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How the Liver Affects Insulin and Vice Versa: Part 2, Obesity and Lipid Metabolism

Andre McMahon, PharmD Candidate, University of Florida College of Pharmacy

Dave Joffe, Editor-in-chief, Diabetes In Control

The metabolic syndrome is associated with many risk factors for type 2 diabetes mellitus and cardiovascular complications which include: central obesity, elevated fasting glucose, elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol, and hypertension. When a person has three or more of these risk factors they are considered to have the metabolic syndrome. Insulin resistance is the most common clinical finding associated with metabolic syndrome and is thought to be the underlying cause of the condition.1

There are various changes in insulin signaling in the metabolic syndrome and these vary with cell type involved.2 The focus of this article is the consequence of metabolic syndrome on insulin signaling in the liver and the resultant dyslipidemia and hypertriglyceridemia.

Obesity is a major contributor to insulin resistance and progression to type 2 diabetes mellitus.

Insulin resistance is most strongly linked to abdominal fat and visceral fat which surrounds organs compared to fat in other depots. There are many molecular factors that link obesity and insulin resistance in fat, muscle, and the liver. These factors include:

  • Insulin itself which down regulates its own receptor in hyperinsulinemia
  • Increases in free fatty acids (FFAs) which impair the actions of insulin leading to lipid accumulation
  • Circulating peptides produced by adipocytes also known as "adipokines"

These adipokines involve the cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) which modify insulin’s actions and are involved in a series of complex mechanisms associated with obesity-linked inflammation. Despite the well-known prevalence of insulin resistance in these individuals, most obese persons do not develop diabetes which suggests that diabetes results from an intricate interaction between obesity-linked insulin resistance and other key factors such as impaired insulin secretion. It’s also well known that there is a genetic link between obesity and the prevalence of diabetes. Nevertheless, obesity is a huge risk factor for diabetes and as many as 80% of patients with type 2 DM are obese.

Insulin resistance in the liver and hyperinsulinemia contribute to the development of dyslipidemia.

Aside from carbohydrate metabolism and glucose homeostasis, insulin plays key roles in metabolism of lipids.

Insulin increases lipid synthesis in the liver by activation of sterol regulatory element binding protein-1c (SREBP-1c) which results in an increase in free fatty acids (FFAs) and triglycerides (TGs). In the metabolic syndrome this pathway remains relatively unaffected. Thus in metabolic syndrome and type 2 DM, as the pancreas secretes more and more insulin to overcome the insulin resistance, the result is hyperinsulinemia.

Thus, hyperinsulinemia causes an increase in circulating levels of FFAs and TGs through overstimulation of the pathway mentioned above.

It’s also known that impaired insulin signaling in the liver affects circulating levels of lipoproteins. A hallmark feature of metabolic syndrome is low HDL cholesterol. In addition, levels of VLDL and LDL also rise and these lipoprotein abnormalities increase the risk of cardiovascular complications. Normally, FFAs are esterified to TGs which are then transported by VLDLs to adipose and muscle tissue.3 VLDLs are primarily acted upon by lipases located in liver and endothelial cells through apolipoprotein CII. These lipases remove FFAs from the lipoprotein and convert VLDL to intermediate-density lipoprotein (IDL) and then IDL to LDL. Since insulin regulates the expression of apolipoprotein CII on the surface of lipoproteins it’s no wonder that hyperinsulinemia leads to increased expression of apolipoprotein CII which leads to hypertriglyceridemia. On top of that, increased levels of FFAs stimulate the release of insulin. Thus, these normal mechanisms are impaired and the higher levels of TGs cause more insulin to be released and worsening the effects of hyperinsulinemia.

References:
  1. Miranda PJ, DeFronzo RA, et al. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am heart J.2005;149:33-45.
  2. Rask-Madsen C, Kahn CR. Tissue-Specific Insulin Signaling, Metabolic Syndrome, and Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2012;32:2052-2059.
  3. Ginsberg HN. New perspectives on atherogenesis: role of abnormal triglyceride-rich lipoprotein metabolism. Circulation. 2002;106:2137.

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