Glycogen synthase kinase-3 (GSK-3) a magic enzyme: it’s role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review / Glicogênio sintase quinase-3 (GSK-3), uma enzima mágica: seu papel no diabetes mellitus e na homeostase da glicose: interações com fluoroquinolonas. Uma mini-revisão

Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer’s disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

O diabetes mellitus (DM) é uma doença não transmissível em todo o mundo, na qual existe nível glicêmico persistentemente alto em relação à normalidade. O diabetes e a resistência à insulina são os principais responsáveis pelas morbidades e mortalidades de humanos no mundo. Essa doença é regulada principalmente por várias enzimas e hormônios, entre os quais a glicogênio sintase quinase-3 (GSK-3) é uma enzima principal e a insulina é o principal hormônio que a regula. A GSK-3, que é a enzima-chave, normalmente mostra suas ações por vários mecanismos que incluem sua fosforilação, formação de complexos de proteínas e outras distribuições celulares e, portanto, controla e afeta diretamente a morfologia celular, seu crescimento, mobilidade e apoptose do célula. Perturbações na ação da enzima GSK-3 podem levar a várias condições de doença que incluem resistência à insulina que leva ao diabetes, doenças neurológicas como a doença de Alzheimer e câncer. As fluoroquinolonas são a classe mais comum de drogas que apresentam efeitos disglicêmicos por meio da interação com a enzima GSK-3. Portanto, é necessário hoje em dia compreender adequadamente as funções e mecanismos da GSK-3, principalmente seu papel na homeostase da glicose via efeitos na glicogênio sintase.

Treadmill exercise prevents diabetes-induced increases in lipid peroxidation and decreases in Cu,Zn-superoxide dismutase levels in the hippocampus of Zucker diabetic fatty rats

In the present study, we investigated the effects of treadmill exercise on lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) levels in the hippocampus of Zucker diabetic fatty (ZDF) rats and lean control rats (ZLC) during the onset of diabetes. At 7 weeks of age, ZLC and ZDF rats were either placed on a stationary treadmill or made to run for 1 h/day for 5 consecutive days at 16~22 m/min for 5 weeks. At 12 weeks of age, the ZDF rats had significantly higher blood glucose levels and body weight than the ZLC rats. In addition, malondialdehyde (MDA) levels in the hippocampus of the ZDF rats were significantly higher than those of the ZLC rats whereas SOD1 levels in the hippocampus of the ZDF rats were moderately decreased. Notably, treadmill exercise prevented the increase of blood glucose levels in ZDF rats. In addition, treadmill exercise significantly ameliorated changes in MDA and SOD1 levels in the hippocampus although SOD activity was not altered. These findings suggest that diabetes increases lipid peroxidation and decreases SOD1 levels, and treadmill exercise can mitigate diabetes-induced oxidative damage in the hippocampus.

Glutamic acid decarboxylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities Study

To efficiently examine the association of glutamic acid decarboxylase antibody (GADA) positivity with the onset and progression of diabetes in middle-aged adults, we performed a case-cohort study representing the ~9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants, initially aged 45-64 years. Antibodies to glutamic acid decarboxylase (GAD65) were measured by radioimmunoassay in 580 incident diabetes cases and 544 non-cases. The overall weighted prevalence of GADA positivity (³1 U/mL) was 7.3 percent. Baseline risk factors, with the exception of smoking and interleukin-6 (P ú 0.02), were generally similar between GADA-positive and -negative individuals. GADA positivity did not predict incident diabetes in multiply adjusted (HR = 1.04; 95 percentCI = 0.55, 1.96) proportional hazard analyses. However, a small non-significant adjusted risk (HR = 1.29; 95 percentCI = 0.58, 2.88) was seen for those in the highest tertile (³2.38 U/mL) of positivity. GADA-positive and GADA-negative non-diabetic individuals had similar risk profiles for diabetes, with central obesity and elevated inflammation markers, aside from glucose, being the main predictors. Among diabetes cases at study's end, progression to insulin treatment increased monotonically as a function of baseline GADA level. Overall, being GADA positive increased risk of progression to insulin use almost 10 times (HR = 9.9; 95 percentCI = 3.4, 28.5). In conclusion, in initially non-diabetic middle-aged adults, GADA positivity did not increase diabetes risk, and the overall baseline profile of risk factors was similar for positive and negative individuals. Among middle-aged adults, with the possible exception of those with the highest GADA levels, autoimmune pathophysiology reflected by GADA may become clinically relevant only after diabetes onset.

The role of AMP kinase in diabetes.

Type 2 diabetes is characterized by abnormal metabolism of glucose and fat, due in part to resistance to the actions of insulin in peripheral tissues. If untreated it leads to several complications such as blindness, kidney failure, neuropathy and amputations. The benefit of exercise in diabetic patients is well known and recent research indicates that AMP activated protein kinase (AMPK) plays a major role in this exercise related effect. AMPK is considered as a master switch regulating glucose and lipid metabolism. The AMPK is an enzyme that works as a fuel gauge, being activated in conditions of high energy phosphate depletion. AMPK is also activated robustly by skeletal muscle contraction and myocardial ischaemia, and is involved in the stimulation of glucose transport and fatty acid oxidation produced by these stimuli. In liver, activation of AMPK results in enhanced fatty acid oxidation and decreased production of glucose, cholesterol, and triglycerides. The two leading diabetic drugs namely, metformin and rosiglitazone, show their metabolic effects partially through AMPK. These data, along with evidence from studies showing that chemical activation of AMPK in vivo with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) improves blood glucose concentrations and lipid profiles, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes and other metabolic disorders.

Studies of neurotransmitter mediating enzyme dopamine-B-hdroxylase, its cofactors and other biochemical parameters in the serum of diabetic heart disease patients

Neurotransmitter mediating enzyme Dopamine-beta-Hydroxylase [DBH], its cofactors and other biochemical parameters such as glucose, protein, albumin serum electrolytes, enzyme profiles, lipid profiles, urea, creatinine etc. are studied at six different age groups of both sexes, namely group I [10-l5 years], group II [15-25 years], group III [25-35 years], group IV [35-45 years] group V [45-55 years] and group VI [55+ years] of diabetic heart disease patients in comparison with the age matched controls. One unit of DBH activity is expressed in nmole/min/ml serum. DBH activity decreased in both males and females in groups I, II, III, IV, V and VI. The values of DBH activity in males and females are: group I [19.95 units and 35.62 units], group II [21.42 units and 36.72 units], group III [26.48 units and 42.82 units], group IV [31.39 units and 51.53 units], group V [26.59 units and 17.95 units] and group VI [36.26 units and 41.53 units], respectively. One of the cofactors, ascorbic acid level slightly decreased in almost all groups. Another cofactor copper, increased in all groups. Triacylglycerol also increased in all the groups. HDL-cholesterol decreased in almost all the groups of both sexes, except in males of groups II, III and IV. Cholesterol and LDL-cholesterol were variabies. The cardiac enzymes such as CK-MB, GOT, LDH1 activity increased in all the groups. Other biochemical parameters such as protein, albumin, serum electrolytes, urea, creatinine, bilirubin etc. were increased in some groups and decreased in some groups, except urea, they were within their respective normal ranges

Isolation of alpha-amylase isoenzymes in serum and saliva in diabetes mellitus

This research included a study of alpha-amylase isoenzymes in serum and saliva in diabetes mellitus, diabetic group were 100 samples and 80 samples as control group, their ages between [5-55] years. Three methods of isolation for alpha-amylase isoenzymes were studied in this research [gel filtration, anion exchange chromatography and electrophoresis]. By using gel filtration method for isolation alphaamylase isoenzymes in normal serum and saliva, the result of this isolation indicated that serum alpha-amylase [total alpha-amylase] was contained seven isoenzymes while in salivary alpha-amylase there were eight isoenzymes. Eleven isoenzymes for normal and abnormal total serum amylase and six isoenzymes for normal and abnormal salivary amylase were isolated by using anion exchange chromatography. By using polyacrylamide gel electrophoresis [PAGE], two or more bands and four bands were observed in normal serum and saliva respectively but seven or more bands and six bands were obtained from abnormal serum and saliva respectively

Plasma lipid peroxide and antioxidant levels in diabetic patients.

The present study was to investigate the levels of plasma lipid peroxide products including malondialdehyde (MDA) and conjugated dienes (CD), and antioxidants including enzyme superoxide dismutase, glutathione peroxidase, catalase, plasma vitamin E and vitamin C in diabetic patients. Fifty-eight diabetic subjects; 16 males and 42 females, aged 30-75 years, were recruited. Eighteen of them had diabetes and forty of them had diabetes with hyperlipidemia. Twenty-seven healthy subjects, 8 males and 19 females, aged 30-75 years, were used as the control group. The results showed that the concentrations of plasma MDA in diabetic patients with or without hyperlipidemia tended to be increased when compared to the controls but there were no significant differences. The CD values were increased significantly in both diabetic groups when compared with control subjects. Significantly elevated levels of plasma MDA and CD were found in diabetic patients with hypertriglyceridemia (> 150 mg%). This increment did not change the antioxidant status in both enzymes and vitamins except that the plasma vitamin E levels and the ratios of tocopherol: cholesterol were increased significantly. An increase of lipid peroxide in plasma may be one important factor in the development of vascular complication and atherosclerosis seen in diabetic patients.

Nucleoside deaminases activity levels in diabetes mellitus, possible new indices for early detection of diabetic nephropathy

The clinical value of assaying the activity of the nucleoside deaminases-cytidine deaminase [CD], guanosine deaminase [GD] and adenosine deaminase [AD] was studied in thirty-nine type I and fifty- three type II diabetic patients together with fifteen completely healthy subjects as controls. The changes were presented in both types of diabetes. The degree of control did not affect the AD activity levels. However, patients with complicated disease had lower activity levels of AD than uncomplicated diabetes. This suggested that AD deficiency in diabetes is at least in part attributing to decreased immunity in diabetic patients. The possibility of being associated with inheritance of type I and type II diabetes could not be excluded. The increased activity levels of CD and GD could arise from evident or latent nephropathy, where the activity levels of both enzymes were significantly high in patients with nephropathy compared with those without nephropathy. The correlation between these two enzymes with either duration of diabetes or fructosamine supported this hypothesis. Thus, these enzymes could be valuable new indices in the early detection of diabetic nephropathy

Serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels in diabetes mellitus.

The activities of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) in 72 Libyan diabetic patients were determined. The respective mean values were 24 +/- 1.1 U/L and 23.03 +/- 0.87 U/L. Significant correlations were found between the activities of GOT or GPT and fasting blood glucose, age, body mass index, heart rate and blood pressure levels. The mean values of GOT and GPT in diabetic patients with secondary complications were significantly higher than those without complications. On the other hand, patients with family history of diabetes have higher mean values of GOT and GPT when compared with those without diabetes in the family.

Menor oxidación de cuerpos cetónicos por mitocondrias de corazón en la diabetes / Decreased oxidation of ketone bodies in heart mitochondrias in diabetes

Ratas diabéticas por inyección de estreptozotocina presentaron concentraciones de 3-hidroxibutirato y acetoacetato en sangre 4,2 y 1,7 veces superiores a las normales, respectivamente. Al mismo tiempo, en las mitocondrias de corazón disminuyó la actividad de las enzimas iniciadoras del metabolismo oxidativo de esos cuerpos cetónicos, a saber, la 3-hidroxibutirato deshidrogenasa (72%) y la succinil-CoA: acetoacetil-CoA (3 - oxoácido - CoA) transferasa (50%). En cambio, la acetoacetil-CoA tiolasa, no varió. La oxidación del 3-hidroxibutirato y el acetoacetato por las mitocondrias enteras de ratas diabéticas, suplementadas con ADP (en estado metabólico "3") disminuyó 42 y 48%, respectivamente, en relación a los testigos normales, no así la oxidación del piruvato o del L-glutamato más L-malato que no varió significativamente. Estas observaciones implican una modificación selectiva de las enzimas correspondientes a los cuerpos cetónicos. La composición lipídica y la depolarización de la fluorescencia del difenil hexatrieno en las mitocondrias diabéticas no presentaron diferencias respecto a las normales, de manera que las variaciones enzimáticas descriptas se pueden atribuir a una síntesis defectuosa de las proteínas mitocondriales