Alexander Marble

Clinical and Chemical Diabetes in Offspring of Diabetic Couples

Abstract A total of 678 glucose tolerance tests (oral glucose, cortisone-primed oral glucose, intravenous glucose and intravenous tolbutamide tests) were performed upon 155 of 274 offspring from 80 conjugal diabetic parents. The diabetic status of the untested offspring was determined by communication with parent or sibling. Administration of multiple tests (of various types) or repeated oral glucose tolerance tests detected a higher frequency of chemical diabetes than that obtained after a single test. The overall frequency of chemical diabetes (41 to 62 per cent, depending on the age and weight of the offspring) was considerably higher than that of overt diabetes (8.8 per cent). The oral glucose tolerance test appeared to be as sensitive as any other glucose tolerance test in detecting chemical diabetes. In such persons, many of whom were nonobese teen-agers and young adults, abnormal tests were frequently followed by one or more normal tests, as were normal tests followed by abnormal tests in no predic...

Elevated serum human growth hormone and decreased serum insulin in prediabetic males after intravenous tolbutamide and glucose

Serum human growth hormone (HGH), serum immunoreactive insulin (IRI), plasma free fatty acids, and blood glucose were measured during intravenous glucose and intravenous tolbutamide tolerance tests in 13 normal and 13 prediabetic (offspring of two diabetic parents) males, closely matched for weight and age. Only prediabetics with normal glucose tolerance during oral, intravenous, and cortisone-primed glucose tolerance tests were evaluated. Mean serum HGH levels were significantly higher in prediabetics in response to intravenous tolbutamide and at the end of the 3-hr intravenous glucose tolerance tests (IVGTT). This is interpreted as a hyperresponsiveness of the growth hormone-releasing mechanisms in prediabetic subjects. The insulin response during the first 10 min of an IVGTT was significantly reduced in prediabetic males as compared to normal controls, whereas the insulin response to intravenous tolbutamide was not significantly different at the same time intervals in the same subjects.It appears, therefore, that measuring IRI during an IVGTT can be valuable in detecting the earliest signs of diabetes even before any disturbance of blood glucose homeostasis is seen. The possibility that growth hormone hypersecretion in prediabetics might play a role in the pathogenesis of human diabetes mellitus is discussed.

STUDIES ON THE MODE OF ACTION OF IRRADIATED ERGOSTEROL: I. Its effect on the Calcium, Phosphorus and Nitrogen Metabolism of Normal Individuals

In the first paper of this series (1), we reported that the administration of adequate doses of irradiated ergosterol to normal individuals resulted in definite alterations in the fecal and urinary excretion of calcium and phosphorus. These changes consisted in a gradual fall in the fecal excretion and a gradual rise in the urinary excretion of both elements with little effect on the total balances of either. These findings are best interpreted as signifying increased absorption from the gastro-intestinal tract without an accompanying increased body retention. The fact that irradiated ergosterol acts as a curative agent in calcium deficiency diseases such as rickets and osteomalacia indicates that an increased retention of calcium and phosphorus must take place when it is administered to individuals with such diseases. In order to determine what changes occur in the calcium and phosphorus metabolism of individuals with calcium deficiency diseases when irradiated ergosterol is administered, two such patients were studied in an effort to ascertain whether the action of irradiated ergosterol was in any way different from that which we had observed in normal individuals.

Nine years' experience with tolbutamide in the treatment of diabetes☆

Abstract Experience with tolbutamide in the treatment of 3,387 selected patients for periods up to 9 years has been presented. These included 526 with “primary” failures and 202 with “indeterminate” failures; 104 other patients received tolbutamide in combination with other hypoglycemic agents. The remaining 2,555 patients achieved satisfactory (good or fair) control for at least 1 month. Of these, 2,056 had continuously satisfactory control throughout the period of observation, whereas secondary failures occurred in 499 patients at an average rate of 25 per cent/year. Men had fewer secondary failures than women. A significantly larger proportion of persons with satisfactory control had a duration of known diabetes of under 1 year as compared to those with primary or secondary failures. The age at onset of diabetes of 60 years and over was significantly more frequent among those with continuously satisfactory control than in the groups with primary or secondary failures. A total of 1,266 patients had been treated with insulin prior to tolbutamide therapy. The proportion of those with continuously satisfactory response on tolbutamide who had received small insulin doses prior to the oral therapy was significantly greater than in those with primary or secondary failures. Continuously satisfactory control with tolbutamide was attained more often among the patients whose diabetes had been controlled satisfactorily also with insulin. Forty-eight per cent of the patients who returned to insulin after a variable period of tolbutamide therapy, showed a higher insulin requirement than before the oral therapy. No other significant differences were found between those patients with continuously satisfactory control and those with secondary failure in this selected population. Four hundred thirty patients had received tolbutamide for 6 to 9 years. The secondary failures in this group amounted to 113 (26 per cent). In this highly selected population, no differences were discernible that would help predict those likely to have a long-term satisfactory control with tolbutimide. The overall attrition rate of patients treated with tolbutamide was high. Only about 10 per cent of patients started on tolbutamide were known to be taking the drug 6 to 9 years later. Reduction in numbers was due chiefly to death (not related to tolbutamide administration), secondary failure, or loss to follow-up. Side effects to tolbutamide were remarkably few and benign. Three patients developed blood dyscrasia (one each with thrombocytopenic purpura, nonthrombocytopenic purpura and neutropenia) documented by tests for circulating antibodies, and in each instance discontinuance of the drug resulted in recovery.

Liver Function in Diabetes Mellitus

MANY reports have been published regarding the outcome of liver-function tests both in healthy persons and in those with pathologic states. The data have shown considerable variation from one study...

Evidence for a peripheral action of chlorothiazidein normal man

Twenty-nine normal volunteers weregiven standard intravenous tolbutamide tests. Nineteen of these received chlorothiazide, 500 mg. 3 times a day for 3 days before the test. Eight of the 19 were also given potassium chloride, 1.0 Gm. 3 times a day for the 3 day period. Blood glucose and serum inorganic phosphorus levels measured at 15 minute intervals for 1 hour showed no difference between the 3 groups in either the fasting blood glucose or fasting serum inorganic phosphorus levels or in the rate of glucose fall following the administration of intravenous tolbutamide. There was a significant difference at 45 and 60 minutes in the per cent of the phosphorus fall from the fasting values between those subjects who had received chlorothiazide and the control group. The addition of potassium chloride did not affect this finding. It is suggested that chlorothiazide may have changed the permeability of the cell membrane to phosphorus.

STUDIES WITH CHLORPROPAMIDE IN DIABETIC PATIENTS

The clinical trials of chlorpropamide reported here were begun in April 1958; our experience to date therefore extends over only 5 months. The studies were initiated with the following four objectives in mind: first, to determine the effectiveness of the drug as a hypoglycemic agent in the management of diabetes, second, to observe serum levels of the compound in patients under control, third, to determine whether or not long-term effectiveness could he predicted by the blood sugar response in a single-dose test and, finally, to study the possible toxicity of the drug by performing serial liver and kidney function tests and hematological studies.

The Banting Memorial Lecture 1967: Angiopathy in Diabetes: An Unsolved Problem

Vascular disease, exceedingly common in persons with long-term diabetes and affecting both large and small blood vessels, presents the greatest problem and challenge in diabetes today. Large vessel involvement is responsible for a frequency of cerebrovascular, coronary and peripheralvascular disease which is significantly greater in diabetic than nondiabetic individuals. However, most characteristic of diabetes is microangiopathy which, although widespread in the body, is seen most forcibly in the eyes (diabetic retinopathy) and kidneys (intercapillary glomerulosclerosis). Since treatment of fully developed complications is unsatisfactory, exploration of ways of prevention offers the best hope for the future. This leads the investigator and clinician alike into the origins of diabetes itself and the relationship of the metabolic defect (insulin deficiency) to vascular disease. That the tendency to diabetes is inherited is commonly accepted but knowledge is lacking as to exactly what the diabetic inherits. Environmental factors such as overnutrition, pregnancy, infections, steroid administration, etc., favor the emergence of the tendency to a state clinically recognizable. Special studies and clinical experience suggest that in the early stages of the diabetic state (“prediabetes” and “chemical diabetes”) there exists a fluid, dynamic condition in which not only progression but also remission are possible, therein affording hope for the eventual discovery of means of halting progression of the metabolic defect. Microvascular disease may be demonstrable (in the form of thickening of the basement membrane of small blood vessels) even in the early stages of the diabetic state. However, present knowledge does not warrant the conclusion that the tendency to vascular disease is inherited as a separate trait which develops independently of the tendency to the metabolic defect. On the contrary, there is increasing evidence to suggest that even in prediabetes the pancreatic release of insulin in response to glucose given intravenously may be subnormal, delayed or inappropriate in relation to the level of blood glucose at the time. With information currently available it is unwarranted to assume that vascular disease in its origin and development is unrelated to the metabolic defect. These considerations lead naturally into the matter as to whether the degree of control of diabetes, i.e., to which insulin deficiency is met, has any influence on the frequency, degree and time of appearance of the vascular sequelae. Evidence is presented from studies in nonhereditary diabetes both in man and animals, from general clinical experience and from special clinical studies, to support the view that there is, indeed, such a relationship and that by careful and consistent control of diabetes, complications may be lessened or delayed.

Clinical Experience with Carbutamide (BZ-55): A Progress Report

From December 1955, through August 1956, we used sulfonylurea compounds in 620 patients with diabetes. Of this number 380 received BZ-55, 3° w e r e given Orinase and 10 SPTD (sulfapropylthiodiazole). In the present paper our experience with BZ-55 alone is reported. This is in the nature of a progress report; a more complete and detailed presentation of results will be made at a later date. Among the 380 who have received BZ-55, 187 patients, including 101 of fifteen years of age and under, were studied only following a single administration of the drug in the course of a response test (see below). The remainder, 193 patients, was observed while being maintained on BZ-55. Of these, in sixteen cases the period of observation was insufficient, in twenty-four the drug was discontinued because of complications and in three the preparation was stopped for other reasons. The results in the remaining 150 patients form the basis of the present discussion. These patients have been maintained on BZ-55 f° periods varying from less than one month (thirty-one cases) to more than six months (twenty cases). Of the 150 patients, 66 were males and 84 females. Most of them (116, or 77 per cent) were between the ages of 40 and 70 years; 14 were under 40 and 20 over 70. Diabetes had been present in 42 (28 per cent) of the group for 10 to 20 years; in 99 (66 per cent) the duration was under 10 years and in 9 (6 per cent) over 20 years. Of the 150 patients, 65 had never received insulin and 75 had been taking less than 40 units daily.

Pathological findings after long-term sulfonylurea therapy.

An evaluation was made of postmortem findings in a group of fifty-five diabetic patients who were treated with sulfonylurea compounds, primarily tolbutamide, from twenty-four to 112 months, for a total of over 2,500 patientmonths and an average of 45.7 months per patient. The results were compared in “blind” fashion to the postmortem findings in two control groups: (a) fifty-five patients, closely matched to the former as to sex, age at death, and known duration of diabetes, who had been treated with insulin and had never received oral hypoglycemic agents; and (b) nineteen patients who had been treated exclusively by dietary restriction. The frequencies of myocardial infarcts, cerebral vascular accidents, diabetic retinopathy and nephropathy, as well as neoplasms, thyroid disease, and ulcers of the stomach and duodenum were not statistically different in the three groups. Peripheral vascular disease (gangrene and/or amputations) occurred more frequently in the insulin-treatedgroup, probably because of the customary use of insulin in patients with these conditions. The findings do not provide evidence that the sulfonylureas influence the pattern ofdiseases or specific complications of diabetes when compared to suitable controls. Islet cell tumors occurred more frequently in sulfonylurea treated patients when compared to the over-all experience of this hospital. The importance of such a finding has to be further substantiated.