Can We Break the Link Between Obesity and Diabetes?

The relationship between obesity and diabetes is tight. Even those who are slightly overweight have a five-fold greater risk of developing type 2 diabetes, and for people who are seriously obese, the risk is 40 times greater.

How does obesity lead to diabetes? A major part of the problem lies in the liver, and research from Ira Tabas’ lab has found a certain series of biochemical events may be key. This biochemical chain reaction kicks in as people get heavier—forcing liver cells to resist signals from insulin and pump more glucose into the bloodstream— thus paving the way for the development of type 2 diabetes.

Dr. Tabas and his colleague, Lale Ozcan, MD, have been uncovering the components in this chain reaction and looking for ways to interrupt it. Their latest work identifies the last missing link in the chain, a molecule called DACH1, which had never been implicated in diabetes.

The two researchers found that as mice become obese, DACH1 levels rise in the liver and help instigate the chain reaction that leads to diabetes.

The same thing may be happening in people, Drs. Tabas and Ozcan found. DACH1 levels in the human liver went up markedly and consistently with increasing obesity, as seen in samples from liver biopsies taken from people undergoing surgery.

Breaking the link between obesity and diabetes may be possible by reducing DACH1 levels in the liver. That tactic worked to improve glucose levels and insulin sensitivity in obese diabetic mice, Drs. Tabas and Ozan found, and could potentially work the same way in people.

A compound that interrupts a protein further upstream in the DACH1 pathway is already being explored for future use in people. “The new information about DACH1 now gives us more opportunities to find the best approach,” Dr. Tabas says.


Full findings from the study were published May 26 online:

Ozcan L, Ghorpade DS, Zheng Z, de Souza JC, Chen K, Bessler M, Bagloo M, Schrope B, Pestell R, Tabas, IT. 2016. Hepatocyte DACH1 is increased in obesity via nuclear exclusion of HDAC4 and promotes hepatic insulin resistance. Cell Reports DOI: 10.1016/j.celrep.2016.05.006

This work was supported by an American Heart Association Scientist Development Grant (11SDG5300022); a Pilot and Feasibility Grant (DK26687) from the New York Obesity Nutrition Research Center; a São Paulo Research Foundation grant (FAPESP/BEPE 2012/21290-4); and NIH grants CA132115-05A1, HL087123 and HL075662.

Ira Tabas, MD, PhD, is the Richard J. Stock Professor and vice chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology & cellular biophysics). Lale Ozcan, MD, is assistant professor of medicine.

Drs. Tabas and Ozcan are members of a group of cofounders of Tabomedex Biosciences LLC, which is developing inhibitors of molecules in the pathway described in this report for the treatment of type 2 diabetes.