In a new study, Professor Gerald Shulman of the Howard Hughes Medical Institute at Yale and colleagues show that just three days of a very-low-calorie diet (VLCD) improve glucose metabolism before weight loss in a rat model of type 2 diabetes, and trace the beneficial metabolic effects to improved liver metabolism.
Perry et al show that three days of a VLCD lowered plasma glucose and insulin concentrations in a rat model of type 2 diabetes (T2D) without altering body weight. Image credit: Perry et al, doi: 10.1016/j.cmet.2017.10.004.
Professor Shulman and co-authors investigated the effects of a VLCD, consisting of one-quarter the normal intake, on the diabetic rats.
They focused on understanding the mechanisms by which caloric restriction rapidly reverses type 2 diabetes.
Using a novel stable isotope approach, they tracked and calculated a number of metabolic processes that contribute to the increased glucose production by the liver.
The method, known as PINTA, allowed the team to perform a comprehensive set of analyses of key metabolic fluxes within the liver that might contribute to insulin resistance and increased rates of glucose production by the liver — two key processes that cause increased blood-sugar concentrations in diabetes.
Using this approach the researchers pinpointed three major mechanisms responsible for the VLCD’s dramatic effect of rapidly lowering blood glucose concentrations in the diabetic animals.
In the liver, the VLCD lowers glucose production by:
(i) decreasing the conversion of lactate and amino acids into glucose;
(ii) decreasing the rate of liver glycogen conversion to glucose;
(iii) decreasing fat content, which in turn improves the liver’s response to insulin; these positive effects of the VLCD were observed in just three days.
“Using this approach to comprehensively interrogate liver carbohydrate and fat metabolism, we showed that it is a combination of three mechanisms that is responsible for the rapid reversal of hyperglycemia following a very low calorie diet,” Professor Shulman said.
The next step for the researchers will be to confirm whether the findings can be replicated in type 2 diabetic patients undergoing either bariatric surgery or consuming very low calorie diets.
“These results, if confirmed in humans, will provide us with novel drug targets to more effectively treat patients with type 2 diabetes,” the scientist said.
The findings are published in the journal Cell Metabolism.
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Rachel J. Perry et al. Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes. Cell Metabolism, published online November 9, 2017; doi: 10.1016/j.cmet.2017.10.004
