Ananda Basu, M.D.A new study led by Ananda Basu, M.D., used novel non-radioactive, stable glucagon tracers for the first time to characterize glucagon metabolism in humans with and without Type 1 diabetes, providing tools for further exploration into pancreatic alpha cell function in both Type 1 and 2 diabetes and other metabolic disorders.
Glucagon is a pancreatic hormone that plays a crucial role in regulating glucose and whole-body energy metabolism. In individuals with diabetes, the pancreatic alpha cells that produce glucagon are dysregulated leading to inadequate response to the body’s blood glucose and resulting in high (hyperglycemia) or low (hypoglycemia) blood sugar.
Ananda Basu, program director of the NIH-funded Diabetes Research Center, S. Richardson Hill, Jr. Endowed Professor in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and senior scientist at the UAB Comprehensive Diabetes Center, is an expert in the development of innovative isotope modeling techniques coupled with organ balance methods to study whole body and regional metabolism and physiology in humans with and without diabetes.
He and collaborators, including UCDC senior scientist Rita Basu, M.D., Endowed Professor of Diabetes Science in the UAB Division of Endocrinology, Diabetes and Metabolism, set out to assess splanchnic (abdominal) and leg glucagon metabolism in humans using stable glucagon isotopes, also known as tracers.
“We wanted to evaluate if splanchnic and leg glucagon metabolism differed between nondiabetic participants and those with Type 1 diabetes at glucagon concentrations spanning the physiological range,” Ananda Basu said.
Their findings, “Splanchnic and Leg Glucagon Metabolism in Healthy and Type 1 Diabetes: First in Human Study using [13C9, 15N1]-Glucagon,” were recently published in Diabetes, the peer-reviewed flagship journal of the American Diabetes Association.
Researchers combined an isotope dilution technique using stable tracers [6,22 13C9, 15N1]-Glucagon and [6,14,19,22 13C9, 15N1]-Glucagon with splanchnic and leg catheterization in nondiabetic (ND) and T1D participants in the overnight fasted state. After the baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance.
Researchers found that whereas splanchnic glucagon extraction did not differ between ND and T1D participants, leg glucagon extraction fell in ND but did not change in T1D as glucagon concentrations increased. Net splanchnic glucagon production did not change with exogenous glucagon infusion.
“We have characterized regional glucagon metabolism across the splanchnic and leg regions in humans with and without T1D using glucagon tracers for the first time,” Ananda Basu said. “Further studies are needed to determine glucagon metabolism during other physiologically relevant conditions, e.g., postprandial, during exercise, during hypoglycemia. An intriguing novel observation was that the leg, representing peripheral tissues, also extracted a significant amount of glucagon in both ND and T1D participants. The mechanisms by which this occurs need to be investigated in future studies.”
Ananda Basu said their observations also have significant translational implications for two current advancements in diabetes treatment and management.
“Our study has implications for dual hormone closed loop control in T1D where glucagon is infused for prevention of hypoglycemia and for investigating the effects of emerging GLP-1, GIP and Glucagon receptor agonists and glucagon clearance,” he said.
This study was funded by NIH: R01-DK 085516. Read the full paper here.