This week’s Grand Rounds was delivered by Dr. Gerald Shulman, M.D., Ph.D., F.A.C.P. Professor of Internal Medicine and Cellular & Molecular Physiology and Investigator at the Howard Hughes Medical Institute of Yale University School of Medicine. Dr. Shulman has been a pioneer in unraveling the molecular mechanisms of insulin resistance.
For many years, Dr. Shulman and his colleagues have employed nuclear magnetic resonance spectroscopy (MRS) on muscle and liver cells to make noninvasive cellular discoveries. C13 MRS helps to measure hepatic and muscle glycogen, proton MRS measures hepatic and muscle triglycerides, and phosphorus MRS assists in measuring the rate of ATP synthesis. Using MRS, patients with insulin resistance were found to have difficulty moving glucose from the blood into its storage form of glycogen. Muscle glycogen concentrations are found to be decreased in diabetics versus non-diabetics and the rate of glycogen synthesis in skeletal muscle is diminished in these patients as well. Glucose-6-phosphate, the intermediate between glucose transport into the cell and hexokinase-induced phosphorylation, is also significantly reduced in diabetics. Taken together, glucose transport into muscle cells is actually the rate-controlling step in glucose disposal/glycogen synthesis and thus represents a therapeutic target of great potential.
The above results were also shown to apply to first-degree relatives of diabetics. Dr. Shulman emphasized that insulin resistance is the best predictor of the development of diabetes in young, lean, nonsmoking offspring of parents with diabetes. Defective insulin-stimulated muscle glycogen synthesis secondary to glucose transport and phosphorylation defects occur in a manner similar to their diabetic parents. Furthermore, studies in this cohort suggest that intramyocellular lipid accumulation and muscle insulin resistance precede the development of hepatic insulin resistance and DM2.
Dr. Shulman then discussed how lipid accumulation in muscle cells can lead to insulin resistance. He hypothesized that insulin-regulated GLUT4 trafficking between intracellular compartments and the cell membrane are disturbed by fatty acid/lipid build-up and suggested that the mechanism behind this was serine phosphorylation on critical sites of insulin receptor substrate 1 (IRS-1). This phosphorylation would then reduce tyrosine phosphorylation of IRS-1 inhibiting binding and activation of phosphoinosital 3-kinase. Next, adipose tissue disorders were discussed emphasizing that a mismatch between energy supply and demand leads to ectopic lipid accumulation. Studies of knock-out mice demonstrated that while too much fat is bad, having no fat is just as malignant. Research with transgenic mice with severe lipodystrophy clearly demonstrated how fat can build up in liver and muscle without the presence of adipocytes. When adipocyte cells were artificially implanted, this fat build-up was reversed. Further, by supplying these knock-out mice with leptin, which was seen to “melt away the fat,” the mice had a normalized fasting glucose and clamp studies revealed increased insulin sensitivity.
- Insulin resistance in skeletal muscle leads to a reduction in insulin-stimulated glycogen synthesis due to reduced glucose transport
- In the liver, insulin resistance is linked to a decreased ability of insulin signaling to inhibit glucose production and increased lipogenesis capability
- Increased delivery/synthesis of fatty acids to or in skeletal muscle and liver may occur when energy intake overwhelms adipose storage capacity
- Lipid accumulation in skeletal muscle and liver may also be secondary to acquired/inherited mitochondrial dysfunction
- Mitochondrial oxidative phosphorylation activity is reduced in the elderly and may explain why healthy elderly patients are more insulin resistant that comparable younger subjects
- Adipocyte dysfunction (obesity and lipodystrophy) is associated with excessive delivery of fatty acids to the liver and skeletal muscle ultimately contributing to insulin resistance
- Weight loss of any kind, even the most modest, is beneficial in insulin resistance. Lifestyle interventions will be an important part of DM2 prevention and treatment
- Proposed mechanism of insulin resistance (IR) leading to diabetes; IR in skeletal muscle-> peripheral and portal vein hyperinsulinemia-> hepatic steatosis-> hepatic IR-> DM2