Extrapancreatic effects of incretin hormones: evidence for weight‐independent changes in morphological aspects and oxidative status in insulin‐sensitive organs of the obese nondiabetic Zucker rat (ZFR)

Abstract

Incretin‐based therapies are widely used to treat type 2 diabetes. Although hypoglycemic actions of incretins are mostly due to their insulinotropic/glucagonostatic effects, they may also influence extrapancreatic metabolism. We administered exendin‐4 (Ex‐4), a long‐acting glucagon‐like peptide receptor agonist, at low dose (0.1 nmol/kg/day) for a short period (10 days), in obese nondiabetic fa/fa Zucker rats (ZFRs). Ex‐4‐treated ZFRs were compared to vehicle (saline)‐treated ZFRs and vehicle‐ and Ex‐4‐treated lean rats (LRs). Blood glucose levels were measured at days 0, 9, and 10. Ingested food and animal weight were recorded daily. On the day of sacrifice (d10), blood was sampled along with liver, epididymal, subcutaneous, brown adipose, and skeletal muscle tissues from animals fasted for 24 h. Plasma insulin and blood glucose levels, food intake, and body and epididymal fat weight were unchanged, but gross morphological changes were observed in insulin‐sensitive tissues. The average size of hepatocytes was significantly lower in Ex‐4‐treated ZFRs, associated with decreased number and size of lipid droplets and 4‐hydroxy‐2‐nonenal (HNE) staining, a marker of oxidative stress (OS). Myocytes, which were smaller in ZFRs than in LRs, were significantly enlarged and depleted of lipid droplets in Ex‐4‐treated ZFRs. Weak HNE staining was increased by Ex‐4. A similar observation was made in brown adipose tissue, whereas the elevated HNE staining observed in epididymal adipocytes of ZFRs, suggestive of strong OS, was decreased by Ex‐4. These results suggest that incretins by acting on OS in insulin‐sensitive tissues may contribute to weight‐independent improvement in insulin sensitivity.

Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis

“…Measurement of individual muscle fiber diameter revealed a significant loss in SOD1 G93A mice as compared to WT mice (P = 0.00001), which was partially corrected in P110-treated G93A mice, indicating decreased atrophy (P = 0.0003) (Fig 4B and E). Since previous studies have attributed muscle atrophy with increased oxidative stress, we determined 4-hydroxy-2-nonenal (4-HNE) adducts on proteins in gastrocnemius muscle (Russell et al, 2003;Colin et al, 2016). 4-HNE is a nine-carbon amphiphilic lipidderived aldehyde formed by oxidation of nÀ6 polyunsaturated fatty acids.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Other effects are suggestive of glucose‐independent effects of GLP‐1R agonists on muscle. Colin et al showed that myocytes from obese, nondiabetic Zucker rates were significantly enlarged and depleted of lipid droplets with exendin‐4 treatment, secondary to modulation of oxidative stress; Takada et al showed improved mitochondrial function and exercise capacity in mice receiving exendin‐4 . Exenatide was reported to prevent sarcoma‐induced cachexia in a mouse model, while liraglutide was shown to improve skeletal muscle capillary density in an animal model of insulin resistance, indicating a protective role against metabolic insulin resistance at the skeletal muscle level .…”