A subanalysis from the Diabetes Remission Clinical Trial (DiRECT) points to changes in hepatic metabolism as a cause for patients with type 2 diabetes entering remission after dramatic weight loss through dietary restriction or bariatric surgery, according to research presented Friday afternoon at the Scientific Sessions.
“When patients lose weight on the DiRECT program, liver fat goes from very high levels, around 16 percent, down to normal, 3 percent, immediately after the weight loss,” said Roy Taylor, MD, Professor of Medicine and Metabolism at Newcastle University in Newcastle-upon-Tyne, U.K. “That change in hepatic fat content is associated with normalizing the export of fat from the liver and normalizing the fat content of the pancreas. We see beta cells wake up and begin producing normal levels of insulin again.”
DiRECT compared the effects of an intensive weight diet of 800 calories a day with usual care. All antidiabetic medications were withdrawn from both groups on day one. A subgroup of patients also underwent magnetic resonance imaging to measure liver and pancreas fat, assessment of very low-density lipoprotein triglyceride (VLDLI-TG) metabolism, and first-phase insulin secretion.
At 12 months, patients in the weight loss group had lost a mean of 10.5 kg. Liver fat, plasma VLDLI-TG, and intrapancreatic fat fell to normal levels, and 37 of 53 patients (69.8 percent) whose A1C returned to normal also showed restored first-phase insulin response. A1C responders had a shorter duration of diabetes than nonresponders, Dr. Taylor said.
Other topics covered during this symposium included:
Metabolic stress acts quickly
Even a short duration of hyperglycemia can lead to increased basal hepatic glucose production and insulin resistance, said Devjit Tripathy, MD, Associate Professor of Medicine at the University of Texas Health Science Center at San Antonio.
After 48-hour glucose infusions, healthy volunteers’ plasma glucose concentration increased about 45 mg/dl above baseline. Volunteers also showed markedly higher hepatic glucose production, hepatic insulin resistance, higher skeletal muscle insulin resistance, and higher plasma glucagon. Dr. Tripathy said this represents the first experimental demonstration that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production.
Glucagon receptor signaling
Inhibiting signaling at the glucagon receptor modulates amino acid metabolism in the liver while also increasing serum glucose, according to Marie Winther-Sørensen, BSc, a researcher in the Department of Biomedical Sciences at the University of Copenhagen, Denmark.
“We saw that a glucagon receptor antagonist decreases blood glucose levels in our mouse model,” Dr. Marie Winther-Sørensen said. “But when glucagon receptor signaling is inhibited, the urea response to an injection of amino acids is also greatly reduced. We see similar reductions of urea response in a mouse model, which has 95 percent of alpha cells deleted, which gives them very low glucagon levels. It appears that glucagon acutely regulates hepatic amino acid metabolism and may contribute to the diabetogenic effect of hyperglucagonemia.”
Elevated nocturnal glucagon
Interventions in type 2 diabetes traditionally focus on daytime measures, but blood glucose remains high all night in patients despite the usual overnight fast.
“The blood sugar a patient with type 2 diabetes has at 10:00 p.m. is the same as 7:00 a.m.,” said Rita Basu, MD, Professor of Endocrinology at the University of Virginia School of Medicine and Center for Diabetes Technology, who added that there’s no suggestion of the “dawn phenomenon” that is seen in type 1 diabetes.
“We found that nighttime blood glucose is high, endogenous glucose production is high, cortisol is high, and glucagon is high in type 2 diabetes,” she continued. “We have now found that it is this high glucagon all night that drives blood sugars to stay up all night. These findings suggest new therapeutic approaches, maybe glucagon receptor antagonists or drugs that suppress glycogenolysis and gluconeogenesis. We clearly need to focus more on what happens with our patients with type 2 diabetes during the nighttime.”
Exercise model in type 1 diabetes
A recent proof-of-concept study suggests that the combination of low insulin and moderately elevated blood glucose levels are safe for moderate to rigorous exercise in type 1 diabetes.
“Hyperinsulinemia, but not hyperglycemia, inhibits exercise-induced compensatory increase in endogenous glucose production,” said Ananda Basu, MD, Harrison Professor of Medicine at the University of Virginia School of Medicine and Center for Diabetes Technology. “Glucose levels between 100 and 150 are probably the safest for patients with type 1 diabetes to exercise.”
Epigenetic effects of prenatal insulin resistance
Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, but few studies have associated maternal diabetes or birth weight with increased risk for NAFLD in offspring.
Mouse studies have identified a novel gene, NREP, that is upregulated during insulin resistance. Maternal expression of NREP has detrimental effects on metabolic adaptation and transcriptional regulation of hepatic metabolism in offspring, according to Dario F. De Jesus, MSc, a PhD candidate at the Joslin Diabetes Center. This is the first indication that prenatal insulin resistance may have intergenerational epigenetic effects that can contribute to the development of NAFLD.
NAFLD shifts endogenous glucose production
In healthy individuals, prolonged fasting prompts the liver to shift from glycogenolysis and glucogenesis to the production of ketone bodies to fuel peripheral tissues. New data suggests that NAFLD inhibits that switch from endogenous glucose production to the production of ketone bodies.
Early-stage studies found that individuals with NAFLD failed to suppress endogenous glucose production compared to matched controls, reported Justin A. Fletcher, PhD, Postdoctoral Researcher at the University of Texas Southwestern Medical Center. Subjects with NAFLD also disposed of less fat than controls and continued to sustain the tricarboxylic acid cycle to support glycogenesis.