The pancreas is a very complex organ composed of both exocrine cells (glands with ducts) needed for digestive purposes and endocrine cells (ductless glands) that secrete hormones involved in blood glucose homeostasis and metabolism. The islets of Langerhans (or Beta cell islets) produce insulin that facilitates glucose entry into the cells during glycolysis (one of the most revered and important pathways in biochemistry related to diabetes). Glucagon, a counter-regulatory hormone, is produced by the alpha cells of the pancreas and serves to stimulate the liver to break down glycogen into glucose in the presence of hypoglycemia (glycogenolysis) to increase the concentration of serum glucose.
Insulin, or the lack thereof, has always been considered to be the culprit in the pathogenesis of type 1 diabetes. However, insulin shares an intimate relationship with glucagon to maintain blood glucose stability with minimal fluctuations. Now we have recent information that Glucagon may be a major "player" in the development of hyperglycemia...in mice! In the January 26, 2011, issue of Diabetes (volume 60, number 2, pages 391-397), Drs. Lee, Wang, Quan Du, Charron, and Unger published a paper, "Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice," that discussed the possible role of glucagon in causing type 1 diabetes.
The objective of the study was to determine the role of the hormone glucagon in glucose metabolism of untreated insulin deficiency. Working with mice that had no glucagon receptors and controls (wild type with glucagon receptors), the authors destroyed the B-cells by using streptozotocin (a potent drug that causes massive beta cell destruction). Note that both groups of mice lost the ability to produce insulin as a result of the loss of beta cells. The results were quite impressive! The "normal" mice with glucagon receptors developed hyperglycemia with blood sugars greater than 500 mg/dl and presented with the typical symptoms of diabetic ketoacidosis (increased drinking, increased urination, and weight loss). However, even with documented Beta cell destruction in the mice without glucagon receptors (and no insulin production due to beta cell destruction), there appeared to be no hyperglycemia or symptoms associated with insulin deficiency as noted in the wild type mice. Upon examination of the pancreas of the experimental mice, despite an increase in alpha cells with associated high levels of glucagon, other enzymes, cyclic AMP, and mRNA were reduced (as compared to the normal, wild type mice), providing evidence that glucagon action had been blocked. Fasting blood sugars and oral glucose tolerance tests were normal.
The authors concluded, "blocking glucagon action prevents the deadly metabolic and clinical derangements in type 1 diabetic mice."
In a commentary by Drs. Edgerton and Cherrington in the same issue of Diabetes, these results led the authors to consider "that insulin action during the absorption of glucose is largely directed toward overcoming the hepatic (liver) actions of glucagon" (which functions to raise glucose levels). They speculated "insulin would have little or no role in a liver not exposed to the action of glucagon because it would be in a permanent glucose storage mode." These findings suggest that the elimination of glucagon release restores glucose levels to normal despite the lack of insulin production. Simply put by Dr. Unger, "if there is no glucagon, it doesn't matter if you don't have insulin."
Keep in mind that despite this exciting research that provides very provocative information, the studies were conducted in mice. There is still a very long road to travel to translate this research into investigational review board approved studies in humans.
In response to "if there is no glucagon, it doesn't matter if you don't have insulin," one must remember that both hormones play other roles in both children and adults. Insulin is an anabolic hormone (a hormone that facilitates growth) and appears to be necessary for the growth and development of children. What about the role of insulin in the brain and the purported relationship to Alzheimer's Disease? What unknown actions of insulin (and glucagon) are required to sustain life? Clearly, additional research will be necessary to tease out these intricate metabolic relationships. However, the key in this genre of research is to "think out of the box" and look for the inter-relationships between glucose, insulin, and the counter-regulatory hormones that may shed light into a potential treatment or cure for type 1 diabetes.
Published On: February 09, 2011