Integrated and translational carbohydrate physiology

The theme of the Basu-Kudva-Basu laboratory continues in the long and rich tradition of clinical investigations directed at understanding the integrative physiology of glucose metabolism in humans with and without diabetes mellitus. This line of investigation was pioneered by Robert A. Rizza, M.D., former chair of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Rochester, Minn., and past president of the American Diabetes Association.

Ananda Basu, MBBS, M.D., of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Minnesota, says: "While continuing to research novel aspects of type 2 diabetes and prediabetes, the group has come a full circle in an attempt to close the loop for type 1 diabetes from the inpatient clinical research-based intravenous insulin Biostator experiments performed by Dr. Rizza in the late 1970s and early 1980s to current ambulatory translational near-term reality using subcutaneous glucose sensing and insulin delivery."

Is closed-loop control with artificial pancreas imminent in type 1 diabetes?

Yogish C. Kudva, MBBS, of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Minnesota, says: "The short answer is a resounding yes! Building upon the almost 20 years of experience (under the tutelage of Dr. Rizza), the laboratory is focused on conducting experiments designed primarily 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 eventually be individualized for each patient with type 1 diabetes."

Some of the factors that the team is currently investigating, in collaboration with Claudio Cobelli, Ph.D., of the University of Padova, Italy, include:

  • Is there a diurnal pattern to insulin action in people with type 1 diabetes?

    Dr. Ananda Basu answers: "In a series of complex and meticulously designed experiments, we have shown that there indeed appears to be a diurnal pattern to postprandial insulin action in type 1 diabetes that is opposite to that observed in healthy controls. We are now exploring possible causes for this difference that could generate new concepts and hypotheses on other circadian hormonal control of glucose metabolism."

  • What is the role of low- and moderate-intensity physical activity on postprandial glucose excursion and glucose variability?

    Dr. Kudva answers: "Applying state-of-the-art techniques and with collaboration from James A. Levine, M.D., Ph.D., of the Division of Endocrinology at Mayo Clinic in Arizona, it is evident that even low-intensity physical activity (that mimics activities of daily living) has a profound impact on postprandial glucose excursions in people with and without type 1 diabetes and can also predict the rate of rise and fall of glucose after a meal. Furthermore, it appears that the timing of the physical activity in relation to the meal is a vital modulator of glucose variability. Additional experiments are being conducted that will help incorporate energy expenditure and physical activity into closed-loop control algorithms."

  • Role of glucagon on hypoglycemia prevention and rescue in type 1 diabetes.

    Rita Basu, M.D., of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Minnesota, says: "Current experiments will determine whether hepatic glucagon sensitivity varies with ambient glucose concentration in people with type 1 diabetes. Such information is critical for the design of the control algorithm, especially for future bihormonal closed-loop control systems."

  • Dawn phenomenon in type 1 diabetes.

    Dr. Kudva explains: "The dawn phenomenon is not only an enigma but also a thorn in the physician's armamentarium that challenges the diabetologist and adversely affects glucose control in type 1 diabetes. The team is applying cutting-edge methods to determine the cause, effect size and reproducibility of this phenomenon. A better understanding of all these issues is vital to achieve optimal overnight glucose control in closed-loop systems."

Can glucose sensing be improved?

The premise of an effective and safe closed-loop control system begins with accurate continuous glucose sensing within the interstitial fluid of the subcutaneous space. Dr. Ananda Basu comments: "However, the Achilles' heel of the closed-loop effort has been limitations in, one, understanding the kinetics of glucose transport between the intravascular compartment and the subcutaneous tissue where the glucose sensors are lodged and, two, precision and accuracy of currently available glucose sensors. The investigative team led by Dr. Rita Basu is 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 physiology of glucose transport and will clearly help refine and improve closed-loop control algorithms that currently account for the kinetic delay by applying an arbitrary time lag in the algorithm.

"Furthermore, the team, led by Dr. Kudva, in collaboration with Steven J. Koester, Ph.D., an electrical engineer at the University of Minnesota, is also exploring novel varactors derived from carbon that could be used as innovative glucose sensors addressing several of the shortcomings with current sensing approaches."