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PubMed1999

Is glycation of low density lipoproteins in patients with Type 2 diabetes mellitus a LDL pre-oxidative condition?

AIMS: The study aimed to evaluate whether low density lipoprotein (LDL) in diabetic patients is more glycated and susceptible to oxidation than in non-diabetic subjects and investigated the hypothesis that LDL glycation is associated with an increased plasma concentration of LDL- (a circulating electronegatively charged LDL), proposed as an index of in vivo oxidation. METHODS: LDL glycation was measured by a competitive enzyme immunoadsorbent assay, using a monoclonal antibody against glycated apoB in 24 Type 2 diabetic patients and 12 healthy controls. LDL- was separated by ion-exchange HPLC in LDL samples obtained after sequential preparative ultracentrifugation (density range 1.019-1.063). In vitro LDL susceptibility to oxidation was evaluated by following the kinetics of conjugated diene formation and by measuring the lag-phase time in the presence of copper (Cu2+) ions. RESULTS: The percentages of glycated apoB (3.33+/-2.54% vs. 1.24+/-0.71%) and of LDL- (3.88+/-1.49% vs. 2.34+/-1.03%) in total LDL were significantly higher in diabetic patients (P<0.01 for both). LDL- was positively correlated with glycated apoB (r = 0.68, P<0.001). LDL isolated from Type 2 diabetic patients showed a significant decrease (P<0.001) in the resistance to oxidative stress, as indicated by the shorter lag-phase time (91+/-12.6 vs. 120+/-24.5 min). The lag-phase time was inversely correlated with glycated apoB (r = -0.65, P<0.001) and LDL- concentrations (r = -0.69, P<0.001). CONCLUSIONS: In this population of Type 2 diabetic patients, LDL were more glycated, more susceptible to in vitro oxidation and had a higher percentage of electronegative LDL. The glycation of apoB is proposed to be associated with a significative increase of in vivo and in vitro LDL oxidation.

Aged↗
PubMed2000

Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus.

AIMS: To evaluate the clinical efficacy and safety of rosiglitazone as a once daily treatment for Type 2 diabetes mellitus (DM). METHODS: Three hundred and sixty-nine patients with Type 2 DM (mean age 63 years; mean body mass index (BMI) 29.4 kg/m2) were enrolled in a double-blind, parallel group, placebo-controlled, dose-ranging study. Patients were randomly assigned to receive placebo or rosiglitazone at doses of 4, 8, or 12 mg daily for 8 weeks. RESULTS: At 8 weeks, fasting plasma glucose (FPG) decreased significantly in the rosiglitazone 4 mg, 8 mg, and 12 mg groups (-0.9, -2.0 and -1.7 mmol/l; P = 0.0003, < 0.0001, and < 0.0001, respectively) compared with placebo (+0.4 mmol/l). The improvements in FPG were dose ordered for 4 and 8 mg/ day. The 12 mg/day dose produced no additional improvement. There were small decreases in haemoglobin and haematocrit in the rosiglitazone treatment groups. The overall incidence of adverse experiences was similar in all treatment groups, including placebo with no evidence of hypoglycaemia or hepatotoxicity. CONCLUSIONS: Rosiglitazone improves glycaemic control when given once daily to treat Type 2 diabetes mellitus and is well tolerated at doses up to and including 12 mg.

Adult↗
PubMed2002

Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in Type 2 diabetic patients inadequately controlled on metformin.

AIMS: To evaluate the efficacy and safety of two dosage strengths of a single-tablet metformin-glibenclamide (glyburide) combination, compared with the respective monotherapies, in patients with Type 2 diabetes mellitus (DM) inadequately controlled by metformin monotherapy. METHODS: In this 16-week, double-blind, multicentre, parallel-group trial, 411 patients were randomized to receive metformin 500 mg, glibenclamide 5 mg, metformin-glibenclamide 500 mg/2.5 mg or metformin-glibenclamide 500 mg/5 mg, titrated with the intention to achieve fasting plasma glucose (FPG) < or = 7 mmol/l. RESULTS: Decreases in glycated haemoglobin (HbA1c) and FPG were greater (P < 0.05) for metformin-glibenclamide 500 mg/2.5 mg (-1.20% and -2.62 mmol/l) and 500 mg/5 mg (-0.91% and -2.34 mmol/l), compared with metformin (-0.19% and -0.57 mmol/l) or glibenclamide (-0.33% and -0.73 mmol/l). HbA1c < 7% was achieved by 75% and 64% of patients receiving metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg, respectively, compared with 42% for glibenclamide and 38% for metformin (P = 0.001). These benefits were achieved at lower mean doses of metformin or glibenclamide with metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg (1225 mg/6.1 mg and 1170 mg/11.7 mg) than with glibenclamide (13.4 mg) or metformin (1660 mg). Treatment-related serious adverse events occurred in two patients receiving glibenclamide. Plasma lipid profiles were unaffected and mean changes in body weight were < or = 1.0 kg. CONCLUSIONS: Intensive management of Type 2 DM with a new metformin-glibenclamide combination tablet improved glycaemic control and facilitated the attainment of glycaemic targets at lower doses of metformin or glibenclamide compared with the respective monotherapies, without compromising tolerability.

Blood Glucose↗
PubMed2002

Troubleshooting the diabetic small animal patient.

Effective troubleshooting for a diabetic small animal patient starts with the initial diagnosis of diabetes. Preempting trouble with a thorough and complete history, physical examination, laboratory assessment, and extensive and thoughtful client education before discharge, are crucial first steps toward avoiding trouble altogether. As problems arise, careful consideration of the many variables that contribute to effective diabetic control is necessary. As monitoring strategies evolve and treatment options expand, the clinician's ability to accurately assess and adjust the glycemic control in his or her troubled diabetic patient improves. Common causes of trouble in diabetic patients are reviewed and various strategies for the diagnosis and management of these disorders are discussed in this article. Every effort was made to draw from recently published reports of clinical cases. Few diseases will tie together owner, patient, and therapy as intimately as diabetes mellitus, and few problems will be solved without fully considering all potential factors.

Animals↗
PubMed1994

Serum antioxidant status in streptozotocin-induced diabetic rat.

To determine whether decrease in serum antioxidants contributes to the increased oxidative stress, we measured the antioxidant activity (AOA), total peroxyl radical-trapping antioxidant parameter (TRAP), and their component individual antioxidants in the serum of diabetic rats. AOA was assayed as the ability of serum to inhibit lipid autoxidation in brain homogenates. TRAP was assayed as the ability to delay lipid peroxidation induced by an azo initiator. Antioxidants measured were ceruloplasmin, unsaturated iron binding capacity (UIBC) and albumin as components of AOA; and uric acid, protein sulfhydryl and alpha-tocopherol as components of TRAP. AOA was decreased markedly in the diabetics due to the decrease in ceruloplasmin, UIBC and albumin. On the other hand, the directly measured TRAP in the diabetics was unaltered. Uric acid and alpha-tocopherol were increased in the diabetics. However, decrease in unidentified scavengers offset the increase brought about by those antioxidants These results suggest that the decreased metal binding capacity contributes to the increased oxidative stress in the diabetic rats.

Animals↗
PubMed2002

Amadori product and age formation during nonenzymatic glycosylation of bovine serum albumin in vitro.

Glucose reacts with the amino groups of protein to form a Schiff base that rearranges to form a ketoamine adduct. These early products eventually undergo irreversible chemical modifications generating advanced glycation end products (AGES). We reacted various sugars and sugar phosphates with bovine serum albumin allowing the formation of Amadori and AGE products. The rates of browning, Amadori and AGE products formed during incubations at 37 and 55 degrees C were compared. The correlation between AGE fluorescence and bitopical (crosslinking) modifications in the protein have been evaluated. Pentoses generated maximum Amadori products. Sugar phosphates were found to be more potent in generating AGEs than free sugars as measured by fluorescence. Though glucose, fructose and glucose-6-P do not generate fluorescence comparable to pentoses, they generate high molecular weight aggregates. In contrast, ribose-5-P, which shows significantly higher AGE and pentosidine fluorescence than the other sugars, did not generate high molecular weight aggregates. We suggest that there may not be a direct correlation between the levels of Amadori products, AGEs and crosslinking.

Amines↗
PubMed1999

Measuring glycated proteins: clinical and methodological aspects.

The recognition that nonenzymatic glycation, wherein free sugar condenses with certain reactive protein amino groups, is increased in hyperglycemic states has led to improved means for assessing diabetic control through the measurement of concentrations of glycated proteins in the circulation. This article reviews the chemistry, methods for measurement, and clinical relevance of circulating glycated proteins in the management of diabetes.

Animals↗
PubMed1987

Low-glycemic index diet in hyperlipidemia: use of traditional starchy foods.

To define those patients most likely to benefit from the hypolipidemic effect of low-glycemic-index (GI) traditional starchy foods, 30 hyperlipidemic patients were studied for 3 mo. During the middle month, low-GI foods were substituted for those with a higher GI with minimal change in dietary macronutrient and fiber content. Only in the group (24 patients) with raised triglyceride levels (types IIb, III, and IV) were significant lipid reductions seen: total cholesterol 8.8 +/- 1.5% (p less than 0.001), LDL cholesterol 9.1 +/- 2.4% (p less than 0.001), and serum triglyceride 19.3 +/- 3.2% (p less than 0.001) with no change in HDL cholesterol. The percentage reduction in serum triglyceride related to the initial triglyceride levels (r = 0.56, p less than 0.01). The small weight loss (0.4 kg) on the low-GI diet did not relate to the lipid changes. Low-GI diets may be of use in the management of lipid abnormalities associated with hypertriglyceridemia.

Adult↗
PubMed1991

The effects of fish oil on triglycerides, cholesterol, fibrinogen and malondialdehyde in humans supplemented with vitamin E.

The effects of fish oils supplemented with 0.3 IU/g and 1.5 IU/g of vitamin E were compared in a double-blind, cross-over study. Twelve healthy volunteers were given 30 mL/day of either oil for 3 wk. Intake of the vitamin E-rich fish oil resulted in a marked decrease in serum triglycerides (48%) and in fibrinogen (11%). After administration of the low vitamin E-containing oil there was a considerably smaller reduction of serum triglycerides and no significant reduction of fibrinogen. Both oils caused an increase in high density lipoprotein cholesterol and a decrease in the atherogenic index, but neither oil altered the total cholesterol level. Serum vitamin E was decreased by 9% and plasma malondialdehyde was increased by 122% after intake of the low vitamin E-containing oil, but both remained normal after intake of the other oil. The effect of vitamin E may be due to inhibition of fatty acid peroxidation with less formation of malondialdehyde and a larger amount of active (n-3) fatty acids in their sites of action in the liver, resulting in a greater decrease in the synthesis of triglycerides and fibrinogen.

Adult↗
PubMed1998

Aromatic hydroxylation in animal models of diabetes mellitus.

Although the involvement of oxidative stress is well documented in the diabetic state, the individual active oxygen species generated have not been demonstrated in animal models of diabetes currently used. Since streptozotocin-induced diabetes mellitus in animals still serves as an animal model of diabetes mellitus, but streptozotocin induces diabetes and generates oxidative stress per se, we decided to study whether aromatic hydroxylation reflecting hydroxyl radical attack was found in three animal models of diabetes mellitus without streptozotocin induction or in streptozotocin-induced diabetes only. For this purpose, we compared lipid peroxidation, aromatic hydroxylation of phenylalanine, glycoxidation in genetically determined diabetic mouse strains db/db and kk, and the diabetic BB rat to these parameters in the streptozotocin-treated rat. Kidney malondialdehyde concentrations, reflecting lipid peroxidation, pentosidine, and Nepsilon-caboxymethyllysine concentrations, reflecting glycoxidation, were significantly elevated in all diabetic groups as compared to their nondiabetic mates. Aromatic hydroxylation was significantly elevated in the streptozotocin-induced diabetic state exclusively. We conclude that biochemical, pathophysiological, and treatment studies in the streptozotocin model of diabetes mellitus may be confounded by the presence of products, reactions, and tissue damage generated by aromatic hydroxylation reflecting hydroxyl radical attack. We suggest it is not the diabetic state but streptozotocin that generates the hydroxyl radical, as reflected by aromatic hydroxylation in this model.

Animals↗
PubMed1998

Increased prevalence of abnormal immunoglobulin M, G, and A concentrations at clinical onset of insulin-dependent diabetes mellitus: a registry-based study. The Belgian Diabetes Registry.

In view of the reported association of insulin-dependent diabetes mellitus (IDDM) with viral infections, (non-) islet-specific immune changes, and partial immunodeficiencies, we used immunonephelometry to measure circulating levels of IgM, IgG, and IgA in a registry-based group of IDDM patients under age 40 years at clinical onset (n = 397) and in age-matched nondiabetic siblings (n = 316) and control subjects (n = 322). Overall, IgM and IgA concentrations were higher, and IgG concentrations lower, in patients than in control subjects or siblings (P < 0.001). In siblings, IgM concentrations were higher than in control subjects (P < 0.001). Using age-adjusted reference intervals, abnormal Ig concentrations were noted in 27% of the patients at onset versus only 10% of the siblings and 7% of the control subjects (P < 0.001). For onset between 20 and 40 years (n = 220), 30% of the patients presented either increased IgM levels (21%) or decreased IgG levels (11%). Both independent phenomena occurred regardless of diabetes-associated immune and genetic markers. In patients and siblings, IgM levels were positively correlated with pancreatic lipase activity. In diabetic children (0-9 years; n = 65), a subgroup presented increased IgA levels (15%) in association with the highest HLA DQ-linked genetic risk and elevated IgM levels. The changes in total Ig concentrations at onset were largely reversed under insulin therapy. They may reflect exposure to environmental triggers, such as viral infections, or to (relative) insulinopenia prior to clinical disease onset. Whatever their cause, different serum Ig levels exist in different age groups of recent-onset IDDM patients.

Adolescent↗
PubMed1984

Correlation between skin glycosylation and glycaemic control in human diabetes.

Glycosylation of human skin has been measured by an adaptation of the thiobarbituric acid reaction on samples obtained mainly at autopsy from normal and diabetic subjects. The mean (+/- 1 SD) glycosylation of skin from 33 normal subjects was 0.072 +/- 0.012 mumol fructosamine/100 mg wet weight tissue compared with 0.127 +/- 0.034 mumol (P less than 0.01) in the 10 diabetic subjects. There was a correlation between mean blood glucose levels in the 6 months before death and skin glycosylation in the diabetics, (r = 0.71, P = 0.025), but no correlation between age, sex, or the presence or absence of diabetic complications and skin glycosylation. Skin glycosylation in samples from four non diabetics was increased from 0.075 +/- 0.015 to 0.126 +/- 0.01 mumol fructosamine/100 mg wet weight tissue (P less than 0.01) after incubation with 50 mmol/l glucose solution for 7 d at 37 degrees C.

Adolescent↗
PubMed1989

Low protein alimentation normalizes renal haemodynamic response to acute protein ingestion in type 1 diabetic children.

The effect of an acute protein load (2 g kg-1 bodyweight [BW]) was studied in nine type 1 diabetic children. Patients were maintained on two different dietary regimens. In study one, patients were on a high protein diet providing from 2.7 to 1.8 g of protein/kg of BW per day. In study two, patients were reevaluated after three weeks of a diet providing from 1.0 to 1.2 g kg-1 of BW per day of protein. In study one (High Protein Diet), we failed to observe any rise in GFR and RPF following the protein meal (137 +/- 21 basal vs. 110 +/- 14 and 472 +/- 93 basal vs. 494 +/- 93 ml/1.73 m2 of SA min-1 at 60 min. This is in contrast with results from seven age matched controls consuming a free diet, which showed a significant rise in both GFR and RPF. In study two (low protein diet), basal GFR was significantly reduced. However after the protein load, both GFR (92 +/- 11 vs. 126 +/- 18 ml/1.73 m2 of SA min-1) and RPF (467 +/- 83 vs. 705 +/- 102 ml/1.73 m2 min-1) rose significantly (P less than 0.05 vs. basal). The data indicate that: 1. short term protein restriction reduces significantly GFR in type 1 diabetic children; 2. diabetic children maintained on an high protein intake show an altered haemodynamic response to protein ingestion; 3. a normal response to protein ingestion can be restored by short term dietary protein restriction.

Adolescent↗
PubMed2005

Evidence for non-enzymatic glycosylation of Escherichia coli chromosomal DNA.

We have recently shown that the process of non-enzymatic glycosylation (glycation) takes place in Escherichia coli under physiological conditions and affects both recombinant and endogenous bacterial proteins. In this study, we further demonstrate that E. coli chromosomal DNA is also subjected to glycation under physiological growth conditions. The E. coli DNA accumulates early glycation (Amadori) products as proven by the nitroblue tetrazolium (NBT) reduction assay. It showed also immunoreactivity to a monoclonal antibody raised against N(in)-(carboxymethyl)lysine and fluorescent properties indicative of modifications with advanced glycation end-products. Two types of fluorophores were detected in the E. coli DNA with excitation maxima at 360 nm and 380 nm and emission maxima at 440 nm and 410 nm. Using the NBT reduction assay, fluorescence spectroscopy and enzyme-linked immunosorbent assay we revealed that glycation adducts accumulate in DNA predominantly in the stationary phase of growth, although they could be detected also in exponential-phase cells. Besides on the growth phase, the extent of DNA glycation depends also on the nutrient broth composition being more extensive in rich media. Thiamine was found to inhibit both DNA glycation and spontaneous point mutations as judged by the decreased rate of the argE3 to Arg(+) reversions in the E. coli strain AB1157.

Chromosomes, Bacterial↗
PubMed2004

Continuous glucose monitoring in children with type 1 diabetes: before and after insulin pump therapy.

OBJECTIVE: The aim of continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus (T1DM) is to mimic as closely as possible the normal physiologic pattern seen in individuals without diabetes. This study was undertaken to determine the specific areas of improved glycemic control in subjects after initiation of insulin pump therapy and times where further improvement is needed. RESEARCH DESIGN AND METHODS: Eight patients with T1DM (age 7.5-17 yr) wore the Continuous Glucose Monitoring System (CGMS) (Medtronic MiniMed, Northridge, CA, USA) for 3 d before and 3 months after initiation of insulin pump therapy. The CGMS, which measures inter- stitial glucose concentrations every 5 min for a 72-h period, was used to evaluate glucose profiles. Patients entered 4-5 fingerstick blood glucose measurements daily into the sensor for calibration. Detailed logs of food intake, exercise, and hypoglycemic symptoms were also recorded. RESULTS: Hemoglobin A1c (HbA1C) was reduced (p < 0.007) following 3 months of insulin pump therapy. Post-CSII continuous glucose profiles demonstrated an overall improvement in hourly mean glucose over a 24-h period (p < 0.001) as well as a reduction in the area under the curve for glucose (27 +/- 4 prepump vs. 8.6 +/- 1.4 mg/dL/d postpump, p < 0.004). This improvement was a result of an attenuation of the maximal postprandial glycemic excursions. Postbreakfast 349 +/- 24 vs. 267 +/- 16 mg/dL, p < 0.003; lunch 340 +/- 16 vs. 217 +/- 20 mg/dL, p < 0.003. Postdinner average similarly decreased after 3 months of CSII by 22%, p < 0.04. CONCLUSIONS: Pump therapy specifically improved the postprandial glucose excursions in children.

Adolescent↗
PubMed1989

Multiple daily insulin injections improve self-confidence.

The efficacy and psychosocial effects of multiple daily insulin injections (three preprandial injections of short-acting insulin (NovoPen) and once daily, bedtime extended-acting insulin) were compared with those of twice daily combinations of short- and intermediate-acting insulin, in a randomized crossover study (two 6-month periods), in 16 adult diabetic patients. HbA1 was not significantly different for the two treatment modalities (8.2 +/- 0.4 vs 7.6 +/- 0.4%). With the pen-injector regimen significantly less state anxiety (36.0 +/- 2.5 vs 39.5 +/- 2.7; p less than 0.05) was found than with the conventional syringe regimen. The patients tended to experience a better self-concept as having diabetes (32.0 +/- 2.1 vs 37.7 +/- 3.0; p less than 0.06), as well as less external ('chance') orientation (18.5 +/- 1.2 vs 20.7 +/- 1.6; p = 0.09) with the pen-injector regimen. A subgroup of patients with lower trait anxiety scores experienced less state anxiety during the pen-injector regimen than during twice daily insulin injections (30.6 +/- 2.6 vs 34.3 +/- 2.7; p less than 0.05). However, this subgroup tended to be less positive about injecting insulin during the pen-injector regimen (34.8 +/- 3.6 vs 29.6 +/- 4.0; p less than 0.08). The subgroup with higher trait anxiety scores experienced a better self-concept as having diabetes (35.3 +/- 2.3 vs 40.1 +/- 2.6; p less than 0.05) and a tendency towards less physician orientation (15.8 +/- 1.8 vs 19.6 +/- 2.7; p less than 0.07) with the pen-injector regimen. Thirteen patients continued with the pen-injector regimen.

Anxiety↗
PubMed1989

Pupillary size in children and adolescents with type 1 diabetes.

Pupillary adaptation to darkness was studied in 63 children and adolescents with Type 1 diabetes using a simple portable pupillometer. Results were compared with those in a group of age-related non-diabetic children and expressed as the ratio of the pupil diameter to the iris diameter (pupil diameter %). In the diabetic patients the pupil diameter % was 61.1 +/- 5.8 (44.4-71.9) % compared with 64.2 +/- 4.1 (53.2-72.6) % in the control subjects (p less than 0.001). Abnormal pupillary adaptation to darkness was found more commonly than abnormal heart rate variation in response to a variety of stimuli in the diabetic patients. Pupillary adaptation to darkness may be useful as an indicator of subclinical autonomic neuropathy in diabetic children.

Adolescent↗
PubMed1990

Free radical activity in type 2 diabetes.

Free radical activity has been implicated in the development of diabetic vascular complications in Type 1 diabetes. The aim of the present study was to investigate the levels of free radical scavengers, particularly erythrocyte superoxide dismutase, plasma and erythrocyte lysate thiol, and caeruloplasmin in 22 Type 2 diabetic patients clinically free of complications, and 15 comparable non-diabetic control subjects. The concentration (median (range] of both superoxide dismutase (23 (10-39) vs 45 (25-75) mumol l-1; p less than 0.001) and plasma thiol (374 (172-523) vs 460 (386-595) mumol l-1; p less than 0.01) were reduced in the diabetic group. There were no significant differences in the concentration of erythrocyte lysate thiol (199 (114-520) vs 188 (114-328) mumol l-1) or plasma caeruloplasmin (18 (9-31) vs 24 (6-50) mumol l-1) between the groups. This reduction in superoxide dismutase and the imbalance in the redox status of the plasma and lysate thiol demonstrated is consistent with an increase in free radical activity in Type 2 diabetes.

Blood Glucose↗