Rafael A. Camerini-Davalos

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...

Diabetic Nephropathy: An Update

Nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus. In the United States, diabetes accounts for one fourth of new cases of end-stage renal disease each year. Complication rates and costs are much higher for diabetic than for nondiabetic patients with end-stage renal disease. Despite numerous studies, the pathophysiology of diabetic renal disease is not completely understood. We reviewed the current status of the structural, functional, biochemical, pathogenetic, and treatment modalities of diabetic renal disease and examined future therapeutic interventions.

Drug-Induced Reversal of Early Diabetic Microangiopathy

We performed three oral glucose-tolerance tests and three muscle biopsies over a period of approximately three years in 41 asymptomatic patients with chemical diabetes. At base line, 13 (32 per cent) had an increased capillary basement-membrane width in muscle. Twenty-three patients received glipizide, a new oral hypoglycemic compound, and 18 received placebo. In the patients receiving placebo the mean width of the muscle capillary basement membrane increased from 135.9 +/- 9.0 nm (S.E.M.) to 169.3 +/- 9.5 nm (P = 0.01), but in those receiving glipizide the value decreased to a level no different from that in subjects without diabetes: from 152.9 +/- 2.9 to 127.5 +/- 5.1 nm (P = 0.01). These findings suggest that microangiopathy, as indicated by an increased capillary basement-membrane width in muscle, may be present in a considerable number of patients with asymptomatic diabetes and that the changes can be reversed by early drug treatment.

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.

Glomerular lesions in a strain of genetically diabetic mice.

Summary In a strain of genetically determined, spontaneously diabetic mice (KK mice) lesions similar to those seen in human diabetic nephropathy were found in the glomeruli. These lesions increased with age and consisted of diffuse and nodular mesangial changes, exudative lesions, and alterations of the basement membranes.

Hereditary Diabetes in the KK Mouse: An Overview

Table III compares metabolic and morphologic characteristics of different species of control and KK mice. The C57BL/6J demonstrates no significant metabolic, clinical or histologic abnormalities. Our two highly inbred Swiss albino groups I and II also do not show significant glomerular lesions, although we found striking intolerance to glucose, hyperinsulinism, and obesity among them. Thus a genetic predisposition may be necessary in addition to various environmental factors to produce microangiopathy in KK mice. The yellow AY mouse is included in this table, since it is strikingly hyperinsulinemic and obese without concomitant vasculopathy such as the other mentioned control strains have. In conclusion, the KK mice develop chemical diabetes preceded by a stage of prediabetes and also demonstrate renal, retinal and neurologic complications similar to those seen in human diabetes. Of particular interest is the development of mild to moderate glomerulosclerosis in the prediabetic stage; with progression to severe glomerulosclerosis and attendant proteinuria later in life. With proper back-crossing, both hyperglycemia and glomerulosclerosis can be transmitted to normal control mice, suggesting that a specific genetic background is necessary for the development of diabetes and diabetic-like microangiopathy. We therefore suggest that the KK mouse serves as an ideal genetic animal for the study of non-insulin-dependent diabetes mellitus and its complications for rational prevention and therapy.

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...

Improved Glucose Disappearance Following Repeated Glucose Administration: Serum Insulin, Growth Hormone and Free Fatty Acid Levels During the Staub-Traugott Effect

The Staub-Traugott effect, the phenomenon of improved tolerance to repeated glucose administration, was investigated in fifteen healthy volunteers. Two glucose loads were administered intravenously forty-six minutes apart. Blood samples were taken periodically after each glucose infusion. The second glucose load was given immediately after the first sampling period. The glucose disappearance rate (K) improved after the second infusion from 2.04 ± 0.23 to 2.87 ±0.16 (p < 0.001). Serum immunoreactive insulin levels rose promptly after the glucose infusions, but while a decrease was noted following the first peak, the levels remained persistently elevated after the second glucose load. Growth hormone levels decreased and were slightly lower yet six to nine minutes after completion of the infusions. A striking reduction of free fatty acid levels followed the first glucose load; values fell to 50 per cent of the fasting levels prior to, and decreased even further following, the second infusion. Thus, the improved K of the second glucose tolerance test was associated with already diminished serum free fatty acid levels.

Diabetic microangiopathy in KK mice. II. Suppression of Glomerulosclerosis by pyridinolcarbamate.

Abstract KK mice with genetic diabetic glomerulosclerosis were treated with 250 mg/kg of pyridinolcarbamate (PDC), an antibradykinin agent, by 20 days of age and the kidney glucosyltransferase activity was measured. This enzyme facilitates the attachment of glucose to hydroxylysine-galactose unit of the basement membrane, which is glycoprotein in nature. No effect of PDC on the glucosyltransferase activity was observed up to 50 days of treatment. However, after 80 days of treatment, the enzyme activity was significantly increased. This finding was associated with a similar increase in total protein synthesis by the renal cortex of the treated KK mice. Amelioration of severity to only mild glomerulosclerosis was observed after 50 days of PDC administration. However, after 80 days of drug treatment, no severe type of glomerulosclerosis was present. PDC had no effect on either the fasting blood sugars or serum immunoreactive insulin levels. However, the oral glucose tolerance appeared to be improved in mice treated for 80 days. Glycogen synthesis by diaphragm muscle and total lipid synthesis by epididymal fat pad were significantly increased after 80 days of drug treatment, indicating increased tissue sensitivity to endogenous insulin. The observation that glucosyltransferase activity responded to PDC treatment with concomitant prevention of diabetic glomerulosclerosis suggests a relationship between this enzyme activity and glycoprotein synthesis in the kidney. It is suggested that PDC is a potential drug for the treatment of diabetic glomerulosclerosis.

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.