exenatide and Chronic-Disease

The pathophysiology of type 2 diabetes mellitus is complex, consisting of far more physiologic defects than simple insulin resistance and β-cell dysfunction. Our understanding of this progressive disease has moved from a "dual defect" to an "ominous octet" description. This multifactoral concept may explain the difficulty in achieving and maintaining glycemic goals with traditional therapies. Glucagon-like peptide-1 (GLP-1) agonists, which improve insulin secretion, decrease glucagon secretion, increase satiety (and therefore decrease food intake), and may have beneficial effects on β-cell function, represent an important addition to treatment options. Their glucose-dependent mechanism limits the risk for hypoglycemia, and they are associated with weight loss. Glucagon-like peptide-1 agonists may be used alone in patients intolerant of metformin or in combination with metformin, thiazolidinediones, and sulfonylureas (or in any combination therereof). Concomitant use of dipeptidyl-peptidase-4 inhibitors is not recommended because they have a similar basis of action. Current US Food and Drug Administration indications do not include the concomitant use of GLP-1 agonists with insulin.

Topics: Algorithms; Chronic Disease; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms

Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE. ApoE. Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice.. These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE

Topics: Adiponectin; Age Factors; Animals; Aorta; Aortic Diseases; Atherosclerosis; Cells, Cultured; Cellular Senescence; Chronic Disease; Diet, High-Fat; Dipeptidyl Peptidase 4; Disease Models, Animal; Endothelial Cells; Exenatide; Foam Cells; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Incretins; Inflammation Mediators; Male; Mice, Knockout, ApoE; Oxidative Stress; Peptide Hydrolases; Peptides; Phenotype; Plaque, Atherosclerotic; Proteolysis; Signal Transduction; Stress, Psychological; Venoms

Diabetes mellitus is an independent risk factor for impaired healing of peptic ulcers, and there are currently no supplementary therapeutics other than the standard antipeptic medicine to improve the ulcer healing in diabetes. This study examined the potential pleiotropic effect of a glucagon-like peptide (Glp)-1 analogue exendin (Ex)-4 on the regeneration of gastric ulcer in streptozotocin-induced diabetic rats.. Chronic ulcer was created in rat stomach by submucosal injection of acetic acid and peri-ulcer tissues were analyzed 7 days after operation. Ulcer wound healing was impaired in diabetic rats with suppressed tissue expression of eNOS and enhanced levels of pro-inflammatory reactions. Treatment with intraperitoneal injection of Ex4 (0.5 μg/kg/d) significantly reduced the area of gastric ulcer without changing blood glucose level. Ex-4 restored the expression of pro-angiogenic factors, and attenuated the generation of regional inflammation and superoxide anions. The improvement of ulcer healing was associated with increased expression of MMP-2 and formation of granulation tissue in the peri-ulcer area.. Administration of Ex4 may induce pro-angiogenic, anti-inflammatory and anti-oxidative reactions in the peri-ulcer tissue of diabetic rats that eventually enhances tissue granulation and closure of ulcerative wounds. Our results support the potential clinical application of Glp-1 analogues as supplementary hypoglycemic agents in the antipeptic ulcer medication in diabetes.

Topics: Animals; Chronic Disease; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Peptides; Rats; Stomach Ulcer; Streptozocin; Venoms; Wound Healing

Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in β-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E β-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects β-cells, mouse and human islets from cytokine-induced apoptosis and preserves glucose-induced insulin secretion in mouse and human islets exposed to cytokines. Moreover, Tpl2 inhibition does not affect survival or positive effects of glucose (i.e., ERK1/2 phosphorylation and basal insulin secretion). The protection against cytokine-induced β-cell apoptosis is strengthened when Tpl2 inhibition is combined with the glucagon-like peptide-1 (GLP-1) analog exendin-4 in INS-1E cells. Furthermore, when combined with exendin-4, Tpl2 inhibition prevents cytokine-induced death and dysfunction of human islets. This study proposes that Tpl2 inhibitors, used either alone or combined with a GLP-1 analog, represent potential novel and effective therapeutic strategies to protect diabetic β-cells.

Topics: Apoptosis; Chronic Disease; Cytokines; Diabetes Mellitus, Type 2; Exenatide; Humans; Inflammation; MAP Kinase Kinase Kinases; Peptides; Venoms

A few case reports suggest that incretin-based therapies could improve psoriasis in patients with type 2 diabetes, the mechanism(s) of which remain unclear.. To determine the effects after 16-20 weeks of treatment with a glucagon-like peptide (GLP)-1 analogue on clinical severity and histopathological aspects of psoriasis in patients with type 2 diabetes, and to examine the presence of γδ T cells and the expression of interleukin (IL)-17 in psoriasis before and after treatment.. Seven patients with type 2 diabetes and psoriasis were followed. Psoriasis Area and Severity Index (PASI) was measured at baseline (T0) and after 7 ± 1 (T1) and 18 ± 2 (T2) weeks' treatment with exenatide/liraglutide. The histopathological pattern of psoriasis, and flow cytometry and immunological data (γδ T-cell percentage and IL-17 expression) were obtained from psoriatic and control sites.. The mean PASI decreased from 12·0 ± 5·9 to 9·2 ± 6·4 (P = 0·04). Histological analysis showed a reduction in epidermal thickness after treatment. The dermal γδ T-cell percentage was higher in psoriatic lesions than in control specimens (P = 0·03), as was IL-17 expression (P = 0·018). A reduction of γδ T cells from 6·7 ± 4·5% to 2·7 ± 3·8% (P = 0·05) was demonstrated in the six patients with improved/unchanged PASI. A correlation between PASI and γδ T-cell percentage evolution during therapy (T2-T0) was noted (r = 0·894, P = 0·007). IL-17 was reduced in the four patients with the highest PASI reductions.. The administration of a GLP-1 analogue improved clinical psoriasis severity in patients with type 2 diabetes. This favourable outcome was associated with a decrease of dermal γδ T-cell number and IL-17 expression. Further studies are needed to establish long-term efficacy in (diabetic) patients with psoriasis.

Topics: Adult; Chronic Disease; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Interleukin-17; Liraglutide; Lymphocyte Count; Male; Middle Aged; Peptides; Prospective Studies; Psoriasis; Severity of Illness Index; Skin; T-Lymphocytes; Treatment Outcome; Venoms