Thomas G. Skillman

The Course of Juvenile Diabetes Treated with Unmeasured Diet

Prospective observations over a ten-year period of 108 juvenile diabetics treated with unmeasured diet are reported. Description is given of the patient material, circumstances at diagnosis, and course of management. Hyperglycemia and glycosuria were common, and ketoacidosis occurred often. Total plasma lipidswere elevated. Chemical control was unsatisfactory according to current popular standards. Growth was less in those with onset before puberty, and the men were underweight. Infections may have been excessive. Adolescent emotional difficulties were exaggerated. Educational, athletic, and vocational achievements probably equaled the normal expectation. Pregnancies were only 55 per cent successful when fetuses were viable. The prevalence of degenerative complication was similar to that reported from restricted diet studies. No factors were found to account for vascular disease. It is surmised that the general course of the patients compared favorably to those reported to be following diets. It is also suggested that if diet control does have favorable effects, then those reported to follow diets are not following them, or factors other than control are more influential on the progression of juvenile diabetic vascular disease.

Interrelationships of Hyperinsulinism and Hypertriglyceridemia in Young Patients with Coronary Heart Disease

Fasting serum lipid levels, glucose tolerance, and immunoreactive insulin concentrations of 50 young patients with coronary heart disease (CHD) and 30 control subjects were evaluated to study the interrelationships of these metabolic factors. Abnormalities in one or more of these factors could be shown in 90% of the patients and 20% of the control subjects. Thirty-four of the 50 patients had elevated cholesterol or triglyceride levels, or both, 30 had abnormally elevated or delayed insulin responses after glucose, and 17 had abnormal glucose tolerance. A significant correlation existed between serum triglyceride and insulin concentrations. When insulin levels were reduced by phenformin, triglyceride concentrations fell toward normal.These findings indicate that carbohydrate, insulin, and lipid abnormalities are rather prevalent in patients with CHD. Excessive insulin secretion secondary to mild glucose intolerance probably induces hepatic synthesis of triglycerides and hypertriglyceridemia. Dietary alterations or pharmacological agents may help to control some of the metabolic abnormalities associated with premature CHD.

The Mechanism of Action of Hypoglycemic Guanidine Derivatives

Renewed interest in guanidine derivatives as possible oral therapeutic agents in the treatment of diabetes has followed the discovery by Ungar et al. that certain biguanides are hypoglycemic agents of low toxicity. This report is concerned with the mechanism of action of this new group of compounds as exemplified by one of them, phenethylbiguanide (DBl), as compared with that of other guanidine derivatives. As long ago as 1918, Watanabe showed that guanidine elicited a pronounced hypoglycemic response in rabbits. However, the toxic manifestations of this substance precluded its trial as a possible therapeutic agent in diabetes mellitus. An intensive search by Frank et al. led to the synthesis of decamethylenediguanidine (Synthalin) which was found to exhibit enhanced hypoglycemic activity associated with markedly diminished toxicity. However, after intensive clinical trial the therapeutic use of Synthalin as an oral hypoglycemic agent was abandoned. Disagreeable side effects including nausea and weakness were frequent. Furthermore, except for lowering blood sugar and diminishing glycosuria, Synthalin therapy did not really correct the aberrant metabolism of the diabetic individual. Elevations in blood and urinary lactate, citrate and other organic acids were observed. In a balance study of diabetics undergoing Synthalin therapy, Kaufmann-Cosla and Vasilco found that urinary glucose was supplanted by large excretions of other organic compounds.

Glucose intolerance mechanism after starvation.

Seven obese nondiabetic subjects were studied during control, total fast, and refeeding periods. Despite refeeding until ketonuria disappeared, a 14-day fast was associated with “starvation diabetes.” Factors known to affect glucose tolerance such as insulin secretion in response to oral glucose, sensitivity to exogenous insulin, human growth hormone (HGH) secretion, free fatty acid (FFA) levels, cortisol concentration, and the effects of complete autonomic blockade on the insulin tolerance test were studied. Exogenous insulin sensitivity, measured by insulin tolerance tests did not differ during any of the three study periods. HGH responses to hypoglycemia were excellent in the control and starvation periods, but slightly depressed during the refeeding period. Complete alpha and beta adrenergic blockade did not affect insulin sensitivity or the HGH response to hypoglycemia. FFA levels were greatest during the starvation period when sensitivity to exogenous insulin was quite adequate. Cortisol concentrations were unchanged throughout the study. The carbohydrate intolerance during the refeeding period was associated with a slightly lower than normal insulin/glucose ratio at the one hour interval of the oral glucose tolerance test. With continued glycemic stimulation, insulin levels subsequently rose to levels greater than those in the control period. It is suggested that a major factor in “starvation diabetes” is a deficient secretion or synthesis of insulin during the early portion of the glucose tolerance test.

THE EFFECTS OF CHLORPROPAMIDE ON ENDOCRINE FUNCTION IN PATIENTS WITH DIABETES MELLITUS AND ITS EFFECTS IN OTHER ENDOCRINE DISORDERS

The continued widespread use of tolbutamide for the treatment of diabetes mellitus has left little doubt about either the efficacy of action or the acceptance by both the physician and patient of this oral agent for the treatment of this disease. Similar drugs are destined to undergo investigation, and certain of these will find a place as competitors with, or substitutes for, tolbu tamide. In order to compete with tolbutamide a compound must be a t least as potent a hypoglycemic agent and equally innocuous from the standpoint of toxicity. Additional attributes of such a drug might include equal effectiveness a t lower dose ranges or blood levels, less expense to the patient, or usefulness as alternate therapy in patients known to be hypersensitive or unresponsive to tolbutamide. It has been the aim of our study to accumulate data on chlorpropamide regarding each of these points. Preliminary results indicate that chlorpropamide is effective as an oral hypoglycemic agent in the same type of diabetic patient that responds to tolbutamide, and that dosages of approximately one third the magnitude of the latter drug result in equal or higher serum levels. Additional data suggest that hypoglycemic reactions are more common with chlorpropamide, but in short-term usage few manifestations of toxicity to vital organs were observed. As with other sulfonylurea derivatives, slight inhibition of thyroid function may occur, but this does not appear to be clinically significant.

COMPARATIVE PHARMACOLOGY AND CLINICAL RESPONSES TO METAHEXAMIDE

RIetahexamide (N-(3 amino-4-methyl benzine-sulfony1)-N1-cyclohexylurea) was studied for the purpose of comparing its hypoglycemic potency, toxicity, and pharmacology with the currently existing compounds used for oral therapy of diabetes. Observations made during a 6-month period in which metahexamide was given in daily doses ranging from SO to 500 mg./day to 73 maturity-onset diabetic patients permit the conclusion that this compound embodies a hypoglycemic potency that is approximately 7 times that of tolbutamide and twice that of chlorpropamide. In addition, normoglycemia is obtained in responsive patients with serum concentrations of metahexamide that range from one fifth to one third as high as the levels needed with the other sulfonylureas. Early studies of the incidence of untoward reactions to metahexamide indicate an incidence of about 10 per cent. This incidence is comparable to that of chlorpropamide. However, preliminary data suggest that alterations of liver function are more frequent with metahexamide than with other compounds.

Acute and chronic studies using a new oral hypoglycemic agent, glyburide

Abstract Acute and chronic studies were done on relatively severe adult-onset diabetics to determine efficacy, safety, and mode of action of a new sulfonylurea agent, glyburide. At regular intervals, diabetic control as well as drug toxicity were evaluated. An oral glucose tolerance test with insulin determinations was done on nine subjects after long-term therapy and compared with tests done after all diabetic medications had been discontinued. During the acute study, 17 of 20 subjects showed some improvement in diabetic control. The mean fasting serum glucose (FSG) decreased from 262 on placebo to 206 mg 100 ml while they were on small doses of glyburide (p 272 to 230 mg 100 ml (p 197 mg 100 ml at the end of the study. Although thymol turbidity was significantly elevated in the acute study, there was no significant difference in this or other studies for toxicity found in the chronic study. The oral glucose tolerance test showed worse results for all nine patients tested after discontinuing the drug. Insulin levels were higher 30 min after glucose in seven of the nine patients while on drug in comparison with levels while off drug. Glyburide is a potent antidiabetic agent of low toxicity. It appears that this drug enhances early release of insulin after oral glucose in some patients, even after treatment for many months.

The clinical usefulness of orally administered hypoglycemic agents.

The three orally administered hypoglycemic agents currently available in the United States are tolbutamide, chlorpropamide and phenformin.When effective, these compounds reduce blood glucose levels, quantitatively reduce glycosuria, and reduce the net hepatic glucose output.Tolbutamide appears to be effective in older patients with mild diabetes; chlorpropamide seems the treatment of choice in more severe cases. Phenformin may be used alone or as an adjunct to insulin therapy. Generally, side effects are sufficiently mild to be counteracted by cessation or reduced dosage of the drugs. In some cases, however, severe and irreversible damage has occurred.