Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

Abstract

Thyfault JP, Rector RS. Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am J Physiol Endocrinol Metab 306: E300 -E310, 2014. First published December 10, 2013; doi:10.1152/ajpendo.00427.2013.-Here, we sought to compare the efficacy of combining exercise and metformin for the treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in hyperphagic, obese, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (age: 20 wk, hyperglycemic and hyperinsulinemic; n ϭ 10/group) were randomly assigned to sedentary (O-SED), SED plus metformin (O-SED ϩ M; 300 mg·kg Ϫ1 ·day Ϫ1 ), moderate-intensity exercise training (O-EndEx; 20 m/min, 60 min/day, 5 days/wk treadmill running), or O-EndEx ϩ M groups for 12 wk. Long-Evans Tokushima Otsuka (L-SED) rats served as nonhyperphagic controls. O-SED ϩ M, O-EndEx, and O-EndEx ϩ M were effective in the management of type 2 diabetes, and all three treatments lowered hepatic steatosis and serum markers of liver injury; however, O-EndEx lowered liver triglyceride content and fasting hyperglycemia more than O-SED ϩ M. In addition, exercise elicited greater improvements compared with metformin alone on postchallenge glycemic control, liver diacylglycerol content, hepatic mitochondrial palmitate oxidation, citrate synthase, and ␤-HAD activities and in the attenuation of markers of hepatic fatty acid uptake and de novo fatty acid synthesis. Surprisingly, combining metformin and aerobic exercise training offered little added benefit to these outcomes, and in fact, metformin actually blunted exerciseinduced increases in complete mitochondrial palmitate oxidation and ␤-HAD activity. In conclusion, aerobic exercise training was more effective than metformin administration in the management of type 2 diabetes and NAFLD outcomes in obese hyperphagic OLETF rats. Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations. exercise training; metformin; nonalcoholic fatty liver disease; hepatic mitochondria; de novo lipogenesis; Otsuka Long-Evans Tokushima Fatty rats NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is a progressive liver disease characterized by hepatic triglyceride (TG) accumulation (Ն5% by weight for diagnosis) that occurs in the absence of excess alcohol consumption (Ͼ20 g/day). It encompasses a histological spectrum ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis (40). NAFLD is considered the hepatic manifestation of the metabolic syndrome (11), and it affects ϳ30% of the US adult population (3, 7) and ϳ70% of type 2 diabetics (52). However, there are currently no clear guidelines for the treatment of NAFLD.A component of prevention and treatment recommendations addressing NAFLD involves lifestyle modifications that alter net energy status. Indeed, both short-term (6) and longer-term caloric restriction (10, 23), a...

Treating NAFLD in OLETF Rats with Vigorous-Intensity Interval Exercise Training

“…Currently it is recommended that adults complete at least 150 minutes of moderate physical activity a week in order to promote health (16) and similar recommendations have effectively treated NAFLD in animal models (23, 36, 40) and humans (17, 45). However, individuals often have difficulty adhering to moderate intensity exercise regimens due to the associated time commitment; therefore, it is important to determine whether alternative exercise training methods may aid in the treatment of NAFLD.…”

“…Additionally, it is estimated that >25% of hepatic TG accumulation in NAFLD patients can be accounted for by de novo lipogenesis (12). We have previously shown a dramatic up-regulation in hepatic de novo lipogenesis in the OLETF rat, which is suppressed with chronic physical activity (24, 36, 40) and moderate intensity treadmill exercise training (23). Here, VIG EX was as effective as MOD EX at lowering ACC, FAS, and SCD-1 protein content and reducing the mRNA expression of Elov6, an elongase that has not only been associated with hepatic steatosis but also implicated in the progression of NAFLD to NASH by promoting inflammation (27).…”

“…By 40 weeks of age, these animals experience a progression of NAFLD that results in hepatocyte ballooning and increased fibrosis and collagen deposition in a progressive pattern similar to the human disease (35–37). We have previously shown that voluntary wheel running effectively prevents and treats NAFLD in the OLETF rat (4, 35, 36), and recently demonstrated that 12 weeks of moderate-intensity aerobic treadmill exercise training is effective in the treatment of NAFLD in these animals (23). However, the effects of lower volume, high-intensity exercise training for the treatment of NAFLD is unknown.…”

Obesity-related changes in bone structural and material properties in hyperphagic OLETF rats and protection by voluntary wheel running

“…Exercise improves overall metabolic health by increasing insulin sensitivity [20], reducing chronic inflammation [21][22][23], and reducing circulating lipids and might, therefore, indirectly benefit bone in obese, diabetic individuals. In addition, in normal weight, healthy individuals, exercise has direct positive effects on bone strength due to increased mechanical loading on the skeleton.…”

Dental Stem Cell Differentiation Toward Endodermal Cell Lineages: Approaches to Control Hepatocytes and Beta Cell Transformation

“…Most patients with this form of diabetes are obese, and the obesity itself causes some degree of insulin resistance [ 67 ]. Patients who are not obese according to the traditional weight criteria may have an increased percentage of body fat distributed mainly in the abdominal region [ 68 ]. In addition, insulin secretion is defective in these patients and insuffi cient to compensate for insulin resistance.…”