Steps towards simultaneously treating diabetes and fatty liver disease
by Amanda Chase, PhD
September 29, 2021
Type 2 diabetes melilites (T2DM) is increasing in prevalence, currently affecting about 1 in 10 people. Normally, cells use sugar (glucose) for energy, and insulin enables the sugar to enter the cells. Type 2 diabetics are insulin-resistant, meaning they cannot respond to insulin in the normal way to make cells take up sugar. To compensate, more insulin is made by the pancreas, but eventually the pancreas cannot keep up and blood sugar accumulates in the blood. High blood sugar leads to serious health problems, including heart disease. In fact, those with T2DM are two times as likely to have heart disease, and to have it at an earlier age. Current treatment heavily relies on lifestyle modifications – healthy eating, increased movement, and decreased stress – combined with insulin or oral medications. The goal of these is to decrease blood sugar levels, that is, the amount of sugar in the blood instead of in cells being used for energy. Current therapies have unwanted side effects, including increased lipid (fat) synthesis that can lead to nonalcoholic fatty liver disease.
Treatment of T2DM, and longer-term patient health, would greatly benefit from a therapy that can both increase sugar uptake and suppress lipid accumulation. Researchers at Stanford, led by first authors Zewen Jiang, Meng Zhao, and Laetitia Voilquin and senior author Katrin Svensson, were able to identify a protein that may address that need. Their work, recently published in Cell Metabolism, identified isthmin-1 (Ism1) as a protein that can both increase sugar (glucose) uptake and suppress lipid synthesis.
Isthmin-1 (Ism1) was identified as a protein with the ability to both increase sugar (glucose) uptake and decrease lipid synthesis. Ism1 has the potential to be a T2DM therapy with advantages over current treatment options.
Ism1 is able to work like insulin in regulating blood sugar levels but surprisingly, also counteracts lipid accumulation in the liver. Using a sophisticated combination of molecular assays and assays in cell lines and mouse models, they were able to show that Ism1 is a secreted factor that controls glucose uptake and improves insulin sensitivity, especially after chronic high levels. Importantly, they also used recombinant Ism1 protein as a therapeutic in a mouse model to show that it can improve established diabetes by both improving glucose tolerance and reversing any established lipid accumulation in the liver. Although, several next-step questions remain, this manuscript provides the compelling argument that Ism1 may be explored for therapeutic purposes and may be useful in combination with other T2DM treatment options.
Other Stanford affiliated researchers include Yunshin Jung, Tanushi Sahai, Ivan Carcamo-Orive, Joshua Knowles, Eric Appel, Caitlin Maikawa, and Christopher Gardner. This was done in collaboration with researchers from Harvard Medical School; University Medical Center Ulm, Germany; University of Sao Paulo, Brazil; and Yale University School of Medicine.
Katrin Svensson, PhD