exenatide and Atrophy

Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice.. We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry.. Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor.. Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.. This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Topics: Animals; Atrophy; Blood Glucose; Cicatrix; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Infarction, Middle Cerebral Artery; Insulin Resistance; Male; Mice; Parvalbumins; Stroke; Vascular Remodeling

Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

Topics: Acute Disease; Animals; Apoptosis; Atrophy; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Necrosis; Pancreas; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms