Earlier this year, Medical News Today reported on a paper published in the BMJ that urged doctors and patients alike to acknowledge the possibility that type 2 diabetes is reversible through weight loss.
Another study we reported on showed that caloric restriction helped 40 percent of the participants in the study to achieve remission. And now, researchers unravel the mechanism by which caloric restriction leads to the reversal of this chronic condition in rats.
The team was led by senior investigator Dr. Gerald I. Shulman, the George R. Cowgill Professor of Medicine and Cellular and Molecular Physiology at Yale University in New Haven, CT, and the first author of the paper is Dr. Rachel J. Perry, from the Department of Internal Medicine at Yale's School of Medicine.
Speaking to MNT about the motivation for her research, Dr. Perry said, "We became interested in this work because [type 2 diabetes] is increasingly being considered a surgical disease."
"[B]ariatric surgeons are able to generate a rapid reduction in plasma glucose concentrations within days of weight loss surgery, such that patients are often able to leave the hospital off all their diabetes drugs," she added.
"Studies by our group [and by others]," Dr. Perry went on, "have demonstrated that a [VLCD] is similarly effective at reversing insulin resistance and type 2 diabetes, suggesting that the forced caloric restriction that occurs with bariatric surgery, rather than the surgical procedure itself, is likely the reason for the [reversal]."
"However, the molecular mechanism by which a VLCD reverses [type 2 diabetes] had not been demonstrated," she said. So, the researchers set out to investigate precisely this mechanism.
Studying the effect of a VLCD in diabetic rats
To do this, Dr. Perry and colleagues restricted the calories in the diets of rats that showed the equivalent of all the type 2 diabetes hallmarks in humans, which are non-alcoholic fatty liver disease, hyperglycemia, obesity, and hyperinsulinemia.
The restricted diets contained a quarter of the normal calorie intake, and the rats were subjected to this kind of diet for 3 days. After that, the diet "markedly lowered [the rodents'] plasma glucose concentrations," Dr. Perry told MNT.
During those 3 days, the team used a novel technique — which they themselves developed — that allowed them to examine a series of metabolic changes that cause the liver to produce glucose in excess.
Speaking to MNT about this innovative method, Dr. Perry explained, "[We] employed a novel positional isotopomer NMR tracer analysis method, which was developed in our laboratory [...] to measure rates of all key pathways that contribute to glucose production in [type 2 diabetes rats] for the first time."
Three reversal mechanisms revealed
Using this method, the researchers found three mechanisms by which the VLCD drastically lowered blood sugar concentrations in the rodents.
- The diet decreased the rate at which lactate and amino acids were turned into glucose.
- It decreased the rate at which hepatic glycogen was turned into glucose.
- It decreased the liver's fat content, which, in turn, made the liver more sensitive to insulin.
"Together," Dr. Perry told MNT, "these three mechanisms promoted glucose lowering in a weight-independent manner."
"[W]e were struck by the impact of just 3 days of caloric deprivation," she said, "without changes in body weight, to lower plasma glucose concentrations."
Dr. Perry also noted, "[I]t is a key novel insight of this study that caloric restriction reduces plasma glucose concentrations by reducing rates of hepatic glycogenolysis and hepatic gluconeogenesis from amino acids and lactate."
Significance of findings and future research
"[A] key strength of the study," she added, "is that we were able to show the effect of a VLCD to lower plasma glucose concentrations in a weight-independent manner (as is seen immediately following bariatric surgery)."
"Our findings, if translated to humans, would suggest that [these three mechanisms] may all be potential therapeutic targets to lower plasma glucose in those with type 2 diabetes."
Dr. Rachel J. Perry
She also shared with MNT some directions for future research, saying, "The next step will be to determine whether any or all of the three components of VLCD-induced reductions in hepatic glucose production that we identified in rats will translate to humans."
Dr. Perry concluded, "Once this is confirmed — if it is confirmed — researchers will need to identify specific molecular targets against any or all of the three pathways that we show work together to produce hyperglycemia in [type 2 diabetes] rats."