Robert McVie

Effect of glycemic control, race (white versus black), and duration of diabetes on reduced glutathione content in erythrocytes of diabetic patients.

We designed this study to examine whether uncontrolled hyperglycemia, duration of diabetes, or race (black v white) have any effect on glutathione levels in erythrocytes of type I diabetic patients. Hyperglycemia was assessed by measuring the level of hemoglobin A1c (HbA1c). Results show that erythrocytes of diabetic patients have a significantly lower glutathione level compared with those of age-matched normal subjects (P < .004). We found a significant negative correlation (r = -.59, P < .001) between the degree of hyperglycemia and the level of reduced glutathione (GSH) in erythrocytes of diabetic patients. There was no significant relationship (r = -.29, P > .12) between the level of GSH in erythrocytes and the duration of diabetes. Erythrocytes of black diabetic patients had significantly lower levels of GSH (P < .05) than those of white diabetic patients. Using erythrocytes as a model, this study suggests that a lower level of GSH may have a role in the cellular damage and impaired insulin secretion in uncontrolled diabetic patients.

The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients

Among many factors, elevated lipids and lipid peroxide levels in blood are major risk factors in the development of cardiovascular disease in diabetic patients. This study has examined whether oral supplementation of vitamin E, an antioxidant, has any effect on blood lipid peroxidation products (LP) and lipid profile of diabetic patients. Thirty-five diabetics(D) were supplemented withdl-α-tocopherol (E) capsule (orally, 100 IU/d) or placebo (P) for three months in double-blind clinical trials. Plasma E was analyzed by HPLC and LP by the thiobarbituric acid-reactivity; serum lipids by auto-analyzer. Data were analyzed using pairedt-test and Wilcoxon Signed Rank Test. Vitamin E supplementation significantly lowered LP and lipid levels in diabetic patients; there were no differences in these parameters after P supplementation. There were no differences in the duration of diabetes and ages of D between P-and E-supplemented groups. This study suggests that vitamin E supplementation significantly lowers blood LP and lipid levels in diabetic patients.

Hyperketonemia (Acetoacetate) Increases the Oxidizability of LDL + VLDL In Type-I Diabetic Patients

The reason for the disproportionately higher level of vascular disease in patients with diabetes is not known. Oxidative modification of low-density lipoproteins has been implicated in impaired cholesterol uptake and its deposition in the arterial wall and atherosclerosis. The present study has examined the effects of hyperketonemia, glycemic control and duration of diabetes on the in vitro oxidative susceptibility to Cu++ of low-density lipoprotein (LDL) + very low-density lipoprotein (VLDL) from 34 Type-I diabetic patients without any clinical sign of vascular disease and 22 age-matched normal individuals. LDL + VLDL was isolated from plasma using a micro-affinity column. LDL + VLDL isolated from diabetic patients and age-matched normal individuals was treated with 25 mM CuCl2 for 1.5, 3 and 5 h. The ketone bodies acetoacetate (AA) and beta-hydroxybutyrate (BHB), as well as glycated hemoglobin (HbA1), were measured in the blood by standard methods. There was no difference in the in vitro oxidative susceptibility of LDL + VLDL at all time periods between Type-I diabetics (n = 34) and age-matched normal individuals (n = 22). However, among diabetics, when patients were separated into normoketonemic (NK) and hyperketonemic (HK) groups, in vitro oxidation of LDL + VLDL at 1.5 h from hyperketonemic diabetics was a 69% greater (p < .02) compared with that of normoketonemic diabetics and 80% greater (p < .02) compared with that of normal individuals. There was a significant correlation (r = 0.38, p < .03) between the in vitro oxidation of LDL + VLDL at 1.5 h and AA levels in diabetic patients. The level of in vitro oxidizability of LDL + VLDL did not have any correlation with levels of BHB (r = 0.20, p > .26), HbA1 (r = 0, p > .99), glucose (r = 0.06, p > .75) or duration of diabetes (r = 0.15, p > .40) in diabetic patients. In vitro incubation of normal plasma with AA resulted in an increase in the Cu + induced lipid peroxidation of LDL + VLDL. This study suggests that frequent episodes of ketosis and elevated levels of AA constitute a risk factor for the oxidative modification of low-density lipoproteins and development of vascular disease in diabetic patients.

Effect of LDL+VLDL oxidizability and hyperglycemia on blood cholesterol, phospholipid and triglyceride levels in Type-I diabetic patients

Oxidative modification of low-density lipoproteins has been implicated in impaired lipid metabolism and its deposition in the arterial wall, and atherosclerosis. This study was carried out to determine the relationship between the in vitro oxidizability of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) and the cholesterol, phospholipid and triglyceride (TG) levels in the blood of Type-I diabetic patients. LDL+VLDL was isolated using a micro-affinity column from serum of diabetic patients (n = 34) and age-matched normal individuals (n = 22). The oxidative susceptibility of LDL+VLDL was determined by treatment with 25 microM CuCl(2) for 1.5 h. The levels of total-, LDL-, and HDL-cholesterol, phospholipids and triglycerides, as well as glycated hemoglobin (HbA(t)), were measured in the blood using standard methods. The diabetics had significantly higher levels of triglycerides and phospholipids, but cholesterol levels were similar between Type-I diabetics and age-matched normals. However, among diabetics, there was a significant correlation between the in vitro oxidation of LDL+VLDL at 1.5 h and total cholesterol (r = 0.49, P<0.002), and LDL cholesterol (r = 0.54, P<0.001) and TG (r = 0.34, P<0.05) levels. The level of in vitro oxidizability of LDL+VLDL did not have any correlation with HDL-cholesterol or phospholipid levels. The level of glycemic control (HbA(1)) did not have any correlation with levels of LDL- or HDL-cholesterol or triglycerides, but was significantly correlated with phospholipid levels (r = 0.48, P<0.005). This study suggests that the levels of LDL-cholesterol and triglycerides in the blood are directly related to the degree of in vitro oxidative susceptibility of low-density lipoproteins in Type-1 diabetic patients.

Soluble HLA Class I Antigens in Patients with Type I Diabetes and Their Family Members

Our objective was to study a possible contribution of MHC genes to S-HLA-I secretion in patients with Type I diabetes. Quantitatively, we used a highly sensitive enzyme-linked immunoassay to measure S-HLA-I in the serum of a total of 39 patients with Type I diabetes, as well as 36 kinships of 12 diabetic patients and 82 normal individuals with known HLA-phenotypes. S-HLA-I levels were abnormally elevated in patients or their non-diabetic relatives compared to normal controls (p < 0.0009). No complete HLA-haplotype had been identified to be correlated with high or low S-HLA-I secretion. Only the HLA-A23 or A24 (splits of HLA-A9) positive individuals sera were found to contain high S-HLA-I concentrations in all populations studied. The difference in S-HLA-I levels of HLA-A24 patients (n = 4) or their HLA-A24 positive non-diabetic relatives (n = 10) to the group of HLA-A24 normal controls (n = 15) was statistically highly significant (p < 0.0005 and p < 0.0009, respectively). The results suggests that HLA-A24 may confer additional independent risk for the disease expression in male children but not in female siblings. Nevertheless, the data implies that the patients or their non-diabetic relatives carrying the HLA-A24 have increased risk of developing ICA associated with high S-HLA-I levels compared to HLA-A24 negative probands or their kinships with low levels of S-HLA-I. This effect occurred irrespective to other diabetes related HLA-DR alleles. In summary, the results show a pronounced genetic heterogeneity of Type I diabetes with MHC control of the expression of S-HLA-I and possible involvement of hormonal factors that might potentiate a specific synthesis of S-HLA-I. The findings have implications for identifying individuals with a possible risk for developing the disease.

The effect of glycemic control and duration of diabetes on cholesterol and phospholipid classes in erythrocytes of type I diabetes.

Abnormalities in the lipid composition of erythrocytes can alter blood rheology and viscosity. These alterations have been implicated in the pathogenesis of microvascular disease in diabetic patients. The present study was undertaken to examine whether or not long-term glycemic control or duration of diabetes has any role in the altered membrane cholesterol and phospholipid composition of erythrocytes in type I diabetes. Long-term glycemic control was assessed by measuring glycosylated hemoglobin (GHb) from diabetic patients and age-matched normal volunteers. There was no significant correlation between GHb or duration of diabetes with total cholesterol, phospholipid, and cholesterol to phospholipid molar ratios in erythrocytes of these patients. Among phospholipid classes, GHb showed a significantly negative relationship with sphingomyelin (SM) (r = .55, P less than .01) levels, but was not related to phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels of erythrocytes. Duration of diabetes had no effect on SM, PC, or PE levels of erythrocytes.

Ketosis, Tumor Necrosis Factor-α and Cardiovascular Disease in Type-1 Diabetic Patients

The molecular mechanisms by which ketosis promotes the vascular disease, morbidity and mortality in type-1 diabetic patients are unclear. Elevated blood level of TNF-¦A, a pro-inflammatory cytokine, is a risk factor in the development of vascular inflammation and cardiovascular disease. This chapter has focused on the following points: (1) Hyperke-tonemic diabetic patients have significantly higher levels of TNF-¦A compared with normoke-tonemic diabetic patients and normal controls. There is a significant correlation between ketosis and oxidative stress as well as between the oxidative stress and TNF-¦A levels in the blood of diabetic patients. (2) Ketone body acetoacetate (AA) treatment increases TNF-¦A secretion and increases oxygen radicals production in U937 monocyte cells. However, ¦Â-hydroxybutyrate did not have any effect on TNF-¦A secretion or oxygen radicals production in U937 cells. (3) Exogenous addition of antioxidant N-acetylcysteine prevents stimulation of TNF-¦A secretion caused by AA alone or with high glucose (HG). The effect of AA or HG on TNF-¦A secretion was inhibited by specific inhibitors of protein kinase A, p38-MAPK and NFkB. Thus, ketosis increases circulating TNF-¦A levels, which can promote the development of cardiovascular disease in diabetic patients.

Hypocalcemic cardiomyopathy as initial presentation of primary hypoparathyroidism

Cardiomyopathy is a rare but life‐threatening condition in children. Myocarditis is the leading cause of dilated cardiomyopathy (DCM) and prognosis is generally poor without heart transplantation. We report a rare case of hypocalcemic DCM due to primary hypoparathyroidism in a male infant. In our patient, aggressive management of hypoparathyroidism significantly improved the manifestations of DCM. He is currently 10 years old and has no symptoms of exercise intolerance. Latest echocardiogram revealed near‐normal cardiac function. Our case emphasizes that early diagnosis of this treatable cause of cardiomyopathy prevents serious sequelae.