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Enzyme Linked to Obesity and Diabetes

A new drug target for obesity and diabetes may be on the horizon….

High plasma glucoses seen in type 2 diabetes have been linked to several different pathophysiologic defects including lack of insulin, decreased sensitivity to insulin, and impaired/overproduction of glucose by the liver. Currently, the top treatment on the market, metformin, targets the overproduction of glucose by the liver and also has minimal effects on improving insulin sensitivity.

Researchers at Columbia University recently found a potential new drug target, a single enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII) or MK2 for short. MK2 has been associated with worsening two defects common to diabetes: reduced insulin sensitivity and glucose overproduction. The enzyme has also been observed to be upregulated/overactive in obese persons as well as obese persons with pre-diabetes.

Researchers attempted to inhibit MK2 activity in mouse models and saw partial improvement in blood glucose control, similar to what metformin produces in mouse models. However, when metformin and a MK2 inhibitor were combined in mouse models, they saw an additive effect. MK2 inhibitors seem to be compatible with metformin and this could lead to a new drug target, especially for those who are obese and diabetic. The combination could potentially also be used to help prevent the development of diabetes. Another benefit of MK2 is that it has been shown to lower cholesterol and has not demonstrated any adverse effects to the cardiac system.

While all the research is currently on murine models, the very large, human genetic study, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM study) has shown that the MK2 pathway is active in human hepatic cells. This study has also shown a link of a key component of the MK2 activation pathway to diabetes.

Practice Pearls:

  • Calcium/calmodulin-dependent protein kinase II (CaMKII) is an enzyme found in the liver and is overactive in obese individuals and obese individuals with pre-diabetes.
  • Inhibiting MK2 has been associated with improving insulin sensitivity, decreasing hepatic glucose production and lowering cholesterol.
  • MK2 is compatible with metformin and when used in combination, the effects are additive.

Ozcan, L. et al. Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Obesity Mediates Suppression of Hepatic Insulin Signaling. Cell Metabolism, Volume 18, Issue 6, 803-815, 21 November 2013