The Integrated Carbohydrate Physiology and Translation Laboratory has four main research programs.
The research is currently directed at developing physiological models to inform, fine tune and eventually personalize an effective closed-loop control artificial pancreas system for patients with type 1 diabetes using cutting-edge insulin pump and glucose sensor technologies.
Other programs are related to defining the role of carotid bodies in the regulation of blood glucose in humans with and without diabetes and obstructive sleep apnea, as well as the role of cortisol in modulating liver glucose metabolism in obesity and diabetes.
Here's an overview of the four research programs:
The primary focus of the artificial pancreas program is conducting experiments designed to better understand the effects and effect sizes of day-to-day factors that influence glucose control and variability in people with type 1 diabetes.
A better understanding of these parameters can then inform and refine a closed-loop control algorithm that would continually be individualized for each patient with type 1 diabetes.
The premise of an effective and safe artificial pancreas system begins with accurate continuous glucose sensing within the interstitial fluid of the subcutaneous space.
However, the artificial pancreas closed-loop system has current limitations in:
- Understanding the kinetics of glucose transport between the intravascular compartment and the subcutaneous tissue where the glucose sensors are lodged
- Precision and accuracy of currently available glucose sensors
The Integrated Carbohydrate Physiology and Translation Laboratory is involved in conducting pioneering experiments applying innovative isotope dilution techniques and methods to determine the kinetics of glucose transport and the modulating effects of meals, activity and obesity.
Defining these parameters will close a vital gap in the understanding of the physiology of glucose transport. It also will help refine and improve closed-loop control algorithms that account for the kinetic delay by applying an arbitrary time lag in the algorithm.
In addition, the research team is collaborating with Steve Koester, Ph.D., an electrical engineer at the University of Minnesota, to explore novel varactors derived from carbon that could be used as innovative glucose sensors. This addresses several of the shortcomings with current glucose sensing approaches.
Role for carotid bodies in glucose metabolism in humans
In a novel series of investigations and in close collaboration with Michael J. Joyner, M.D., of the Department of Anesthesiology at Mayo Clinic, the laboratory has successfully established the singular role of the carotid bodies as a prominent player in glucose counter-regulation during hypoglycemia in people with and without type 1 diabetes.
The investigations reveal that hyperoxia blunts secretion of counter-regulatory hormones in response to hypoglycemia.
Preliminary experiments conducted in patients with bilateral carotid body resections have confirmed carotid bodies as the central site of the crosstalk between blood glucose and blood oxygen levels.
Current experiments will determine the translational role of the carotid bodies in people with type 1 diabetes with and without hypoglycemia awareness.
People who lack hypoglycemia awareness don't recognize when they have low blood sugar and are unable to respond by eating or drinking sugary substances when their blood sugars fall to dangerously low levels. This research will pave the way for therapies aimed at treating this condition.
Role of 11-beta-hydroxysteroid dehydrogenase-1 on glucose metabolism in humans
The laboratory was the first to establish the definitive role of the enzyme 11-beta-hydroxysteroid dehydrogenase-1 in extra-adrenal cortisol production in people with and without type 2 diabetes.
The research team also established in experiments performed with the help of Michael G. Sarr, M.D., of the Department of Surgery at Mayo Clinic, that the liver was the primary site of this enzyme activity in people who are obese and undergoing bariatric surgery.
In addition, in experiments performed in conjunction with Alan Cherrington, Ph.D., of Vanderbilt University, the lab demonstrated that blockade of this enzyme activity reduces extra-adrenal cortisol production with concomitant lowering of endogenous glucose production and plasma glucose levels in an experimental dog model.
Future studies are needed to test 11-beta-hydroxysteroid dehydrogenase inhibitors for treatment of excess cortisol in the liver in humans.