Abstract
BackgroundAlthough type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. To date, curcumin (CUR), a natural polyphenol and primary component of turmeric, shows putative therapeutic properties such as reducing the incidence of obesity-related diseases in mice. However, the mechanism by which CUR regulates insulin levels remains unclear.MethodsThis study investigates how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the diet-induced obesity (DIO) mouse model. Male C57BL/6 J mice were fed a control, a high fat/high sugar (HFS) or a HFS diet containing 0.4% (w/w) curcumin (HFS + CUR) (N = 16 per group) for 16 weeks.ResultsMice given HFS + CUR had reduced body weight and fat accumulation in the liver and had lower blood insulin levels under fasting conditions compared to mice on HFS alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE). We also observed restoration of phosphoinositide 3-kinase (PI3K), especially class Ia catalytic subunits, p110α and p110β, and class Ib regulatory subunit, p101, and phosphorylated protein kinase B (AKT) expression levels in liver on HFS + CUR diet. Additionally, HFS + CUR fed mice had significantly smaller islets of Langerhans and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas. The expression of thioredoxin interacting protein (TXNIP), a pro-oxidant and pro-apoptotic protein, was significantly elevated in mouse and human islets cultured under HFS mimicking conditions, which was mitigated by CUR treatment.ConclusionsCUR supplementation in obese subjects may alleviate the burden imposed by HFS diets. Our data indicate administration of dietary CUR reinstates PI3K, AKT and IDE levels in obese mice. Additionally, CUR treatment preserves islet integrity by downregulation of TXNIP transcription levels. Therefore, dietary CUR may have the potential to serve as a novel therapeutic agent to address the underlying links of obesity and T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease
Assessment of metabolic parameters of mice on diets We found that C57BL/6 J mice (N = 16 per each group) administered a high fat/high sugar diet (HFS) for 16 weeks had a significant increase in body weight (46.5 ± 1.3 g) compared to those on a control diet (30.9 ± 1.0 g) (Fig. 1a)
Mice administered a HFS diet containing 4 g/kg of curcumin (HFS + CUR) had significantly lower body weights (42.1 ± 1.1 g) compared to HFS diets alone from week 10 onwards. Both HFS and HFS + CUR fed mice had lower biweekly feed efficiency ratio compared to mice on a control diet, there were no significant differences between each other (Fig. 1b)
Summary
Type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. In Type 2 diabetes mellitus (T2DM), pancreatic insulin secretion and insulin sensitivity become impaired, compounded by excessive gluconeogenesis, which leads to chronic dysglycemia [2] In both obesity and T2DM, the levels of plasma free fatty acids (FFA) are elevated, which is conducive to insulin resistance and impaired insulin secretion [3]. In attempts to uncover better treatment options for T2DM, we have been investigating the therapeutic potential of nutraceuticals One such compound is Curcumin (CUR), the most active component of the spice turmeric. In terms of regulation of circulating insulin levels, the underlying mechanism and the relationship between insulin sensitivity and islet integrity by CUR treatment are still unclear
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