Insulin requirements in 242 patients with type II diabetes mellitus.

The purpose of this study was to determine the subcutaneous insulin requirements for rapid, effective regulation of blood glucose in patients with poorly controlled type II diabetes mellitus by using an intravenous insulin infusion protocol. The insulin infusion achieved a mean (+/-SD) overnight blood glucose concentration of 101 +/- 15 mg/dL and 24-hour glucose concentration of 118 +/- 18 mg/dL. The intravenous insulin requirement of 81 +/- 32 U/day correlated well (P<0.001) with the subsequent subcutaneous insulin requirement of 84 +/- 43 U/day necessary to maintain preprandial glucose values of 112 +/- 15 mg/dL. Insulin requirements ranged from 0.2 to 2.0 U/kg per day (95% confidence interval, 0.4 to 1.6). Weaker correlations were noted between total insulin requirements and weight (r = 0.60) or body mass index (r = 0.57); no correlations were observed with age, duration of diabetes, or antecedent glycemic control as reflected by glycosylated hemoglobin values. These findings may be useful for initiating insulin treatment on an ambulatory basis.

Delayed onset and decreased incidence of diabetes in BB rats fed free radical scavengers.

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Effects of chronic non-ketotic diabetes and aging on myocardial function and fatty acid oxidation.

The effects of aging and chronic non-ketotic diabetes on contractile properties, oxygen consumption, palmitate oxidation and morphology were studied in isolated, perfused working hearts of 2, 9, 12 and 22 month old rats. The heart rate, coronary flow, and oxygen consumption were no different among the 9, 12 and 22 month control and diabetic hearts. Cardiac work was not depressed in control hearts until 22 months of age. Depression of cardiac output due to aging in the control hearts progressed in stages. The superimposition of chronic diabetes in the 9, 12 and 22 month rats did not further depress the cardiac work or cardiac output. [1-14C] palmitate oxidation in the 2 and 9 month control hearts was higher than that of the 12 and 22 month controls. Chronic diabetes did not affect fatty acid oxidation in the 9 and 12 month rats compared to their controls, but was diminished in the 22 month diabetic rat heart. These results suggest that impairments in the contractile properties of the isolated hearts of the chronically diabetic, senescent rats were primarily due to aging.

Stimulation by acetoacetate of hepatic triacylglycerol synthesis.

The factors responsible for the huge accumulation of hepatic triacylglycerols in the ketotic diabetic state are not established. Our earlier work suggested a role for ketone bodies in the increased hepatic triacylglycerol synthesis observed in the ketotic diabetic state. Isolated hepatocytes obtained from normal fed rats were incubated with sodium acetoacetate or sodium chloride (control) and [1-14C]palmitate in Krebs-albumin buffer. Acetoacetate stimulated triacylglycerol synthesis in a concentration-dependent manner without increasing palmitate uptake or inhibiting palmitate oxidation. Beta hydroxybutyrate showed no effect on palmitate esterification to triacylglycerols. Isolated hepatocytes of normal fed rats were incubated with either sodium acetoacetate or sodium chloride and the nuclear-free homogenate was incubated with [U-14C]glycero-3-phosphate and cofactors. The synthesis of triacylglycerol and the activity of the cytosolic phosphatidate phosphohydrolase were increased in the cells pre-incubated with acetoacetate. The results of this study demonstrate that the increases in triacylglycerol synthesis and the cytosolic activity of phosphatidate phosphohydrolase previously observed by us in the ketotic diabetic liver, could be reproduced in normal fed rat liver cells by incubating them with acetoacetate. The results identify acetoacetate as a potential factor, in the regulation of hepatic triacylglycerol synthesis and for hepatic accumulation of triacylglycerols observed in the ketotic diabetic state.

Increased fatty acid uptake, a factor in increased hepatic triacylglycerol synthesis in aging rats.

The mechanisms responsible for the increased hepatic triacylglycerol synthesis in aging are not established. We studied [1-14C] palmitate uptake and its esterification to triacylglycerols in the isolated hepatocytes of 2-month, 10-month and 20-month-old normal rats. In all hepatocytes, palmitate uptake and its esterification were linearly related to medium palmitate concentration, but palmitate uptake and triacylglycerol synthesis by the hepatocytes of 10-month and 20-month-old rats were nearly double that observed with the cells of 2-month-old rats. These results suggest that increased fatty acid uptake by the liver cells was a contributory factor in the increased triacylglycerol synthesis observed in the liver of senescent rats. The changes in the hepatocyte leading to increased fatty acid uptake and hence increased triacylglycerol synthesis are detected as early as middle age of the rat.

Diabetic thoracic radiculopathy: electrodiagnostic study.

We investigated the diagnostic value of electromyographic (EMG) examination of the anterior abdominal wall muscles (AWMS) in thoracic radiculopathy and compared it with examination of thoracic paraspinal muscles (TPSM). Technically, examination of AWMS was much easier compared to TPSM. In eight patients with thoracic diabetic radiculopathy at the level of T7-T12, AWMS was abnormal in all and was considered to be diagnostic, whereas AWMS was normal in diabetic lumbar radiculopathy, patients with diabetes mellitus without radiculopathy, patients with unspecified gastrointestinal pain, and patients with musculoskeletal-type back pain. We conclude that EMG evaluation for possible thoracic radiculopathy should include examination of AWMS, and if abnormal, would be of great diagnostic help in patients with unspecified gastrointestinal symptoms.

Altered tissue oxygen tension responsiveness in diabetes.

Subcutaneous oxygen tension (tissue PO2) was measured by a polarographic method in the legs of insulin-dependent diabetics (IDDM) and controls. Current flow was measured continuously using a five-stage protocol: baseline; 4 min of complete arterial occlusion; during recovery from ischemia; baseline approximately re-established; induction of hyperemia by local application of heat. Eleven patients with IDDM of 4-32 years of duration, without peripheral arterial disease, were studied and compared with 10 controls. The mean baseline subcutaneous PO2 in diabetics was less than controls; however, the difference was not statistically significant. At the end of arterial occlusion the mean decrease in tissue PO2 was less (P less than 0.025) in diabetics (4.7 +/- 0.9 mm Hg, SEM) compared to controls (10.2 +/- 1.6 mm Hg). With induction of hyperemia the increase in tissue PO2 was lower (P less than 0.001) in diabetics (7.4 +/- 0.4 mm Hg) than in controls (18.6 +/- 1.7 mm Hg). The observed differences provide for the first time direct evidence of altered tissue PO2 responses in diabetes.

Inhibition by adenosine triphosphate of heart microsomal neutral lipase activity.

Triacylglycerol lipolysis was inhibited by palmitate in the isolated perfused normal rat heart. Acetate or acetylcarnitine could reproduce the inhibitory effects of palmitate. Since heart neutral lipase plays an important role in the lipolysis of heart triacylglycerols, the effects of acetylcarnitine, acetyl CoA and related metabolites on the microsomal neutral lipase activity were studied. ATP inhibited the enzyme activity in a concentration-dependent manner without a lag phase. AMP and adenylyl imidodiphosphate, two compounds structurally related to ATP but whose phosphate groups cannot be transferred, did not inhibit the microsomal lipase activity. These results suggested that ATP inhibited the lipase activity through the transfer of its phosphate group. It is proposed that cellular ATP concentration is a determinant of tricylglycerol lipolysis in the heart.

Effects of epinephrine and perfusion pressure on the peak aortic pressure development and glucose transport in the isolated perfused heart of normal and diabetic rats.

The effects of increased perfusion pressure and epinephrine stimulation on the contractile parameters and glucose transport in the isolated perfused hearts of control and ketotic diabetic rats were studied. An increase in perfusion pressure from 60 mm Hg to 100 mm Hg resulted in increases in coronary flow and peak aortic pressure development in control and diabetic hearts. The responses of the diabetic heart were similar to the control. Epinephrine produced lower increments in peak aortic pressure development in control and diabetic hearts under the higher perfusion pressure. Glucose uptake, although stimulated about 4-fold in both control and diabetic hearts on increasing the perfusion pressure, was still lower in the diabetic heart. Epinephrine stimulated glucose uptake in both control and diabetic hearts at 60 mm Hg, but the control heart showed a greater response. At 100 mm Hg perfusion pressure, the stimulatory effect of epinephrine on glucose uptake was abolished in both control and diabetic hearts. The results of this study show that the contractile and glucose stimulatory effects of epinephrine were influenced by the perfusion pressure. Epinephrine did not correct the impairment in glucose transport in the diabetic heart.

Regulation of hepatic triglyceride synthesis in diabetic rats.

The syntheses of triglyceride and its precursors were increased when liver homogenates of ketotic diabetic rats were incubated with [U-14C]-glycero 3-phosphate and cofactors. Triolein sonicates produced a concentration-dependent inhibition of the synthesis of both diglyceride and triglyceride, whereas monoolein sonicates had no effect. Rat serum very low density lipoproteins, like triolein sonicates, inhibited the synthesis of diglyceride and triglyceride. Furthermore, the intracellular form of very low density lipoproteins, namely nascent very low density lipoproteins, also inhibited the synthesis of diglyceride and triglyceride. A higher apparent I50 (concentration of inhibitor that produces 50% inhibition of activity) was observed in liver homogenates of ketotic diabetic rats for inhibition of triglyceride or diglyceride synthesis by triolein sonicates, serum very low density lipoproteins, high density lipoproteins, and nascent very low density lipoproteins. Insulin treatment of the diabetic rats reversed the I50 values to control. In studies on the site of inhibition of triglyceride synthesis in the overall biosynthetic pathway, serum very low density lipoproteins produced a concentration-dependent inhibition of liver cytosolic phosphatidate phosphohydrolase activity. A higher I50 value was obtained with the hepatic enzyme of the diabetic rats. This higher I50 value was reversed to control by insulin treatment of the diabetic rats. These results indicated that the activity of this enzyme was less sensitive to inhibition by very low density lipoproteins in the ketotic diabetic state. The reduced sensitivity of phosphatidate phosphohydrolase activity to triglyceride inhibition observed in the present studies could explain our previous observation of an increased rate of triglyceride synthesis in ketotic diabetic liver homogenates.

Regulation of heart triglyceride synthesis in diabetes.

Heart triglyceride content and triglyceride synthesis were studied in control, ketotic diabetic, and insulin-treated rats. Heart triglyceride content was increased in the ketotic diabetic state but was reversed to control values on insulin treatment of the diabetic rats. Triglyceride synthesis in heart homogenates was sensitive to incubation temperature. Triglyceride synthesis from [U-14C]sn-glycero-3-phosphate was increased in the diabetic state, suggesting that increased synthesis played a role in heart triglyceride accumulation. The addition of the end product of triglyceride synthesis, e.g., triolein, to incubation mixtures resulted in inhibition of triglyceride synthesis in heart homogenates of control and diabetic rats. The results suggested that the enzymes of heart triglyceride synthesis were less sensitive to feedback inhibition in the diabetic state.

The heart and diabetes. Vascular and metabolic aspects.

The metabolic changes in the heart--increased glycogen, triglycerides, and cyclic AMP, and decreased ATP and creatine phosphate--indicate that diabetes is a generalized disorder of cellular metabolism. The summarized observations provide additional biochemical reasons for early detection and treatment of patients with diabetes mellitus. Cognizance of three metabolic events are relevant to the treatment of the diabetic patient during acute cardiac events such as myocardial infarction.