Lipid-induced Insulin Resistance

Obesity is a well-established risk factor for the development of insulin resistance. Obesity is associated with the increased deposition of lipids in non-adipose tissue with subsequent decreases in insulin sensitivity. Currently, the mechanisms by which increased fat accumulation leads to insulin resistance and metabolic syndrome are not completely understood.

Obesity may set up a state of inflammation in the body leading to increased production of inflammatory cytokines that negatively impact insulin sensitivity. This theory is consistent with studies showing elevated levels of the proinflammatory cytokines IL-6 and TNF-α in individuals with insulin resistance and type 2 diabetes. Alternatively, hormone production by adipose tissue may be dysregulated leading to the increased production of adipokines that cause insulin resistance.

A third theory examines the capacity of adipose tissue to store lipids. This theory postulates that an individual's capacity to store lipids in adipose tissue has a set maximal limit. When this limit is exceeded, excess lipids spill over into plasma resulting in elevated plasma free fatty acid and triglyceride levels. This results in the increased import and storage of these molecules in non-adipose tissues such as skeletal muscle and liver. The ectopic storage of lipids in non-adipose tissues may result in metabolic derangements via lipid-induced toxicity (lipotoxicity). Lipotoxicity may also contribute to the loss of pancreatic β cells that occurs during the development of type 2 diabetes.

The lipotoxicity hypothesis is supported by studies in which cells are cultured with an excess of long-chain saturated fatty acids complexed to serum albumin. In these studies, apoptosis is induced in a dosedependent manner and is enhanced by high-glucose treatment. Further evidence for the lipotoxicity theory comes from the study of lipidystrophy patients who have generalized or partial loss of adipose tissue. These individuals with reduced lipid storage capacity often present with severe insulin resistance, dyslipidaemia, and fatty liver.

Hormones, Cytokines, and Adipokines Involved in Insulin Resistance

Adipose tissue is an endocrine organ that secretes multiple hormones, cytokines, and adipokines. These bioactive peptides and proteins can influence multiple metabolic processes, including insulin sensitivity.

Enzymes Involved in Fatty Acid Release

Insulin resistance in adipose tissue results in a reduction in the uptake of circulating free fatty acids and an increase in the hydrolysis of stored triglycerides by lipases. The net result of these actions is an increase in circulating free fatty acids.

Kits and Reagents for Measuring Lipids and Fatty Acids

Insulin resistance in adipose tissue results in a reduction in the uptake of circulating free fatty acids and an increase in the hydrolysis of stored triglycerides by lipases. The net result of these actions is an increase in circulating free fatty acids.