Arthur R Colwell

Profile of Insulin Release Due to Intrapancreatic Glyburide Infusion

Intrapancreatic glyburide infusion in dogs (0.02 mg. per kg. of body weight) for five minutes provoked immediate, marked insulin release into the portal venous blood. Compared to control animals, the normal intrinsic insulin levels were exaggerated at intervals of approximately eighty minutes. Lack of immediate hypoglycemia suggests that the insulin release is merely secondary in contributing to the anti-diabetic property of this agent. An amount of tolbutamide fifty times as great caused a weak, delayed insulin response. The delayed blood glucose response is probably caused by the combined action of glyburide and circulating insulin.

Regulation of Insulin Release by Pancreatic Glucagon

In order to localize the site of its insulinogenic stimulus, glucagon was infused individually into the pancreas, liver, and peripheral circulation of normal dogs. Blood levels of insulin, glucose and nonesterified fatty acids were monitored in the femoral artery, portal and hepatic veins. The pancreatic artery infusions provoked a more rapid and marked insulin release initially than the same amount of glucagon given into the portal or femoral vein. The degree of hyperglycemia was comparable in the three groups, although the pancreatic group had more suppression of fatty acids probably related to the enhanced insulin secretion. Intrapancreatic infusion of glucagon in amounts sufficient to release insulin always produced concomitant hyperglycemia. In comparison, small amounts of glucose administered by the same route released insulin without elevating the blood glucose level. Larger quantities of glucose, calculated to produce insulin levels similar to those attained with glucagon, provoked hyperglycemia of lesser magnitude and shorter in duration. The effect of epinephrine on glucagon-stimulated insulin infusion. A quantity of intrapancreatic epinephrine which normally inhibits the glucose stimulus had no effect on delaying the insulin response until the amount of epinephrine was tripled. Simultaneous measurements of insulin and glucose in the hepatic venous blood during the intrapancreatic infusion resulted in response curves similar to those found in the portal vein. Even though the hepatic venous glucose values were almost identical during the infusions at the three different sites, insulin values were two to three times lower with portal or femoral than with pancreatic infusions. We conclude from the data that glucagon does play an independent role in the release of insulin from the pancreas, but that its effectiveness is less than glucose under normal circumstances. The glucagon stimulus is effective despite the presence of ordinary amounts of epinephrine. Since the magnitude of the insulin released from intra-portal glucagon is limited and delayed, the importance of its action as a gut factor in response to an oral glucose load is challenged.

Vascular Disease: Panel Discussion

MODERATOR COLWELL: I would like to introduce the members of this panel. Dr. Forrest E. Kendall is the Chief of the Biochemical Section of Goldwater Hospital and Professor of Biochemistry, College of Physicians and Surgeons, Columbia University. Dr. LeCompte is Director of the Laboratories at the Faulkner Hospital in Boston and Clinical Assistant Professor of Pathology at Harvard Medical School. Dr. Bernard Becker is Professor and Head of the Department of Ophthalmology, Washington University School of Medicine, St. Louis. Dr. Louis K. Alpert is Clinical Professor of Medicine, George Washington School of Medicine, Washington, D.C. I am Dr. Arthur R. Colwell, Sr., Professor and Chairman of the Department of Medicine at Northwestern University Medical School, Chicago. We will discuss vascular disease, both in and out of diabetes, with emphasis on diabetes. Whereas the audience might hope that the panel will provide practical information, I fear that we will have very little to offer that can be applied. If anyone in the audience would like to supplement our discussion please raise your hand for recognition. As you see, the panel is heavily weighted with men who have spent a great deal of time studying vascular disease at fundamental levels. In fact, it appears to many students of the disease that it is at such levels that practical knowledge will emerge. Our discussion,

Treatment of Diabetes: Selection of Technic according to Severity

The following doctrines are fundamental in current understanding and treatment of diabetes mellitus. They are accepted and employed by the great majority of informed physicians in this country. Almost all human diabetes is idiopathic, in the present state of knowledge. In some instances it has a demonstrable organic cause, or is intensified by one. When this is true, and when the cause can be removed or relieved, that should be done, of course. When there is no demonstrable cause supportive treatment must be used. Normal behavior can be attained in the majority of cases by proper use of such measures. When it cannot, it should be approximated as closely as is feasible in the individual case. Supportive methods of treatment now consist, for the main part, of limitation of the food supply, with or without the daily use of insulin, as required by the individual patient. Adjunctive measures include regulation of physical exercise, reduction of excess weight, and elimination of infection and other physiologically abnormal states such as emotional stress. In this review of therapy it will be assumed that organic factors and adjunctive measures are appreciated, and that nutritional rules are understood and applied. The chief objective here will be a correlation of different grades of severity of diabetes with the most effective methods of treatment for each. Selective therapy with diet and insulin is the intention.

Teaching of diabetes in medical schools. Proceedings of the Diabetes Program Directors' workshop.

This conference was concerned with methods of education, research and care of patients with diabetes in the medical schools in the United States. Its primary purpose was an interchange of useful information among educational institutions. Two principles guided its program: first, the tacit understanding that the earlier and more efficient the educational process, the better the product; and second, the idea that free communication among intelligent and interested people yields good dividends. Accordingly, the American Diabetes Association and the National Institute of Arthritis and Metabolic Diseases of the National Institutes of Health again joined forces to bring together national leaders in diabetes teaching, research and practice. Their immediate focus was teaching and training in American medical schools. Many zones of activity in diabetes revolve around the work of the schools, such as research, training of ancillary personnel, education of patients, development of future faculties, and postgraduate education of physicians. Therefore, discussions at the conference reached beyond the schools. Attendance: Seventy-nine individuals from various parts of the country participated. They included fifty Program Directors of diabetes training grants from the National Institutes of Health, or their delegates, in forty-

Oral Hypoglycemic Agents: Panel Discussion

PRESIDENT REED: The panel will discuss some of the new oral hypoglycemic agents. I take this opportunity to introduce Dr. Arthur R. Colwell, St., of Northwestern University Medical School, who will moderate the program. DR. COLWELL: The release is imminent for general use of a sulfonamide compound which, when given by mouth, has unquestioned ability to lower blood sugar values both in normal and in many diabetic subjects. All are properly interested in several major points. How does the substance act? How should it be used in treatment? Are there risks in its use? What is its relationship, if any, to insulin? This panel will endeavor to provide answers to these and other questions. If there is disagreement among us it will reflect the difficulties which have been encountered in trying to find reliable answers to many important questions, particularly concerning mechanisms of action. A great deal of experimental and clinical data has been accumulated during the last two years or so concerning the sulfonylurea compounds. The experts at my side are well-informed concerning them and have contributed generously to their study. To start the discussion, I will ask each of the panelists to give us a brief orientation on certain aspects of the subject. For the most part, this will concern the sulfonylurea compounds, and specifically tolbutamide, which is marketed under the trade name of Orinase, the only compound available now clinically in this country. Dr. Root, will you give a brief historical background and identification of these compounds?

Hypoglycemia Due to Intrapancreatic Infusion of Leucine

Introduction of L-leucine (0.2 gm.) in saline into the pancreatic artery in anesthetized dogs pretreated with chlorpropamide caused a marked peripheral venous hypoglycemia. Intraportal administration of leucine to sensitized dogs failed to produce the effect, as did injection of leucine or tolbutamide separately into the pancreas in the absence of pretreatment. Fall in blood glucose caused by infusion of leucine and tolbutamide concurrently into the pancreatic artery was not significantly different from that due to infusion into the portal vein. The hypoglycemia is most likely due to insulin secretion from pancreatic islets sensitized by action of chlorpropamide to the stimulating effect of leucine. Intraportal infusion of tolbutamide and leucine produced a greater fall in venous blood glucose than a doubled amount of tolbutamide alone. This might support the idea of a second action of leucine that might enhance the effect of endogenous insulin on the liver.

Histology of small blood vessel disease in diabetes.

Number of deaths Cause of death Males Females All causes Diabetic coma (primary) Cardio-renal-vascular Arteriosclerotic Cardiac Coronary Renal Diabetic nephropathy Cerebral Gangrene Site unassigned Other circulatory and rheumatic disease Infections, total Pneumonia and respiratory Gall bladder Kidney, acute Other infections Cancer Accidents Suicides Insulin reactions Other diseases Average age at death (years) Average duration of diabetes (years) 150 1 110 110 64 45 25

Insulin-Zinc Suspensions

the care of diabetic patients with lesions of the feet will welcome any form of treatment which may improve results or shorten the prolonged period of disability. Surgical debridement has been disappointing unless the lesion is such as to permit total excision and immediate split-thickness graft and this is the rare type of lesion. Chemical or enzymatic dissolution of the necrotic tissue has likewise given unsatisfactory results up to this time. Encouraging results following the use of trypsin are reported by Pote elsewhere in this issue. My limited experience with this agent has been less impressive. The true value of this method will be indicated by the role it plays in the management of these lesions in wellorganized diabetes clinics in the years ahead. Until the efficacy of this or any unproven method of local therapy is definitely established, great care must be exercised by all concerned lest injudicious or unnecessarily prolonged trial of enzymatic treatment may lead to unnecessary expense to the patient, delay in the institution of radical treatment when indicated and even to unnecessary loss of limb or life.

The Natural History and Identification of Diabetes: Panel Discussion

MODERATOR MULHOLLAND: Dr. Colwell, I believe you have made the statement in a published article that diabetes is a syndrome and not a disease. Will you explain what you mean by that term? DR. COLWELL: From my viewpoint, Dr. Mulholland, diabetes mellitus is not a disease. It is a syndrome, characterized by relatively persistent hyperglycemia and glycosuria when untreated. In the majority of cases the cause cannot be determined or removed, but, like fever, hypertension, and tachycardia, for example, the syndrome can be due to a variety of causes, some of which can be determined and a few removed. Our habit of thinking of diabetes as a disease entity stems from the fact that in the ordinary case a cause cannot be assigned.