ubiquinone and Diabetes-Mellitus--Type-1

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes.

Topics: Animals; Blood Glucose; Cell Respiration; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electron Transport; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Rats; Reactive Oxygen Species; Superoxides; Ubiquinone

Functional state of the kidneys, severity of metabolic disturbances, intensity of LPO, and activity of the antioxidant system in 30 patients (18-36 years old) with type 1 diabetes mellitus and diabetic nephropathy of different compensation were studied before and after standard therapy or combination treatment with coenzyme Q10. Similar parameters were evaluated in 20 healthy subjects of the same age group. The development of metabolic disturbances in patients with type 1 diabetes mellitus (decompensated form) was accompanied by activation of LPO and inhibition of the antioxidant system. These patients were characterized by oxidative stress, diabetic nephropathy with associated proteinuria, and impairment of water excretion, electrolyte excretion, and nitrogen excretion in the kidneys. Combination therapy with coenzyme Q10 had a positive effect on LPO and antioxidant system. This treatment was followed by the relief of hyperglycemia, decrease in the concentrations of glycosylated hemoglobin and LDL cholesterol, and improvement of nitrogen metabolism.

Topics: Adult; Antioxidants; Cholesterol, LDL; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Electrolytes; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Lipid Peroxidation; Male; Nitrogen; Proteinuria; Ubiquinone

To investigate the effect of ubiquinone (coenzyme Q10) on glycaemic control and insulin requirement in patients with Type 1 diabetes mellitus (DM).. We investigated 34 patients with Type 1 DM in a randomized, double-blind, placebo-controlled study. Patients received either 100 mg Q10 or placebo daily for 3 months. The insulin doses were adjusted according to patients' home measurements of blood glucose concentrations and reported experience of hypoglycaemia.. At randomization no differences existed between the Q10 and the placebo groups in age, body mass index (BMI), HbA1c, daily insulin dose or mean daily blood glucose concentration. Serum Q10 concentration increased in the Q10 group (mean +/- SD: 0.9+/-0.2 vs. 2.0+/-1.0 microg/ml, P<0.005), with no change in the placebo group (0.9+/-0.3 vs. 0.9+/-0.3 microg/ml, not significant (NS)). Following intervention no differences existed between the Q10 and the placebo groups regarding HbA1c (7.86+/-0.88 vs. 7.84+/-0.84%), mean daily blood glucose concentrations (8.06+/-1.86 vs. 8.53+/-1.88 mM), mean insulin dose (52.1+/-13.2 vs. 52.6+/-21.4 U), hypoglycaemic episodes (2.0+/-1.8 vs. 2.5+/-2.1 episodes/week), or cholesterol concentrations (4.81+/-0.91 vs. 4.78+/-1.07 mM). Furthermore, no differences existed in the well-being of the patients reported from a visual analogue scale (physical: 0.67+/-0.21 vs. 0.71+/-0.18, psychological: 0.70+/-0.25 vs. 0.73+/-0.24).. Q10 treatment does not improve glycaemic control, nor does it reduce insulin requirement, and it can therefore be taken by patients with Type 1 DM without any obvious risk of hypoglycaemia. No major beneficial or unfavourable effects on the investigated parameters could be demonstrated and no major changes in the sense of well-being occurred in the patients.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Treatment Outcome; Ubiquinone

Topics: Adult; Blood Glucose; Body Mass Index; Cholesterol; Coenzymes; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Insulin; Male; Treatment Failure; Ubiquinone

Major long-term complications in patients with diabetes are related to oxidative stress, caused by the hyperglycaemia characteristic for diabetes mellitus. The anti-oxidant coenzyme Q10 (CoQ10) has therefore been proposed as a beneficial supplement to diabetes treatment. Apart from its anti-oxidative function, CoQ10 appears to modulate immune functions by largely unknown mechanisms. The aim of this study was therefore to investigate the effect of CoQ10 on antimicrobial peptides and natural killer (NK) cells, both innate immune components implicated in the pathogenesis of diabetes and diabetes-associated long-term complications such as cardiovascular disease. We determined serum levels of antimicrobial peptides and the phenotype of NK cells isolated from peripheral blood of patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) and from healthy controls. In addition, the same parameters were determined in diabetic patients after a 12-week period of CoQ10 supplementation. Two antimicrobial peptides, the human cathelicidin antimicrobial peptide (CAMP) and the human beta defensin 1 (hBD1), were reduced in serum from patients with T1DM. This defect was not reversible by CoQ10 supplementation. In contrast, CoQ10 reduced the levels of circulating hBD2 in these patients and induced changes in subset distribution and activation markers in peripheral NK cells. The results of the present study open up novel approaches in the prevention of long-term complications associated to T1DM, although further investigations are needed.

Topics: Adult; Aged; Antimicrobial Cationic Peptides; Antioxidants; beta-Defensins; Biomarkers; Case-Control Studies; Cytokines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Immunity, Innate; Inflammation; Killer Cells, Natural; Middle Aged; Oxidative Stress; Ubiquinone

Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22(phox), p47(phox) and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV -dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-α, with a similar trend for interleukin IL-1β). Coenzyme Q10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Humans; Hyperglycemia; Lipid Peroxidation; Male; Mice; Oxidative Stress; Reactive Oxygen Species; Ubiquinone; Up-Regulation; Ventricular Remodeling

The study included 39 patients with DM1, symptoms of peripheral diabetic angiopathy and metabolic disorders either compensated, subcompensated or decompensated 20 subjects served as controls. All the patients were given basal therapy with short-acting and intermediate-acting insulins, Some subcompensated patients were treated with hypoglycemic agents in combination with coenzyme Q10. The following parameters were measured: lipid peroxidation, activity of antioxidative enzymes, total nitric oxide (NO) metabolites, cholesterol (CH) metabolism, ALT AST GGT blood flow in the lower extremities was evaluated from rheovasograms. It was shown that patients with decompensated or subcompensated DM1 experienced oxidative stress accompanied by reduced NO levels and bioavailability. Elevated concentration of total CH and LDLP and decreased HDLP levels promoted endothelial dysfunction and were risk factors of atherosclerosis. Traditional therapy relieved disorders of carbohydrate and lipid metabolism but failed to correct hemodynamic disturbances in the lower extremities. Combined treatment with coenzyme Q10 reduced lipid peroxidation, increased activity of antioxidant enzymes, total NO metabolites and bioavailability, decreased the level of atherogenic LDLP. Improvement of metabolism was associated with normalization of elasticity of microvessels and pulse blood filling of the lower limb vessels, reduced tone and modulus of elasticity of arterioles and capillaries, correction of venous hyperemia. Reduced resistance of the microcirculatory bed resulted in normalization of arterial pressure.

Topics: Adolescent; Adult; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Male; Oxidative Stress; Risk; Treatment Outcome; Ubiquinone; Vascular Resistance; Young Adult

Oxidative stress is a key factor implicated in the development of diabetic neuropathy. This study evaluates the prophylactic and antinociceptive effects of the antioxidant coenzyme Q10 (CoQ10) on diabetes-induced neuropathic pain in a diabetic mouse model.. Total 56 mice with type 1 diabetes induced by streptozotocin were used, 20 normal mice were used as control. Mechanical and thermal nociceptive behavioral assays were applied to evaluate diabetic neuropathic pain. Tissue lipid peroxidation, immunohistochemistry, reverse transcription, and polymerase chain reaction were used to evaluate the molecular mechanisms of CoQ10. Data are presented as mean ± SEM.. CoQ10 administration was associated with reduced loss of body weight compared with nontreated diabetic mice, without affecting blood glucose levels. Low dose and long-term administration of CoQ10 prevented the development of neuropathic pain. Treatment with CoQ10 produced a significant dose-dependent inhibition of mechanical allodynia and thermal hyperalgesia in diabetic mice. Dorsal root ganglia, sciatic nerve, and spinal cord tissues from diabetic mice demonstrated increased lipid peroxidation that was reduced by CoQ10 treatment. CoQ10 administration was also noted to reduce the proinflammatory factors in the peripheral and central nervous system.. The results of this study support the hypothesis that hyperglycemia induced neuronal oxidative damage and reactive inflammation may be pathogenic in diabetic neuropathic pain. CoQ10 may be protective by inhibiting oxidative stress and reducing inflammation by down-regulating proinflammatory factors. These results suggest that CoQ10 administration may represent a low-risk, high-reward strategy for preventing or treating diabetic neuropathy.

Topics: Analgesics; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reverse Transcriptase Polymerase Chain Reaction; Ubiquinone; Vitamins; Weight Loss

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)⁻(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)⁻(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2(+/)⁻(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

Topics: Animals; beta Catenin; Blood Glucose; Cell Nucleus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fibrosis; Glomerular Mesangium; Immunohistochemistry; Insulin; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Mitochondria; Phosphorylation; Smad2 Protein; Smad3 Protein; Ubiquinone

Hyperglycaemia has been reported to cause increased production of oxygen free radicals. Oxidative stress may contribute to the pathogenesis of diabetic complications. Coenzyme Q(10) (CoQ(10)) is known for its key role in mitochondrial bioenergetics and is considered as a potent antioxidant and free radical scavenger. This study was conducted to evaluate plasma and blood cell concentrations of CoQ(10) in accordance to its redox capacity in children with diabetes mellitus type 1. CoQ(10) plasma and blood cell concentrations and redox status were measured using high-performance liquid chromatography with electrochemical detection in 43 children with diabetes mellitus type 1 and compared with 39 healthy children. In addition, the diabetic patients were subdivided according to their haemoglobin A1c (HbA1c) values into two groups, that is, those with good control (<8%) and those with poor control (>8%), and the CoQ(10) status was compared between the two groups. Children with type 1 diabetes showed increased plasma levels of CoQ(10) in comparison to healthy children. While CoQ(10) erythrocyte and platelet concentrations did not differ, in the diabetes group, the platelet redox status differed with a significantly increased part of reduced CoQ(10). This difference in concentration and redox status in comparison to healthy controls may be attributed to the subgroup of patients with poor control, as the subdivision of diabetic patients according to their HbA1c values shows. In diabetic children, especially in those with poor control, an increase in plasma concentration and intracellular redox capacity of the antioxidant CoQ(10) may contribute to the body's self-protection during a state of enhanced oxidative stress.

Topics: Adolescent; Antioxidants; Child; Child, Preschool; Diabetes Mellitus, Type 1; Erythrocytes; Female; Glycated Hemoglobin; Humans; Male; Oxidation-Reduction; Prospective Studies; Ubiquinone

Topics: Adolescent; Antioxidants; Child; Coenzymes; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hyperglycemia; Oxidative Stress; Ubiquinone; Vitamin E

Diabetes, which causes enhanced oxidative stress, is a multifactorial disease that leads to deleterious effects in many organ systems within the body. Ubiquinones (coenzyme Q(9) and Q(10)) are amphipathic molecular components of the electron transport chain that function also as endogenous antioxidants and attenuate the diabetes-induced decreases in antioxidant defense mechanisms. Insulin-like growth factor 1 (IGF-1) is considered to be an "essential surviving factor", the level and function of which are compromised in diabetes. This study investigated the impact of IGF-1 supplementation on ubiquinone levels in a rat model of type I diabetes. Adult male Sprague-Dawley rats were divided into four groups: control, control plus IGF-1, diabetic and diabetic plus IGF-1. Diabetic animals received a single intravenous injection of streptozotocin (STZ, 55 mg/kg). IGF-1 supplementation groups received a daily intraperitoneal dose of 3 mg IGF-1 per kilogram body weight for 7 weeks. Coenzyme Q(9) and Q(10) levels were assessed by ultraviolet detection on high pressure liquid chromatography. STZ caused a significant reduction in body weight and an elevation in blood glucose level, which were not prevented by IGF-1 supplementation. In addition Q(9) and Q(10) levels in diabetic liver were significantly elevated. IGF-1 supplementation prevented liver alterations in Q(10) but not Q(9) levels. Q(9) and Q(10) levels in diabetic kidney were significantly depressed, and these deleterious effects were abolished by IGF-1 treatment. These data suggest that IGF-1 antagonizes the diabetes-induced alterations in endogenous antioxidants including coenzyme Q(10), and hence may have a therapeutic role in diabetes.

Topics: Animals; Coenzymes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Disease Models, Animal; Insulin-Like Growth Factor I; Kidney; Liver; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reference Values; Ubiquinone

Oxidative modification of lipoproteins in vessel walls plays a key role in atherogenesis. Patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis despite severe hyperlipidemia. We analyzed antioxidative defense and oxidative stress in plasma and serum of patients with GSD Ia (n = 17) compared to patients with type I diabetes mellitus (DMI, n = 17), familial hypercholesterolemia (FH, n = 18), and healthy controls (n = 20). We measured the total radical-trapping antioxidant parameter (TRAP), single antioxidants (sulfhydryl groups, uric acid, vitamin C, alpha-tocopherol, coenzyme Q10), malondialdehyde, oxidized low density lipoprotein (LDL) antibodies, lipid profile [cholesterol, triglyceride, lipoprotein (a)], homocysteine, and hemoglobin (Hb)A(1C). TRAP levels were elevated in the GSD Ia group (p <.01) and correlated with elevated uric acid levels (r = 0.72, p =.001). None of the other plasma antioxidants correlated with TRAP levels. DMI patients showed decreased sulfhydryl groups (p <.01) and a reduced ubiquinol-10 fraction (p <.01). Malondialdehyde (p <.001) and oxidized LDL autoantibodies (p <.05) were increased in the diabetic group. In FH patients, parameters of oxidative stress and TRAP did not differ from controls. We conclude that in GSD Ia an increased antioxidative defense in plasma may protect against lipid peroxidation and thus against premature atherosclerosis. Furthermore, we demonstrated that in DMI increased oxidative mechanisms are already present in childhood.

Topics: Adolescent; Adult; Antioxidants; Ascorbic Acid; Child; Child, Preschool; Cholesterol; Chromatography, High Pressure Liquid; Coenzymes; Diabetes Mellitus, Type 1; Female; Glycogen Storage Disease Type I; Hemoglobins; Homocysteine; Humans; Hyperlipoproteinemia Type II; Infant; Lipoproteins, LDL; Male; Malondialdehyde; Sulfhydryl Compounds; Triglycerides; Ubiquinone; Uric Acid; Vitamin E

Plasma ubiquinol was measured in diabetics, patients on haemodialysis (HD) therapy, patients maintained by continuous ambulatory peritoneal dialysis (CAPD), hyperlipidaemic patients and control subjects. Ubiquinol values were standardized using total cholesterol (mumol/mmol). Diabetics, HD and CAPD patients were found to have plasma ubiquinol levels which were lower than the control subjects. There was no difference in values between the control subjects and hyperlipidaemic patients. Values for diabetics with poor metabolic control were similar to those with good control, and patients with diabetic complications had values which were not significantly different from those for patients with no complications. IDDM patients were found to have values which were lower than the control group, whereas values for the NIDDM patients were not significantly different. These results suggest that increased oxidative stress in certain patient groups may be the result of, and/or the cause of, decreased plasma ubiquinol. This could be due to increased demand or to decreased ability to regenerate the effective form of antioxidant.

Topics: Adolescent; Adult; Aged; Cholesterol; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Male; Middle Aged; Oxidative Stress; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Triglycerides; Ubiquinone