Philip Raskin

Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus

BACKGROUNDnRestriction of dietary protein may slow the progression of renal failure in diverse renal diseases, but the extent to which such a diet is beneficial in patients with diabetic nephropathy is uncertain.nnnMETHODSnWe studied the effect of reduced intake of protein and phosphorus on the progression of renal disease in 35 patients with insulin-dependent (Type I) diabetes mellitus and clinically evident nephropathy. The low-protein, low-phosphorus diet contained 0.6 g of protein per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of sodium. The control diet consisted of the patients prestudy diet with the stipulation that it contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of phosphorus. Renal function was assessed by measurement of iothalamate and creatinine clearances at intervals of 3 to 6 months, and the patients were followed for a minimum of 12 months (mean, 34.7). The declines in mean glomerular filtration rates were compared between groups by linear-regression analysis of the glomerular filtration rate as a function of time.nnnRESULTSnThe patients who followed the study diet for a mean of 37.1 months had declines in iothalamate clearance of 0.0043 ml per second per month and in creatinine clearance of 0.0055 ml per second per month. The comparable values in the control group were 0.0168 and 0.0135, respectively (P less than 0.05). Blood pressure was well controlled, and the degree of glycemic control was comparable in both groups.nnnCONCLUSIONnDietary restriction of protein and phosphorus can retard the progression of renal failure in patients with Type I diabetes mellitus who have nephropathy. We believe that wider use of this treatment is indicated.

Lipoprotein (a) Levels in Diabetes Mellitus: Relationship to Metabolic Control

OBJECTIVEnTo determine the influence of diabetes control on serum lipoprotein (a) concentrations.nnnSETTINGnDiabetes clinic of a large metropolitan public hospital, with primary- and secondary-care patients.nnnDESIGNnA cross-sectional study. Comparisons of lipoprotein (a) concentrations were made between a normal control group, a group of diabetic patients with glycated hemoglobin (HbA1c) less than 8.0%, and a group of diabetic patients with HbA1c of 8.0% or higher.nnnPATIENTSnNinety-five normal controls and 93 diabetic subjects (49 with insulin-dependent diabetes mellitus and 44 with noninsulin-dependent diabetes mellitus).nnnRESULTSnSixty diabetic subjects with HbA1c levels of 8.0% or higher had higher (25 mg/dL) median levels of lipoprotein (a) when compared with either 93 normal controls (8.8 mg/dL) or 33 diabetic patients with HbA1c less than 8.0% (7.5 mg/dL) (P = 0.008 and P = 0.012, respectively). A similar pattern of distribution of lipoprotein (a) levels according to degree of metabolic control was seen in patients with insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus. No difference in the lipoprotein (a) distribution was noted between diabetic men and women. No correlation was observed between lipoprotein (a) levels and total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels.nnnCONCLUSIONnLipoprotein (a) levels are elevated in poorly controlled diabetic patients. Increased levels of lipoprotein (a) may be a contributing factor to the high risk for atherosclerosis observed in diabetic patients.

Relationship between diabetes control and pulmonary function in insulin-dependent diabetes mellitus

PURPOSEnTo evaluate the effect of different levels of glycemic control on the pulmonary function of subjects with type I insulin-dependent diabetes mellitus.nnnPATIENTS AND METHODSnEighteen subjects with type I insulin-dependent diabetes mellitus with no history or physical findings of respiratory disease. Patients were given insulin therapy with a standard twice-daily insulin injection regimen (standard treatment group) or a subcutaneous insulin infusion device (insulin pump) (intensive treatment group). Glycosylated hemoglobin (HbA1c) levels were determined at quarterly intervals in both groups of patients (standard treatment group, n = 10; intensive treatment group, n = 8). Pulmonary function and diffusing capacity for carbon monoxide (DLCO) were measured after 6 years of continuous follow-up.nnnRESULTSnThe average HbA1c in the standard treatment group was significantly higher than that of the intensive treatment group throughout the 6 years of follow-up (p less than 0.001). The forced vital capacity of the standard treatment group was 85 +/- 3% of predicted as compared with 106 +/- 4% of predicted in the intensive treatment group (p less than 0.001). The DLCO was also significantly diminished in the standard treatment group as compared with that in the intensive treatment group (65 +/- 2% versus 87 +/- 4% of predicted) (p less than 0.001).nnnCONCLUSIONnThese data confirm previous reports of abnormal respiratory function in subjects with insulin-dependent diabetes mellitus and suggest that long-term near-normoglycemia may be beneficial in preventing the deterioration of pulmonary function associated with diabetes mellitus.

Crucial Role of Aldose Reductase Activity and Plasma Glucose Level in Sorbitol Accumulation in Erythrocytes From Diabetic Patients

Increased sorbitol levels have been demonstrated in tissues of diabetic patients. Although tissue sorbitol levels correlate with plasma glucose levels, a large variability in sorbitol levels has been observed among diabetic patients with similar plasma glucose levels. This variability in tissue sorbitol levels may be due to differences in the activity of aldose reductase, the enzyme that converts glucose to sorbitol. In this study, we isolated aldose reductase from erythrocytes of 31 diabetic patients and 6 nondiabetic control subjects, measured its activity, and compared it to simultaneously measured erythrocyte sorbitol levels. The activity of erythrocyte aldose reductase was increased in diabetic patients compared with control subjects (28.1 ± 1.4 vs. 22.4 ± 1.7 nmol · min−1 · g−1 Hb, P < 0.05), but there was an ∼ threefold variation in aldose reductase activity among diabetic patients. Erythrocyte aldose reductase activity and fasting plasma glucose levels significantly correlated with the erythrocyte sorbitol level in all individuals (r = 0.48, P < 0.005 and r = 0.63, P < 0.005, respectively). The sorbitol level was higher in patients with high aldose reductase activity than in those who had low enzyme activity for any given level of glycemia. The sorbitol production rate calculated from Km and Vmax values showed a better correlation with the erythrocyte sorbitol level (r = 0.80, P < 0.005), and there was also a good correlation between the erythrocyte sorbitol level and the product of aldose reductase activity by plasma glucose level (r = 0.70, P < 0.005). We conclude that both aldose reductase activity and the ambient plasma glucose concentration are important determinants of the level of sorbitol that accumulates in tissues of diabetic patients.

Glycemic Control and Diabetic Complications

The relationship between glycemic control and diabetic complications remains unclear. Epidemiological studies reveal that ∼25% of diabetic individuals do not develop complications, irrespective of degree of glycemic control. Studies of genetic factors, including HLA type, capillary basement membrane thickness, genetic predisposition to hypertension, and familial clustering of diabetic complications, suggest that there is a genetic component to developing the complications of diabetes. On the other hand, clinical trials have demonstrated that the progression of early, mild background retinopathy, microalbuminuria, and parameters of nervous system function are stabilized with improved glycemic control. Other metabolic parameters, such as serum lipoprotein levels, are significantly improved with near normoglycemia. No studies to date have evaluated the effect of blood glucose control on the prevention of diabetic complications. The degree of glycemic control required to impact on diabetic complications is unknown. In addition, achieving near normoglycemia carries increased risk for severe hypoglycemia and weight gain. Further study is needed to determine the long-term benefits of blood glucose control and to weigh that against the risks of improving glycemic control. Further investigation also is needed to address the probable interrelationship of genetic factors and glycemic control on the development of diabetic complications.

A comparative evaluation of glycosylated haemoglobin assays: feasibility of references and standards

SummaryFour assays; high pressure liquid chromatography, colorimetric with thiobarbituric acid, affinity columns, and microcolumn cation exchange were compared for (1) ability to discriminate between samples taken from diabetic and normal subjects; (2) correlation with each other; (3) stability over time at different temperatures; and (4) reproducibility between laboratories. The most discriminatory (10 samples from a diabetic and 10 samples from a normal group) was the microcolumn cation exchange method (t=5.25; p<0.001), but all were significantly different at p<0.005. The intra-assay coefficient of variation was 1%–6%, except for the affinity column method which was 13% in normal subjects. High pressure liquid chromatography was used as a reference and the other assays correlated well (r=0.93–0.99). Storage at-80 °C, -20 °C, 4 °C, and 24 °C showed marked differences. The thiobarbituric acid method results were stable except for 24 °C. Microcolumn cation exchange was labile under all conditions. Affinity column was stable for up to 15 days, only if samples were stored as whole blood. High pressure liquid chromatography showed an increase in haemoglobin A1a+b and a decrease in the haemoglobin A1c. Haemoglobin A1c was reproducible for 4 days when stored at 4 °C and up to 11 days when stored at -80 °C. Samples exchanged between centres at 4 °C and performed within 5 days by high pressure liquid chromatography for haemoglobin A1 and haemoglobin A1c correlated well (r=0.98 and 0.99). Samples exchanged between centres after storage (up to 40 days -80°C) correlated (r=0.99) by the thiobarbituric acid method. Thus, standards can be prepared for the thiobarbituric acid method and this method with high pressure liquid chromatography could be used to establish references for clinical assays.

Hypoglycemia induced by angiotensin-converting enzyme inhibitors in patients with non-insulin-dependent diabetes receiving sulfonylurea therapy

C aptopril and enalapril have become popular medications for use in the treatment of essential hypertension and hypertension associated with diabetes mellitus. They are effective antihypertensive medications either when used alone or in combination with other agents [1]. Their use has been proven to be safe with few side effects [2] and they have been suggested as excellent choices of medication for use in the hypertensive diabetic patient [3,4]. In addition, they have been shown to reduce albumin excretion [5-7] and improve insulin sensitivity [8]. This latter effect, although potentially beneficial by reducing hyperinsulinemia, thought to be a risk factor for the development of atherosclerosis, could also predispose to the development of hypoglycemia in patients receiving hypoglycemic therapy. We report two patients with stable noninsulin-dependent diabetes in whom hypoglycemic episodes occurred almost immediately after the initiation of angiotensin-converting enzyme (ACE) inhibitor therapy for hypertension.

Effect of glycemic control on microvascular complications in patients with type I diabetes mellitus

The relation between the control of blood glucose levels and the progression of early diabetic retinopathy and the width of skeletal muscle capillary basement membrane was studied in 54 insulin-dependent diabetic patients. After initial ophthalmologic evaluation including seven-field fundus photography and fluorescein angiography and measurement of levels of glycosylated hemoglobin and width of skeletal muscle capillary basement membrane, the patients were divided into two groups: an experimental group of 30 patients who were treated with continuous subcutaneous insulin infusion and a control group of 24 patients who continued to receive conventional treatment--usually two injections of insulin daily. After a mean follow-up period of 31.4 months, the experimental group had a significant decrease in glycosylated hemoglobin levels as compared with baseline values (mean +/- SEM, 7.2 +/- 0.3 percent versus 10.1 +/- 0.4 percent), reflecting improved control of blood glucose levels. The conventional treatment group had no change in glycosylated hemoglobin levels after a mean of 33.5 months of follow-up. With use of either a modified Early Treatment Diabetic Retinopathy Study grading system or macular microaneurysm counts, the experimental treatment group showed significantly less progression of retinopathy (p less than 0.05). The skeletal muscle capillary basement membrane width was significantly reduced only in the experimental treatment group with stable or improved retinopathy and was unchanged in the control group. There was a tendency for skeletal muscle capillary basement membrane width to increase in thickness over time in those patients whose retinopathy worsened irrespective of treatment. It is concluded that meticulous diabetic control may slow the progression of early diabetic retinopathy. Changes in skeletal muscle capillary basement membrane width may reflect the course of diabetic retinopathy.

The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy

The objective of this study was to evaluate the effects of ponalrestat, an aldose reductase inhibitor, on the progression of diabetic retinopathy. In this study, 62 patients with diabetes mellitus underwent a double-masked placebo-controlled clinical trial comparing the effect of ponalrestat 600 mg per day with a placebo on the progression of diabetic retinopathy. Both groups were comparable in terms of age, gender distribution, diabetes duration, metabolic control, and presence and severity of diabetic retinopathy. Seven-field stereo fundus photographs were performed at 0 (baseline), 12, and 18 months; 49 patients completed the study (26 in the ponalrestat group and 23 in the placebo group). In both treatment groups, a significant progression of diabetic retinopathy as evaluated by the Early Treatment Diabetic Retinopathy Study classification was observed (Wilcoxon Rank-Sum Test, p less than 0.05). No difference was observed in the progression of retinopathy between the two treatment groups (p = 0.96). The number of microaneurysms increased in the two study groups (from 5.6 +/- 1.2 to 10.5 +/- 1.3 in the placebo group and from 10.3 +/- 1.4 to 12.7 +/- 1.4 in the ponalrestat group); however, the increase was statistically significant only in the placebo group (p less than 0.05). When the increase in the number of microaneurysms was evaluated by change of category of microaneurysm count, no significant difference was observed. We conclude that ponalrestat at a dose of 600 mg per day has no clinically significant effect on the progression of diabetic retinopathy.

Effect of Intensive Diabetes Treatment on Low-Density Lipoprotein Apolipoprotein B Kinetics in Type I Diabetes

The metabolism of low-density lipoprotein (LDL) was studied in six insulin-dependent (type I) diabetic patients during a 7-wk period of conventional and intensive therapy with insulin. Plasma glucose and HbA1c were normalized, demonstrating the effectiveness of our intensive treatment program. Plasma lipoprotein profiles and LDL apolipoprotein B kinetic parameters were estimated during conventional and then during intensive therapy for each patient. Intensive therapy resulted in a significant reduction of plasma and LDL cholesterol and an increase in high-density lipoprotein (HDL) cholesterol. The lower LDL levels resulted from a decreased production of lipoprotein rather than an increased fractional catabolic rate. These results are consistent with our previous observations of very-low-density lipoprotein (VLDL) metabolism during intensive therapy. VLDL production is significantly reduced; thus, a decreased production of LDL supports the contention that intensive therapy with insulin in normolipemic type I diabetic patients reduces the production of lipoproteins containing apolipoprotein B rather than increasing the clearance, and therapy also increases HDL cholesterol. Both of these effects may be beneficial in reducing the risk for coronary heart disease in type I diabetes.