An alteration in calcium metabolism in cardiac muscle was observed in diabetic rats 3 mo after streptozotocin treatment. Depression of cardiac output and left ventricular pressure development were more sensitive to decreased extra-cellular calcium in hearts from diabetic than from control animals and occurred within the normal physiological range of freely ionized serum calcium. This decrease in calcium sensitivity was not present after 2 wk of diabetes. In vivo treatment with insulin for 1 mo completely reversed the effect. Addition of octanoate (0.3 mM) to the perfusate of isolated hearts completely reversed the defect, whereas epinephrine (25 nM) only partially reversed it. When the glucose concentration of the perfusate was decreased, the function of diabetic hearts declined and was further diminished at decreasing calcium levels. Hearts from normal rats were unaffected. These results suggest that there is a defect in calcium metabolism or flux in the chronic diabetic rat heart.

Serum hyperosmolarity is commonly associated with the poorly controlled diabetic state. The current investigation revealed that increased perfusate osmolarity using either glucose or mannitol caused a gradual decline in the aortic output of hearts from both normal and diabetic rats. However, aortic output decreased less rapidly in hearts from diabetic rats. Decreasing the extracellular calcium concentration to a level resulting in one-third of the maximal aortic output elicited a greater and more prolonged increase in aortic output from the diabetic compared with the normal heart when perfusate osmolarity was progressively increased. The coronary conductance of diabetic rat hearts improved when hyperosmolar solutions of either mannitol or glucose were utilized, irrespective of the external calcium ion concentration. In normal hearts, the coronary conductance tended to decline at higher perfusate osmolarities. The increased coronary conductance may play a role in the enhanced performance of diabetic hearts at higher levels of osmolarity. Hyperosmolar solutions influence the performance of hearts from chronic diabetic rats in a positive inotropic manner at low extracellular calcium concentrations (1 mM). These lower calcium levels are close to the normal physiological range of the freely ionized serum calcium. This effect is greater in hearts from diabetic animals than from normal animals and is similar to that obtained when perfusate calcium is increased. The results suggest that hyperosmolar solutions enhance calcium availability in the hearts of diabetic animals.

Twenty-six patients with symptoms suggestive of postprandial hypoglycemia were investigated by oral glucose tolerance test (OGTT). During the OGTT, symptomatic hypoglycemia occurred in 10 (38.5%). Nine of these 10 sugjects were given mixed meal tolerance tests (MMTT) and symptomatic hypoglycemia failed to occur in any case. During the OGTT the nadir glucose was significantly lower than that during MMTT (44.1 +/- 1.5 vs. 77.3 +/- 4.8 mg/dl +/- SEM, respectively; p less than 0.0005). Serum insulin during MMTT peaked significantly earlier than during OGTT (46.7 +/- 7.3 vs. 86.7 +/- 11.7 minutes (SEM, respectively; p less than 0.0125). The early secretion of insulin during MMTT may explain the lack of symptomatic hypoglycemia in these patients. We conclude that reactive hypoglycemia, when tested by a more natural stimulus (such as mixed meal) rather than by OGTT, is uncommon.

HbA1 was determined in 16 subjects with normal oral glucose tolerance test (OGTT), in 8 subjects with normal fasting plasma glucose (FPG) but with abnormal OGTT (chemical diabetes mellitus) and in 25 subjects with overt diabetes mellitus. The HbA1 values were 7.53 +/- 0.1%, 8.37 +/- 0.17% and 11.92 +/- 0.42% (+/- SEM), respectively. The HbA1 values of subjects with chemical diabetes mellitus were significantly higher (p less than 0.0025) than those of subjects with normal OGTT. Thus, the determination of HbA1 may prove to be useful to substantiate a significantly abnormal glucose tolerance (chemical diabetes mellitus).

Insulin antibodies were determined as percentage binding of 125I-insulin in the sera of normal persons and of diabetic subjects treated and untreated with insulin. The effect of the dilution of the serum, circulating insulin and extraction of free and total insulin was evaluated. The determination of insulin antibodies in samples at a final dilution of 1:10 clearly discriminated between insulin-treated and untreated subjects. In insulin-treated subjects, the determination of insulin antibodies in samples at a final dilution of 1:100 gave false-negative results in 28 per cent. However, the determination of insulin antibodies at a final dilution of 1:100 discriminated between insulin-resistant and non-resistant diabetic subjects. Extraction of total insulin at pH 3.0 using 0.1 N HCl increased the percentage of 125I-insulin binding significantly. Extraction of free insulin by charcoal from the samples did not increase the binding of 125I-insulin. The injection of crystalline insulin 4 hours prior to withdrawing the samples did not decrease binding of 125I-insulin.

The future in diabetic research is both stimulating and exciting. Diagnostic subclassification as to specific etiology appears well underway and will provide a more scientific basis for therapeutic approaches. The importance of the histocompatibility complex and its many secrets are rapidly becoming apparent in the etiology of juvenile diabetes. Further studies in obesity and the neuroendocrines may solve adult-onset diabetes. Pancreatic transplantation and artificial devices may provide important therapeutic approaches. Further genetic explorations will, no doubt, provide clarity to the somewhat muddy picture of both etiology and complications. The challenges are here, let's hope that enough young scientists hear the call to provide the manpower to solve this major dilemma.

The inhibitory effect of epinephrine on basal and tolbutamide-stimulated insulin release was studied in 5 patients with hyperinsulinemic hypoglycemia. Epinephrine inhibited both basal and tolbutamide-induced insulin release in patients with beta-cell adenoma and hyperplasia, but failed to inhibit insulin release in a patient with beta-cell carcinoma. The inhibition of basal insulin with epinephrine was maximum in patients with beta-cell hyperplasia. This differential inhibitory effect of epinephrine on insulin release may prove to be a useful screening test in the preoperative diagnosis of the nature of the lesion producing hyperinsulinemia.

An insulin-resistant diabetic patient who also has chronic lymphocytic leukemia and very high plasma levels of free and total insulin along with high levels of insulin antibodies is described. In response to prednisone therapy, his insulin requirement decreased, but the total and free insulin concentrations increased as insulin antibody measured as the maximal insulin-binding capacity of plasma remained unchanged. In insulin resistance, persistent hyperglycemia, in spite of high levels of immunoreactive free insulin, presumably reflects peripheral tissue unresponsiveness to insulin. The beneficial effect of prednisone treatment in this patient is discussed, and it is postulated to be the result of either increased availability of free insulin or an increased responsiveness of the tissues to insulin or both.

Twelve diabetic subjects who were not previously treated with insulin were divided into two groups of six each. Group I was treated with single component pork insulin and Group II was treated with standard (USP) insulin for 5 to 10 months. Three out of six in Group I, and five in Group II, developed circulating insulin antibodies. Daily insulin requirement in the two groups were almost the same. Insulin antibody titer did not fall in three insulin-treated diabetic subjects when single component pork insulin was substituted for USP beef-pork insulin. This study shows that the single component insulin is antigenic in human subjects.

Glipizide, a new low dose sulfonylurea, was evaluated for its efficacy and toxicity in a double-blind controlled study. Forty adult-onset diabetics were treated with either chlorpropamide or glipizide. In ten out of twenty patients "excellent" to "good" control of hyperglycemia was achieved with glipizide and two patients evidenced "fair" control. In nine out of eighteen patients "excellent" to "good" control was achieved with chlorpropamide. Eight of the sixteen patients who were primary or secondary failures on the two drugs responded to glipizide and phenformin combination with "excellent" to "good" control. No therapeutic advantage was found in giving more than 25 mg/day glipizide in ten patients. Toxicity was low and side effects were uncommon over a period of 26 months.

Annals of the New York Academy of SciencesVolume 71, Issue 1 p. 71-80 STUDIES ON THE SITE OF ACTION OF THE ARYLSULFONYLUREAS IN MAN. II. Albert E. Renold, Albert E. Renold Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass.Search for more papers by this authorDonald B. Martin, Donald B. Martin Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass. Postdoctoral Fellow of the United States Public Health Service.Search for more papers by this authorBuris R. Boshell, Buris R. Boshell Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass. Research Fellow in Medicine of the American College of Physicians.Search for more papers by this authorGeorge W. Thorn, George W. Thorn Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass.Search for more papers by this author Albert E. Renold, Albert E. Renold Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass.Search for more papers by this authorDonald B. Martin, Donald B. Martin Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass. Postdoctoral Fellow of the United States Public Health Service.Search for more papers by this authorBuris R. Boshell, Buris R. Boshell Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass. Research Fellow in Medicine of the American College of Physicians.Search for more papers by this authorGeorge W. Thorn, George W. Thorn Departments of Medicine, Harvard Medical School and the Peter Bent Brigham Hospital, and the Baker Clinic Research Laboratory, New England Deaconess Hospital, all in Boston, Mass.Search for more papers by this author First published: July 1957 https://doi.org/10.1111/j.1749-6632.1957.tb54577.xCitations: 19 The work on which this paper is based was supported in part by grants from the John A. Hartford Foundation Inc., New York, N. Y.; The Upjohn Company, Kalamazoo, Mich.; The Lilly Research Laboratories, Indianapolis, Ind.; and The Nutrition Foundation, Inc., New York, N. Y. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume71, Issue1The Effects of the Sulfonylureas and Related Compounds in Experimental and Clinical DiabetesJuly 1957Pages 71-80 RelatedInformation

These studies were designed to define the mechanism by which the tryptophan metabolite, quinolinic acid, blocks gluconeogenesis and to determine the role it plays in influencing this process under physiologic and pathologic conditions. An alteration in the level of gluconeogenic intermediates occurred at a quinolinic acid content of 43 ng. per gram of liver. At a content of 10 μug. per gram of liver there was no significant change in the level of these intermediates. The concentration of quinolinic acid (3.7 × 10−4 M) which was associated with inhibition of P-enolpyruvate carboxykinase in vivo correlated well with K1 (1 × 10−4 M) derived for ferrous quinolinate in vitro. This level of quinolinic acid was reached by the intraperitoneal administration of approximately one fourth and the intragastric administration of approximately one half the daily dietary intake of L-tryptophan. The content of quinolinic acid in the liver of fasted animals was twenty-five-fold lower than the level required to inhibit the carboxykinase reaction and there was no increase in the quinolinic acid content of the liver on a diet containing the usual amount of tryptophan. The effects of various parameters on the conversion of tryptophan to quinolinic acid were also investigated and the clinical implications of these findings are discussed.