Dietary, Lifestyle and Pharmaceutical Interventions for the Treatment of Metabolic Diseases

Abstract

The global prevalence of obesity and type 2 diabetes increases and current treatment options are not satisfactory. This thesis will investigate the efficacy of novel dietary, lifestyle, and pharmaceutical interventions to treat these metabolic disorders. In rodents, acute-isoleucine treatment lowers blood glucose levels and protects from diet-induced weight gain, suggesting chronic-isoleucine may be beneficial in treating obesity and type 2 diabetes. This study aimed to investigate chronic-isoleucine treatment on body weight and glucose tolerance in lean and obese mice. Male C57BL/6 mice, fed a standard-laboratory-diet (SLD) or high-fat-diet (HFD) for 12-weeks, were randomly allocated to 1) Control (water); 2) Acute (0.3 g/ kg isoleucine); 3) Chronic (1.5% isoleucine in drinking water for 6-weeks). At 17-weeks, mice underwent a glucose tolerance test (GTT). In SLD- and HFD-mice, there was no difference in body weight between treatment groups. Acute-isoleucine did not improve glucose tolerance in SLD- or HFD-mice. Chronic-isoleucine impaired glucose tolerance in SLD-mice. In conclusion, chronic-isoleucine supplementation was not effective for weight loss and glucose intolerance in mice. Shift-work increases obesity risk partly through circadian desynchrony. In rodents, time-restricted feeding (TRF) during the dark-phase (DP) reduces weight gain and entrains the circadian rhythms of metabolic genes. Whether TRF during the light-phase (LP) is also effective is unknown. This study aimed to compare TRF-LP and TRF-DP on body weight and circadian rhythmicity of hepatic glucose (Slc2a2, Irβ & Gys2) and lipid (Acc1α) metabolic markers in lean and obese mice. Male C57BL/6 mice were fed a SLD or HFD for 12-weeks. After 4-weeks, mice were randomly fed to 1) ad libitum (AL); 2) during the LP (Zeitgeber (ZT)0-12); 3) during the DP (ZT12-24). In HFD-AL mice, energy intake, weight gain, fat mass, plasma lipids and mean blood glucose levels were elevated compared to SLD-mice. These parameters of obesity were similarly reduced in HFD-LP and HFD-DP mice compared to HFD-AL mice. In general, TRF during the LP or DP aligned circadian rhythms of hepatic markers of glucose and lipid metabolism to the timing of food intake. Human glucagon-like-peptide-1 (GLP-1) is a short-acting, blood glucose-lowering hormone. Comparatively, monotreme GLP-1s are potent, long-acting GLP-1 receptor agonists, resistant to degradation in humans and mice, suggesting monotreme GLP-1s may be beneficial in treating type 2 diabetes. This study aimed to investigate monotreme GLP-1 treatment on glucose tolerance in lean and obese mice. Male C57BL/6 mice were fed a SLD or HFD for 14- weeks. At 13-weeks, mice were randomly allocated to 7-groups and injected twice-daily with either 1) phosphate buffer (PB); 2) exendin-4 (Ex-4); 3) echidna GLP-1 (eGLP-1); 4) F8S; 5) platypus GLP-1 (pGLP-1); 6) N14S; or 7) S26K for 7-days. At 14-weeks, mice underwent a GTT. In SLD-mice, the glucose AUC was reduced in all treatment groups compared to PB controls. In HFD-mice, treatment with Ex-4, pGLP-1, N14S, and S26K reduced the glucose AUC compared to PB controls. In conclusion, monotreme GLP-1s may be effective in treating type 2 diabetes.