabetic neuropathies have been widely recognized. However, molecular mechanisms underlying the neuroprotective effects of GLP-1 receptor agonists against high glucose (HG)-induced neuronal damages is not completely elucidated. Here, we investigated the underlying mechanisms of GLP-1 receptor agonist treatment against oxidative stress, mitochondrial dysfunction, and neuronal damages under HG conditions mimicking a diabetic hyperglycemic state in SH-SY5Y neuroblastoma cells. We revealed that treatment with exendin-4, a GLP-1 receptor agonist, not only increased the expression of survival markers, phospho-Akt/Akt and Bcl-2, but also decreased the expression of pro-apoptotic marker, Bax, and reduced the levels of reactive oxygen species (ROS) defense markers (catalase, SOD-2, and HO-1) under HG conditions. The expressions of mitochondrial function associated genes, MCU and UCP3, and mitochondrial fission genes, DRP1 and FIS1, were decreased by exendin-4 compared to non-treated levels, while the protein expression levels of mitochondrial homeostasis regulators, Parkin and PINK1, were enhanced. In addition, blockade of Epac and Akt activities was able to antagonize these neuroprotective effects of exendin-4. Collectively, we demonstrated that stimulation of GLP-1 receptor propagates a neuroprotective cascade against the oxidative stress and mitochondrial dysfunction as well as augments survival through the Epac/Akt-dependent pathway. Therefore, the revealed mechanisms underlying GLP-1 receptor pathway by preserving mitochondrial homeostasis would be a therapeutic candidate to alleviate neuronal dysfunctions and delay the progression of diabetic neuropathies.

Topics: Apoptosis; Diabetic Neuropathies; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Mitochondria; Neuroblastoma; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-akt

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

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 μg/kg). One group of diabetic rats was treated with Byetta® (1 μg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.

Topics: Animals; Arginine; Blood Glucose; Diabetic Neuropathies; Dose-Response Relationship, Drug; Exenatide; Gene Expression Regulation; Glycated Hemoglobin; Hyperalgesia; Insulin; Islets of Langerhans; Locomotion; Male; Organ Size; Rats; Rats, Wistar; Sciatic Nerve

Comorbid neurobehavioral disturbances and type-2 diabetes mellitus (T2DM) warrant immediate research attention. Exenatide, which is a potent and selective agonist for the glucagon-like peptide-1 (GLP-1), is used in the treatment of T2DM. Exenatide displays a multitude of effects in the central nervous system. The aim of this study was to investigate the anxiolytic- and antidepressant-like effects and analgesic effects of exenatide in a type-2 diabetic mouse model.. Modified elevated plus-maze test for anxiolytic-like, forced swimming test for depression-like behavior and hotplate test for neuropathy were used as behavioral tasks. Behavioral parameters were investigated in a streptozocin--(100 mg/kg, i.p.) and nicotinamide--(240 mg/kg, i.p.) induced type-2 diabetic mouse model. Exenatide (0.1 µg/kg, s.c., twice daily) was administered for 2 weeks. Vehicle (control), diabetic, and exenatide-treated diabetic mice were tested.. Our results confirm that exenatide exerts anxiolytic- and antidepressant-like effects and might be effective in diabetic neuropathy in a diabetic mouse model.. Exenatide may be a good candidate as a treatment option for depression, anxiety, and neuropathy in patients with type-2 diabetes.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Exenatide; Immobilization; Male; Maze Learning; Mice, Inbred BALB C; Motor Activity; Peptides; Reaction Time; Time Factors; Venoms

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Drug Therapy, Combination; Evidence-Based Medicine; Exenatide; Female; Humans; Hypertension; Hypoglycemic Agents; Male; Metformin; Peptides; Venoms

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

The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated.. The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell-conditioned media in the presence or absence of GLP-1 (7-37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated.. The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7-37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell-conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA(1c) levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4.. Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Exenatide; Ganglia, Spinal; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Male; Mice; Neural Conduction; Peptides; Receptors, Glucagon; Schwann Cells; Sciatic Nerve; Venoms