John I Malone

A Randomized Trial of Intensive Insulin Therapy in Newly Diagnosed Insulin-Dependent Diabetes Mellitus

A period of early, intensive insulin treatment is thought to improve subsequent beta-cell function in insulin-dependent diabetes mellitus (IDDM). To study this hypothesis, we randomly assigned adolescents with newly diagnosed IDDM to receive either conventional treatment (n = 14) (NPH insulin, 1 U per kilogram of body weight per day, in two divided doses) or an experimental treatment (n = 12) (a two-week hospitalization with maintenance of blood glucose levels between 3.3 and 4.4 mmol per liter by continuous insulin infusion delivered by an external artificial pancreas [Biostator]). During the two-week intervention, the experimental-therapy group received four times more insulin than the conventionally treated group, and their endogenous insulin secretion was more completely suppressed, as evidenced by a urinary C-peptide excretion rate one seventh that of the conventionally treated group. After the first two weeks, both groups were treated similarly and received similar amounts of insulin. At one year, the mean (+/- SEM) plasma level of C peptide was significantly higher after mixed-meal stimulation in the experimental-therapy group than in the conventionally treated group (0.51 +/- 0.07 vs. 0.27 +/- 0.06; P less than 0.01). The experimental-therapy group also had better metabolic control, as evidenced by lower glycohemoglobin values (7.2 +/- 0.7 vs. 10.8 +/- 1.2 percent; P less than 0.01). We conclude that suppression of endogenous insulin by intensive, continuous insulin treatment during the first two weeks after the diagnosis of IDDM may improve beta-cell function during the subsequent year.

A Prospective Study of the Development of Diabetes in Relatives of Patients with Insulin-Dependent Diabetes

BACKGROUND The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race. METHODS From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors. RESULTS Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

Joint contracture—common manifestation of childhood diabetes mellitus

Sixty-five of 229 seven to eighteen-year-old campers with diabetes were found to have contractures of finger joints; in two thirds of affected children only the fifth finger was involved. Stiff resistance to passive finger manipulation and thickened adherent skin over the dorsa of the hands were additional features. Short stature was associated with involvement of more than one finger; the shortest youngsters also had contractures of large joints. Joint changes were independent of age, sex, age of onset of diabetes, and control of diabetes, but correlated with duration of the diabetes.

Nonosmotic diabetic cataracts.

ABSTRACT: It has been suggested that sugar cataracts associated with diabetes mellitus result from the accumulation of excess sorbitol within lens fibrils. Swelling of lens fibrils occurs when water moves in to maintain osmotic balance; the excess water causes disruption of fibrils and cataract formation. Other studies have indicated that more than sorbitol-induced osmotic stress is involved. Our study used lenses collected from rats after 21 or 44 d of streptozotocin diabetes. Cataracts formed in untreated 44-d streptozotocin diabetic rats, but were not apparent in the 21-d untreated diabetic animals. Lens sorbitol increased in the diabetic animals both before and after cataract formation. Lens taurine varied inversely with the sorbitol content in a fashion that resulted in no net change in total lens osmoles. Lens water did not increase in the diabetic animals with or without cataracts. The aldose reductase inhibitor Sorbinil prevented the increase in lens sorbitol in both the 21− and 44-d streptozotocin diabetic rats; cataract formation was prevented in the 44-d diabetic animals. The lens water in untreated diabetic animals with cataracts did not differ from lens water in the Sorbinil-treated diabetic animals that did not develop cataracts. Sorbinil treatment of diabetic animals was associated with normalization of both lens sorbitol and taurine levels. Taurine has been shown to serve both as an osmoregulator and as an antioxidant. The apparent increase in lens osmolality attributed to sorbitol was counterbalanced by an equimolar reduction in taurine concentration. The reciprocal relationship between taurine and sorbitol reduces the likelihood of an osmotic mechanism for sugar cataractogenesis; the reduced lens taurine, however, may increase the risk of lens protein oxidation and subsequent cataract formation. Thus in vivo sugar cataract formation may be an oxidative process rather than an osmotic phenomenon.

The Effect of Hyperglycemia on Nerve Conduction and Structure Is Age Dependent

The nerve conduction velocity (NCV) of nondiabetic male Wistar rats continues to increase until ∼ 26 weeks of age. Rats made hyperglycemic at 6 weeks of age manifest reduced NCV by 10 weeks of age and show morphological differences in the sciatic tibial nerve after 5 months of hyperglycemia when compared with age-matched controls. Fiber diameter, myelin width, and the number of large myelinated fibers were decreased in the tibial nerves of the hyperglycemic animals. Rats made hyperglycemic at 26 weeks of age had elevated glycosylated hemoglobin and sciatic nerve sorbitol levels but maintained normal NCVs and had little change in morphology after 7 months of hyperglycemia. Thus, animals with maturing peripheral nerve structure and function exposed to chronic hyperglycemia manifest greater pathological alterations than those that occur when more matured nerves are exposed to similarly elevated glucose concentrations for an even greater duration. We suggest that immature animal models commonly used to study diabetic peripheral neuropathy may not be appropriate for understanding a process that commonly develops in humans who become hyperglycemic after maturation of the peripheral nerves.

Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes.

Acetyl-L-carnitine reduces the latencies of electroretinogram oscillatory potentials in healthy humans. The effect of acetyl-L-carnitine (50 mg · kg−1 · day−1) on the increased electroretinogram latencies found in rats with STZ-induced hyperglycemia of 3-wk duration was evaluated. The aldose reductase inhibitor sorbinil, which has been shown to normalize abnormal electroretinogram tracings associated with STZ-induced diabetes, was used as a positive control. Aldose reductase inhibitors are thought to lower tissue sorbitol while increasing myo-inositol. The electroretinograms of the STZ-induced diabetic rats in this study were abnormal; treatment with acetyl-L-carnitine as well as sorbinil significantly improved electroretinogram b-wave amplitude and decreased the latencies of oscillatory potentials 2 and 3. Acetyl-L-carnitine treatment of STZ-induced diabetic rats did not affect hyperglycemia or erythrocyte polyol pathway activity as reflected by erythrocyte sorbitol levels. In contrast, sorbinil did reduce elevated erythrocyte sorbitol levels. This suggests that the impaired electroretinograms associated with STZ-induced diabetes may not be caused solely by increased polyol pathway activity.

Comparison of Insulin Levels After Injection by Jet Stream and Disposable Insulin Syringe

Intermediate-acting biosynthetic human (NPH) insulin was administered by disposable insulin syringe into the right upper thigh of nine insulin-dependent diabetic youths. Seven days later, the same amount and type of NPH insulin was given in the same anatomic site with a Medi-Jector II, which delivers insulin as a jet stream. Blood was collected before insulin injection and at hourly intervals subsequently for the measurement of glucose and insulin. The total serum insulin measured before the first morningdose with the needle and syringe and the Medi-Jector II was 41.2 ± 10.7 μU/ml and 46.2 ± 10.7 μU/ml, respectively. During the next 9 h, the areas under the respective total insulin curves were not different, but the area under the free-insulin curve after jet injection was greater than the free-insulin area after needle injection (P < .01). The ratio of free/total serum insulin was 0.31 ± 0.02 after needle injection and 0.40 ± 0.03 after jet injection (P < .0025). The peak of total insulin concentration occurred 4.2 h after jet injection of NPH: 1 h earlier than the peak after needle injection. The plasma glucose at time zero was 197 ± 15 mg/dl before needle injection and 242 ± 19 mg/dl before jet injection. Although the diet consumed by each subject on the 2nd study day was identical to that of the 1st day, the mean glucose increase was greater after needle-injected insulin than after jet-spray injection. This indicates that the greater amount of free insulin observed after jet-injected insulin had a direct effect in lowering the plasma glucose. Jet injection may reduce insulin requirements by increasing the availability of free insulin.

The Value of Electrocardiogram Monitoring in Diabetic Ketoacidosis

Electrolyte abnormalities cause fatal cardiac arrhythmias in patients with diabetic ketoacidosis. A patient is reported with electrocardiogram (ECG) abnormalities characteristic of toxic hyperkalemia and hypocalcemia. The ECG abnormalities were noted during the first hour after arriving at the hospital. The laboratory values confirming the electrolyte abnormalities were not available for more than 1 h after the ECG indicated the danger of myocardial toxicity. During the initial 2 h of therapy the patient was urinating and not in shock. ECG monitoring of this patient prevented the routine administration of intravenous potassium, which was potentially lethal. The clinical importance of electrolyte levels in the management of diabetic ketoacidosis is the prevention of cardiac arrhythmias. ECG monitoring should be a minimal standard in the management of diabetic ketoacidosis.

Erythrocyte Hexokinase Isoenzyme Patterns in Hereditary Hemoglobinopathies

Abstract Three forms of hexokinase activity can be demonstrated in hemolysates of normal human erythrocytes by starch-gel electrophoresis. The similarity of these isoenzymes to Types I, II and III hexokinases found in other mammalian species has been confirmed by isolation of Types I and II erythrocyte hexokinases by chromatography on DEAE-cellulose. Type II is the predominant isoenzyme in the erythrocytes of newborn infants, but it is present in low or undetectable levels in those of normal adults. The presence of significant Type II hexokinase activity does not appear to be a function of erythrocyte age; increased activity has been demonstrated in the erythrocytes of adults who are homozygous for hemoglobins S, C or F or who are heterozygous for hemoglobins S or F. These observations suggest a previously unsuspected relation between the regulation of hemoglobin synthesis and the enzymatic composition of the erythrocyte.

Improvement in peripheral nerve function after one year of Sorbinil

The effect of 250 mg day-1 of the aldose reductase inhibitor, Sorbinil, upon peripheral nerve function was assessed in 23 adult diabetics with clinical neuropathy. Sorbinil was given for 4 weeks to 10 subjects, while 13 received placebo in this double-blind study. Open label treatment with Sorbinil was then continued for 52 weeks in 10 of the 23 subjects. Red cell sorbitol, hemoglobin A1c, vibratory sensation, median nerve sensory and motor conduction velocities were measured at 0, 4 and 52 weeks. There were no measurable changes in peripheral nerve function after 4 weeks of Sorbinil treatment. After 52 weeks significant improvement was found in the median nerve motor and sensory conduction velocities. This was associated with no change in blood glucose control but a reduction of erythrocyte sorbitol levels.