A causal role for hyperinsulinemia in obesity

Abstract

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity

“…By demonstrating that removal of dietary fructose (the macronutrient most closely associated with hepatic DNL) concomitantly reduces liver fat and improves insulin dynamics irrespective of calories or weight, we are able to suggest a causative mechanism of metabolic dysfunction in these children by linking DNL to both liver fat and insulin resistance. We also demonstrated that despite an increase in the glucose (starch) content of the diet, insulin secretion decreased, thus protecting against beta-cell exhaustion, thought to be important in the pathogenesis of type 2 diabetes; 7 and reducing total body insulin burden, thought to contribute to both obesity 49 and risk for cardiovascular disease. 50 These data also suggest an achievable dietary approach to improve metabolic dysfunction in similarly affected children who are high sugar consumers.…”

Hyperinsulinemia: a Cause of Obesity?

“…These data support the notion that prevention of initial weight gain by reduction of HI may be favorable to reduction of HI as a treatment for obesity. This topic has just been reviewed by the group of Johnson [17••].…”

Hesperidin attenuates altered redox homeostasis in an experimental hyperlipidaemic model of rat

“…Therefore the hyper‐lipidaemic oxidative stress creates an extra burden on normal metabolic processes and plays a very important role in the progression of heart disease . Studies show that a high‐fat diet is also responsible for insulin resistance in rats . The mechanism behind insulin resistance is explained on the basis of the accumulation of intramyocellular lipids and a decrease in the number of mitochondria …”