Simeon Margolis

The Dawn Phenomenon, an Early Morning Glucose Rise: Implications for Diabetic Intraday Blood Glucose Variation

Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 ± 81.1 m/dl; mean ± SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P < 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.

Acute pancreatitis with hyperlipemia: Evidence for a persistent defect in lipid metabolism

Abstract Hyperlipemia has been recognized with increasing frequency in patients with acute pancreatitis. The significance of this association is unknown. Twenty-two such patients were electively readmitted to a metabolic ward for study of their lipid metabolism during a quiescent period. Persistent fasting hypertriglyceridemia was found in 16 and abnormal lipoprotein electrophoretic patterns in 17. In addition, response to a lipid load was abnormal; in 20 of the 22 patients triglyceride levels rose over 500 mg/100 ml, and in 10 over 1,000 mg/100 ml. It is concluded that the lipid abnormalities detected during the acute attack of pancreatitis were not secondary but persisted long after the patient had recovered. Such underlying lipid abnormalities may play an intermediary role in the pathogenesis of pancreatitis.

Localization of histaminase (diamine oxidase) in rat small intestinal mucosa: Site of release by heparin

Abstract Previous studies have suggested that in the rat, small intestine is the source for rise in plasma histaminase levels seen after heparin administration. The cellular location of histaminase in intestine and the mechanism of heparin release have not been previously investigated. The present study identifies intestinal villus cells rather than crypt cells as the location of intestinal histaminase; at this site, the enzyme is not associated with brush border. Heparin added to incubations containing isolated intestinal cells did not release histaminase into the medium. Perfusion of intestinal vasculature with heparin caused a prompt release of this enzyme into venous effluent. The present investigation. therefore, suggests that heparin releases histaminase from vascular binding sites rather than directly from parenchymal cells. The use of isolated intestine with perfusion of the vasculature could serve as a useful tool for further defining the relationship between the sites of synthesis and the binding sites involved with heparin releasable enzymes such as histaminase.

Correlation of Urinary Excretion of C-Peptide with the Integrated Concentration and Secretion Rate of Insulin

The secretion rate of insulin (SR-I) of 50 normal subjects was calculated from the 24-h integrated concentration of insulin (IC-I), the peripheral metabolic clearance of insulin (pMCR-l), and the mean fractional hepatic insulin extraction (fhMCR-l) that was derived from our data. fhMCR-l was determined as the difference in the molar secretory rate of C-peptide (SR-C) and the molar peripheral clearance of insulin (pMCRI × IC-I) divided by SR-C. The IC-I in our 50 subjects was 1.19 ± 0.38 ng/ml and the IC-C was 2.93 ± 0.58 ng/ml. Based on these data, the fhMCR-l was 0.40 and the SR-I was estimated to be 54.8 ± 18.0 U/24 h. The 24-h urinary C-peptide excretion (U-C), 44.9 ± 20.4 μg/24 h, had a statistically significant correlation with SR-I (r = 0.838, P < 0.0001), while the IC-I correlated significantly with the 24-h urinary C-peptide/g of creatinine (r = 0.823, P < 0.0001). The U-C may thus serve as a practical method for estimating the SR-I.

Integrated concentrations of growth hormone, insulin, C-peptide and prolactin in human obesity

Twenty-four hour integrated concentrations of growth hormone (IC-GH) were significantly lower in young, obese subjects than in young subjects who were lean. Significant inverse correlations were found between IC-GH and body mass index (BMI) as well as the IC-GH and the 24 hr integrated concentrations of insulin (IC-I) and C-peptide (IC-C) in obese subjects below 30 yr of age. Since IC-GH decreases with age, the effect of obesity on IC-GH could not be demonstrated in the older subjects; a weak inverse correlation (p less than 0.05) between IC-GH and IC-C was found. Prolactin was significantly lower in the older subjects but did not correlate with IC-GH and was similar in lean and obese. Lipid deposition in adipose cells is promoted by high concentrations of insulin as well as low concentrations of growth hormone. We found a significant correlation between the IC-I/IC-GH ratio and BMI of both the young and older subjects. Correlations between these two factors do not necessarily imply a cause and effect relationship. It is plausible, however, that the elevated IC-I/IC-GH of the obese may facilitate their lipid storage and counter their efforts at weight reduction.

Simplified method for isolation of intact avian and rat liver parencymal cells

Abstract A new, simplified procedure is described for the isolation of intact liver cells from cockerel or rat liver. The technique involves a 15 min perfusion of the liver in situ through the portal vein with a solution of collagenase and hyaluronidase, and subsequent incubation of the minced liver in the enzyme solution. The yield of cells was excellent. Most cells excluded a vital stain and were undamaged when viewed with the electron microscope. The cells actively incorporated labeled precursors into lipids and proteins without specific cofactor requirements and responded to insulin in vitro . The biosynthetic capacity of the cells was retained for several days in culture.

Fasting Hyperglycemia and Associated Free Insulin and Cortisol Changes in “Somogyi-Like” Patients

Blood glucose levels were measured over a 24-h period in eight insulin-dependent diabetic subjects who were difficult to control and who presented with morning fasting hyperglycemia. At least seven exhibited clinical characteristics suggestive of the Somogyi phenomenon. A continuous glucose monitoring apparatus was used to relate the concentrations of glucose during the day to concomitant levels of free insulin and cortisol. In all patients a significant (P < 0.01) rise in fasting morning glucose started at about 0600 h, while they were still asleep. In six patients the morning elevation of blood glucose was preceded by stable, almost normal glucose levels during the night (117 ± 2.5 mg/dl); one of the two remaining patients (no. 7) exhibited high overnight glucose levels (268 ± 7.2 mg/dl), whereas the other (no. 8) had a mild hypoglycemic episode (45 mg/dl) 6 h before the hyperglycemic period. In all patients the fasting glucose rise was associated with the usual morning cortisol surge (P < 0.05) and with a significant decrease in the concentration of serum free insulin (P < 0.01). The free insulin levels in patient no. 8 were higher, while those of patient no. 7 were lower, than in the other six patients. We conclude that the diurnal morning rise in cortisol may cause hyperglycemia in insulindependent diabetic patients if insufficient exogenous insulin remains and/or endogenous insulin is not secreted. In such patients the high levels of fasting glucose in the morning may misrepresent their overnight control of blood glucose and lead to an erroneous impression of the Somogyi phenomenon.

Effects of pravastatin, a new HMG-CoA reductase inhibitor, on vitamin D synthesis in man☆☆☆

The HMG-CoA reductase inhibitors, a new class of lipid-lowering agents being used with increasing frequency, inhibit synthesis of cholesterol in vivo. Thus, one potential side effect of these drugs is alteration of other metabolic pathways requiring intermediates in the cholesterol biosynthetic pathway. We hypothesized that pravastatin, a new HMG-CoA reductase inhibitor, may impair vitamin D3 synthesis in the skin and alter mineral homeostasis by diminishing the availability of vitamin D precursors. Basal serum levels of calcium, phosphorus, parathyroid hormone (PTH), vitamin D3, and 1,25-dihydroxyvitamin D were measured, and dietary intakes of calcium and vitamin D were calculated in a control hypercholesterolemic group and an experimental group treated with pravastatin 10, 20, and/or 40 mg orally twice daily for at least 3 months. Basal parameters of mineral metabolism were similar in the two groups. To assess the capacity of the skin to synthesize vitamin D3 and as an indirect measure of its precursors, all subjects received whole body ultraviolet irradiation (UVI) in a phototherapy chamber for varying time intervals. Subjects in both groups showed significant (P less than .001) dose-dependent increases in vitamin D3 production after equivalent UVI exposures. However, for equivalent UVI exposure, the serum vitamin D3 response was identical in controls versus pravastatin-treated subjects. We conclude that hypercholesterolemic patients have normal mineral metabolism and the use of pravastatin at these doses for up to 3 months does not alter vitamin D3 synthesis in the skin.

Hypolipidemic, uricosuric, and thyroxine-displacing effects of MK-185 (halofenate).

MK‐185, an ester structurally related to clofibrate, was given to hypertriglyceridemic patients for 6 week periods in a controlled double‐blind crossover trial. Serum triglycerides decreased an average of 50 per cent during the trial, but little change was noted in serum cholesterol. An average decrease of 30 per cent was noted in the serum uric acid, and 5 patients showed a uricosuric effect of the drug independent of the glomerular filtration rate. Plasma thyroxine (T4) showed a significant increase while patients were taking MK‐185. Further studies showed a decrease in protein‐bound iodine and T4 by column. An increase in the dialyzable fraction of T, in vivo suggested a thyroxine‐displacing effect from thyroid‐binding proteins. This hypothesis was confirmed by in vitro displacement by MK‐185 free acid of 131I‐labeled T4 bound to thyrOid‐binding globulin.

Nutritional management of plasma lipid disorders.

Prevention of vascular disease and acute pancreatitis is the goal of hyperlipidemia treatment. The risk of coronary heart disease (CHD) increases with increasing plasma cholesterol levels because low-density lipoprotein (LDL), the major carrier of cholesterol in the plasma, is atherogenic. High-density lipoprotein (HDL), especially the HDL2 subfraction, protects against CHD. Hypertriglyceridemia, although not an independent risk factor for CHD, is generally accompanied by low HDL cholesterol (HDLch), which may predispose to CHD. Reducing plasma LDL and raising HDL levels are thus goals in preventing CHD. Serum LDL levels may be lowered by reducing saturated fat and cholesterol intake; weight loss may decrease LDL but is more effective in lowering plasma triglycerides and raising HDLch. The percent of total calories from polyunsaturated, monounsaturated, and saturated fats should be less than 10%, up to 10-15%, and less than 10%, respectively. High cholesterol intake increases the flux of cholesterol, which may be harmful to arterial walls, but beyond a certain point does not increase plasma cholesterol levels. Some diets change the composition rather than the level of LDL and apoproteins. Weight reduction and maintenance are the most effective dietary measures to lower plasma triglycerides; omega-3 fatty acids (fish oils) have shown promise in reducing triglyceride but not cholesterol levels. Substitution of starch for sugar lowered triglyceride levels toward normal in hypertriglyceridemia patients. Fasting triglyceride levels rise in all individuals fed high-carbohydrate diets, but the high levels persist in hypertriglyceridemia patients. Weight loss, cessation of cigarette smoking, increased physical activity, good control of diabetes, and moderate alcohol use all raise HDLch levels. Vitamin E deficiency causes neurological sequelae in children with severe malabsorption problems due to abetalipoproteinemia or cholestatic liver disease.