Ivo H. De Leeuw

Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome

The aetiology and pathogenesis of the Chronic Fatigue Syndrome (CFS) are still largely unresolved. Accompanying metabolic disorders such as selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in its pathogenesis. In order to investigate this hypothesis, oxidant-antioxidant status and its impact on lipoprotein peroxidation in vitro was examined in 61 patients with unexplained fatigue lasting more than 1 month. They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988 Center of Disease Control criteria for CFS and group CFS- did not but was similar as regards age, sex distribution and clinical characteristics. Antioxidant status was similar in the 2 groups except for lower serum transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73 (2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in vitro, suggesting additional pro-oxidant effects. These results indicate that patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

Magnesium Status and Parameters of the Oxidant-Antioxidant Balance in Patients with Chronic Fatigue: Effects of Supplementation with Magnesium

Objective: Magnesium deficiency and oxidative stress have both been identified as pathogenic factors in aging and in several age-related diseases. The link between these two factors is unclear in humans although, in experimental animals, severe Mg deficiency has been shown to lead to increased oxidative stress. Methods: The relationship between Mg body stores, dietary intakes and supplements on the one hand and parameters of the oxidant-antioxidant balance on the other was investigated in human subjects. Results: The study population consisted of 93 patients with unexplained chronic fatigue (median age 38 years, 25% male, 16% smokers and 54% with Chronic Fatigue Syndrome (CFS). Mg deficient patients (47%) had lower total antioxidant capacity in plasma (p=0.007) which was related to serum albumin. Mg deficient patients whose Mg body stores did not improve after oral supplementation with Mg (10 mg/kg/day) had persistently lower blood glutathione levels (p=0.003). In vitro production of thiobarbituric acid reactive substances (TBARS) by non-HDL lipoproteins incubated with copper was related to serum cholesterol (p<0.001) but not to Mg or antioxidants and did not improve after Mg supplementation. In contrast, velocity of formation of fluorescent products of peroxidation (slope) correlated with serum vitamin E (p<0.001), which was, in turn, related to Mg dietary intakes. Both slope and serum vitamin E improved after Mg supplementation (p<0.001). Conclusions: These results show that the lower antioxidant capacity found in moderate Mg deficiency was not due to a deficit in Mg dietary intakes and was not accompanied by increased lipid susceptibility to in vitro peroxidation. Nevertheless, Mg supplementation was followed by an improvement in Mg body stores, in serum vitamin E and its interrelated stage of lipid peroxidation.

Relationship of Body Fat Distribution Pattern to Atherogenic Risk Factors in NIDDM: Preliminary Results

Because recent knowledge indicates that the distribution of fat deposits in men may be a better predictor of cardiovascular disease than the degree of obesity alone, some risk factors for atherosclerosis were evaluated in 51 middle-aged men with non-insulin-dependent diabetes mellitus. Abdominal adiposity (waist/hip ratio, WHR) was related to parameters of metabolic control, lipid parameters, and known vascular complications in three different groups. In groups with abdominal obesity, mean annual hemoglobin A1 was significantly (P < .01) higher than in patients without an abdominal fat distribution. Atherogenic index was significantly increased in the group with the highest WHR and highdensity lipoprotein cholesterol (HDL-chol) levels were significantly decreased in both groups with upper-body fat distribution. The frequency of peripheral vascular disease, coronary ischemic heart disease, and hypertension was most prominent in diabetic subjects with an abdominal fat mass distribution. A highly significant (P < .001) correlation was present between WHR and HDL-chol and WHR and the total-cholesterol/ HDL-chol ratio; this significant correlation remains after correction for body mass index. A similar correlation could be found between WHR and systolic and diastolic blood pressures. These results demonstrate an association of excess abdominal fat, even without manifest obesity, with worse diabetes metabolic control, cardiovascular complications, and blood lipid levels actually considered to play an important role in atherogenesis.

Complementation of HLA-DQA and -DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus

Lack of an aspartic acid 57 in the HLA-DQ beta chain was introduced as a genetic marker of insulin-dependent diabetes mellitus (IDDM). Because 25% of the control population carries the same marker, we analyzed the DQ locus for the presence of more specific disease susceptibility markers, taking into account a possible role for the polymorphic DQA gene. We thereby identified the DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) genotype which was detected in 30% of the 268 typed IDDM patients and only in 1% of the 331 typed healthy controls, resulting in a relative risk of 35. This genetic marker was more frequent in patients with clinical onset before age 18 years (36%) than in patients diagnosed between age 18 and 40 years (22%) and was not observed in patients with non-IDDM. The new susceptibility genotype DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) may explain the well-known excess of DR3/DR4 heterozygous IDDM patients and is expected to help identify individuals at risk for developing the disease.

Serum and erythrocyte magnesium levels in type I and type II diabetics

SummarySerum and red blood cell magnesium (RBC-Mg) concentrations of 195 type I and III type II diabetic outpatients with different degree of control and 40 control subjects have been evaluated using atomic absorption spectrophotometry. In the total group, no significant difference in serum and RBC-Mg levels in type I and II diabetic outpatients could be found. However, poor control was often associated with lower serum magnesium levels. A negative correlation was found between serum magnesium levels and HbA1. A particular group of male patients with severe macroangiopathy showed high RBC-Mg levels; this finding was probably due to atherosclerotic and hypertensive renal involvement.

Current concepts in gastric motility in diabetes mellitus

This review addresses the current concepts in our understanding of the epidemiology, mechanisms, symptoms, clinical consequences, diagnosis and treatment of delayed gastric emptying in patients with diabetes. Upper gastrointestinal symptoms, particularly postprandial fullness, nausea, vomiting and abdominal bloating, occur in 30-50% of patients with diabetes. The use of scintigraphic techniques, and more recently breath test, has shown that as many as 50% of diabetic patients have gastroparesis. Diabetic gastroparesis comprises a decrease in fundic and antral motor activity, a reduction or a lack of the interdigestive migrating motor complex, gastric dysrhythmias, and pylorospasms. The mechanisms involved include: autonomic neuropathy, acute hyperglycaemia, and abnormalities in gastrointestinal hormones and neuropeptides. Other possible contributing factors such as hypothyroidism and H. pylori infection are discussed as well. Because treatment is possible by means of dietary advise, prokinetics or surgical procedures, it is important to identify risk factors for and to diagnose gastroparesis to prevent morbidity by controlling gastrointestinal symptoms, and to enhance glucoregulation. Understanding the current advances is key to the development of novel therapeutic strategies and for making rational choices in the management of diabetic gastroparesis.

Autoimmune hepatitis, autoimmune gastritis, and gastric carcinoid in a type 1 diabetic patient: A case report

The history of a 45-year-old male type 1 diabetic patient is presented. At the age of 29 years, he was diagnosed to have an autoimmune hepatitis with incipient liver cirrhosis. Five years later, a successful liver/pancreas transplantation was performed. Eighteen months later, however, pancreatic insufficiency occurred due to thrombosis of the pancreatic graft. Besides these conditions, iron deficiency, pernicious anemia, and autoimmune gastritis were also diagnosed. Serum parietal cell antibodies (PCA) and intrinsic factor antibodies (AIF) were positive. At 45, this patient was found to have a gastric carcinoid tumor. The clinical importance of PCA is discussed with regard to chronic atrophic gastritis and pernicious anemia, which both predispose toward gastric carcinoid tumors. Autoimmune type 1 diabetic patients who have a high prevalence of PCA should be screened for gastric autoimmune manifestations and tumors, as the history of this patient illustrates.

Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes

The prandial glucose regulator repaglinide has a rapid onset of action, a short half-life and is metabolised mainly by the liver. Here we report the findings of a 10-week, double-blind, parallel, placebo controlled, randomised trial with repaglinide in 25 diet-treated, sulphonylurea-naive patients with Type 2 diabetes. Repaglinide was titrated, based on capillary blood glucose, from 0.5 mg to a maximum of 4 mg, preprandially with breakfast and dinner. After 10 weeks, repaglinide was associated with a decrease in HbA1c of 2.3%Hb relative to the placebo group (P=0.018). This reflected a 30% decrease within the repaglinide group from a mean HbA1c of 7.0 to 4.9%Hb (P<0.002). Repaglinide was also associated with a decrease in fructosamine, by 0.88 mmol/l, relative to placebo (P<0.001), with a 20% decrease (from 3.80 to 3.04 mmol/l) within the repaglinide group (P<0.001). Fasting and postprandial blood glucose concentrations decreased in association with repaglinide by 3.6 and 6.4 mmol/l, respectively, relative to placebo (P<0.001 in each case). Within the repaglinide group fasting and postprandial blood glucose decreased by 3.9 and 6.2 mmol/l, respectively (P<0.001 in each case). The number of patients reporting hypoglycaemia in the repaglinide group was similar to placebo (15 vs. 20, respectively; NS). Test meal assessments confirmed that repaglinide effectively controls glucose levels by stimulating mealtime insulin secretion. Fasting serum insulin concentration was not raised compared to baseline or placebo during repaglinide therapy, albeit that fasting glucose levels were decreased by repaglinide. Twice-daily meal-related insulin secretagogue therapy with repaglinide, a new short and rapid-acting prandial glucose regulator, is capable of improving all measures of glycaemic control without increased hypoglycaemia or fasting hyperinsulinaemia.

Platelet prothrombinase activity, a final pathway platelet procoagulant activity, is overexpressed in type 1 diabetes: no relationship with mean platelet volume or background retinopathy

There is overwhelming evidence that platelets from diabetic individuals are hyperreactive, not only when mi crovascular complications are apparent, but already at an early stage of the disease. There is still controversy about the ques tion of whether primary hyperreactive platelets may contribute to the origin or progression of microangiopathy or whether diabetic platelet hyperfunctionality is just a logical conse quence of a continuous low-grade activation of platelets by contact with a diseased microvascular wall. As a consequence of platelet activation, the outer layer of its phospholipid mem brane is more procoagulant than in the quiescent state, stimu lating thrombin formation in plasma. This platelet function is called platelet procoagulant activity. We studied platelet pro thrombinase activity (PPA), a final pathway platelet procoagu lant activity of type 1 diabetic platelets, and looked for an eventual correlation with microvascular disease (background retinopathy) and mean platelet volume (MPV). Stypven clot ting times (SCTs), reflecting PPA expression, and MPV of citrated platelet-rich plasma (PRP), were measured in 21 pa tients with type 1 diabetes—10 with and 11 without back ground retinopathy—under clinically acceptable metabolic control and compared them to 20 disease-free voluntary con trols. We also compared PPA expression and MPV in diabetic individuals with and without retinopathy. With the SCT, a se lective test adapted for studying PPA in PRP, we found hyper expression of PPA in all diabetic patients. We found no differ ence in MPV between diabetic and control PRP. Comparing patients with and without background retinopathy we found no significant difference in PPA expression. From these results, we suggest that the phospholipid surface of diabetic platelets, more than the surface of normal control platelets, stimulate the expression of PPA. This diabetic platelet coagulant anomaly was not related to an increased platelet mass (higher MPV) nor to the presence of microangiopathy. We conclude that PPA hyperexpression is associated with patients with type 1 diabe tes, already occurring in an early stage of the disease, and not necessarily a consequence of early-stage microvascular disease, because the anomaly is also demonstrable, in the same degree, in patients with diabetes without microangiopathy.

Vitamin E status in patients on parenteral nutrition receiving intralipid

Low vitamin E levels have been found to be a frequent side effect in patients on total parenteral nutrition (TPN). In the present study, the vitamin E content of fat emulsions (Intralipid) was measured and the influence of the intravenously administered lipid emulsion on plasma vitamin E levels was investigated. The majority of vitamin E was provided in the beta + gamma-tocopherol fractions (68.7% of total tocopherol). Vitamin E levels in patients were significantly lower (p less than 0.05) as compared to age- and sex-matched normal controls. Although sufficient amounts of vitamin E (16.9 +/- 0.8 IU daily) were infused, according to RDA requirements, E-plasma levels decreased even further during the course of TPN. It was concluded that high amounts of biologically less active tocopherol isomers are not sufficient to maintain vitamin E plasma levels. Supplemental sources of alpha-tocopherol are needed and more attention should be paid to the different tocopherol isomers in the quantitation of the daily allowances of vitamin E.