News & Research

    Washington University in St. Louis, St. Louis, Missouri

Physiology of hypoglycemia and its pathophysiology in diabetes

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Complications\Hypoglycemia

Type of Grant: Clinical Translational Research

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Research Description

Physiology of Hypoglycemia and Its Pathophysiology in Diabetes

Glucose (sugar) from the blood is the fuel for the brain. Falling blood glucose concentrations cause the brain to send distress signals and low blood sugar concentrations (hypoglycemia) can cause the brain to fail. The actual low blood glucose concentration that causes delivery of glucose from the blood to the brain to fall below the normal brain glucose consumption is not known. We hypothesize that it is the level of hypoglycemia that causes symptoms of hypoglycemia, and will test that by measuring blood-to-brain glucose transport and brain glucose metabolism (with a noninvasive method called positron emission tomography) at various controlled blood sugar levels in nondiabetic people. Episodes of hypoglycemia occur commonly in people with type 1 diabetes and in some people with advanced type 2 diabetes.

That is started by too much treatment with insulin (either injected insulin or sometimes insulin stimulated by pills) but is largely due to failed defenses against hypoglycemia in those people with diabetes. The mechanism of those failed defenses is not known. We hypothesize it is due to increased uptake of an alternative (to glucose) brain fuel called lactate and will test that by measuring blood-to-brain lactate transport, again with positron emission tomography. We anticipate that better understanding of such features of abnormal mechanisms will lead to treatment strategies that will minimize the risk of hypoglycemia in people with diabetes.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

Blood sugar is an obligatory fuel for the brain. Hypoglycemia (low blood sugar) is the limiting factor in the glycemic management of type 1, and advanced type 2, diabetes. It causes many frightening episodes and sometimes causes death. Treatment with insulin or with drugs that increase insulin release starts falling blood sugar levels but hypoglycemia develops because the normal blood sugar-increasing systems are compromised. Those compromised blood sugar defenses include attenuated adrenal epinephrine and sympathetic neural responses (termed sympathoadrenal responses). Our long-term goal is to determine why those sympathoadrenal responses are attenuated, and how that might be prevented, in diabetes.

This project tests a physiological question - at what low blood sugar level does the delivery of sugar (glucose) to the brain become limiting to brain glucose metabolism, both measured with positron emission tomography - and a more diabetes-specific question - does increased blood-to-brain transport of lactate, a theoretical alternative brain fuel to glucose, explain why sympathoadrenal responses to hypoglycemia are attenuated in people with diabetes, with lactate transport into the brain also measured with positron emission tomography.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Episodes of hypoglycemia (low blood sugar) are a serious problem for most people with type 1 diabetes and many with advanced type 2 diabetes.

1. They cause an average of two symptomatic episodes per week and one episode requiring the assistance of another person per year, and are sometimes fatal.
2. They generally preclude maintenance of truly normal blood sugar levels over a lifetime of diabetes and, thus, full realization of the benefits of blood sugar control.
3. They lead to additional episodes of hypoglycemia.
4. Elimination of hypoglycemia from the lives of people affected by diabetes would permit complete blood sugar control, without frightening and disruptive episodes and without the risk of death produced by hypoglycemia, over a lifetime of diabetes.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

My research has focused on hypoglycemia for decades. It started with study of the normal mechanisms that prevent or correct hypoglycemia in people without diabetes and then moved to study of how these normal defenses against low blood sugar fail in people with diabetes. While a great deal has been learned, we need to better understand the basic mechanisms of the problem in humans, including those with diabetes. The premise is that understanding of those mechanisms will lead to interventions, perhaps with drugs, that prevent the compromised defenses against falling blood sugar levels in people with diabetes. My thoughts on how that might be accomplished will appear in the January 2011 issue of Diabetes.

In what direction do you see the future of diabetes research going?

Diabetes research, including hypoglycemia research, will move increasingly to studies of the role of the brain. To accomplish this, we are using state-of-the-art positron emission tomography methods to measure blood-to-brain transport and metabolism of glucose and of lactate by the brain to answer fundamental questions in humans.