Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type

A retrospective study of 839 hospital records with various dementia diagnoses showed that 63 cases had a diagnosis of diabetes mellitus as well. None of these were found in the group of patients with senile dementia of Alzheimer type (SDAT). Oral glucose tolerance tests (OGTT) were performed in patients with SDAT, multiinfarct dementia (MID), cerebrovascular disease (CVD), hospitalized control patients (Chosp) and healthy elderly persons (Celd). Fasting blood sugar was significantly lower and the areas under the OGTT curves were significantly smaller in the SDAT group than in the CVD and the Chosp group. SDAT patients had higher insulin levels than Celd during the OGTT and on a statistically significant level 90 min after ingestion of sugar. Our findings suggest that SDAT and diabetes mellitus may not co-exist and that patients with SDAT have decreased blood sugar concentrations and elevated serum insulin levels. It is discussed whether this is an effect of the transmitter deficiencies in SDAT or may serve to explain these deficiencies.     

Cytokine Secretion in Long-standing Diabetes Mellitus Type 1 and 2: Associations with Low-grade Systemic Inflammation

Low-grade systemic chronic inflammation is a very well-known feature of diabetes mellitus (DM). The purpose of this study was the assessment of the proinflammatory cytokine secretion profile in long-standing diabetes along with the presence of features of systemic inflammation. Metabolic parameters and serum high-sensitivity C-reactive protein, interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels were determined in 20 patients with type 1 DM and 21 patients with type 2 DM and compared to 34 healthy subjects. The number of cytokine-secreting peripheral blood mononuclear cells (PBMCs), before and after mitogenic stimulation, was also determined in the same groups. Adverse lipid profile, higher levels of inflammatory markers, and higher count of cytokine-secreting cells were observed more prevalently in type 2 diabetics than in controls. After stimulation, the increase in number of cytokine-secreting cells was higher in controls. In conclusion, patients with DM have evidence of low-grade inflammation and abnormal PBMC function that could be related to long-term sequelae, the accelerated atherosclerotic process, and the susceptibility to infections.     

Ladostigil prevents age-related glial activation and spatial memory deficits in rats

Oxidative stress and glial activation occur in the aging brain. Ladostigil is a new monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitor designed for the treatment of Alzheimer's disease. It has neuroprotective and antioxidant activities in cellular models at much lower concentrations than those inhibiting MAO or AChE. When ladostigil (1 mg/kg/day) was given for 6 months to 16-month-old rats it prevented the age-related increase in activated astrocytes and microglia in several hippocampal and white matter regions and increased proNGF immunoreactivity in the hippocampus towards the levels in young rats. Ladostigil also prevented the age-related reduction in cortical AChE activity and the increase in butyrylcholinesterase activity in the hippocampus, in association with the reduction in gliosis. The immunological and enzymatic changes in aged rats were associated with improved spatial memory. Ladostigil treatment had no effect on memory, glial or proNGF immunoreactivity in young rats. Early treatment with ladostigil could slow disease progression in conditions like Alzheimer's disease in which oxidative stress and inflammatory processes are present.     

Effects of tetrahydroaminoacridine on M1 and M2 muscarine receptors

Tetrahydroaminoacridine (THA) has been reported to improve the memory of persons with Alzheimer's disease, but its mechanism of action is uncertain. We found that clinically effective concentrations, 0.03-0.3 microM, readily inhibit acetylcholinesterase and butyrylcholinesterase from rabbit hippocampal tissue in artificial cerebrospinal fluid (CSF) at 37 degrees C with physiological levels of substrate Above 1 microM, THA was found to act at primary and allosteric sites on M1 and M2 muscarine receptors as an antagonist. This is not clinically important, and low levels of THA do not improve the binding of the agonist, oxotremorine-M. Only 10-1000 microM THA has been shown to block K+ channels. Thus THA probably acts as an esterase inhibitor.     

肥胖2型糖尿病患者血清E-选择素水平与氧化应激的关系

目的： 探讨肥胖2型糖尿病（DM）患者血清E-选择素及氧化应激变化的关系。 方法： 检测肥胖2型DM患者血清E-选择素、氧化低密度脂蛋白胆固醇（ox-LDL）、血清丙二醛(MDA)含量和血清超氧化物歧化酶（SOD）活性。 结果： 非肥胖和肥胖2型DM患者E-选择素、ox-LDL和MDA含量均显著高于正常对照组（P<0.05），HDL-C、HDL2-C和HDL3-C含量均显著低于正常对照组（P<0.01），肥胖2型DM患者SOD活性显著低于正常对照组（P<0.01）。肥胖2型DM患者的E-选择素和MDA含量均明显高于非肥胖2型DM患者（P<0.05）,而SOD活性明显低于2型DM患者（P<0.01）。肥胖2型DM患者E-选择素与HbA1c、腰围、TC、ox-LDL和MDA正相关（r=0.352, P<0.05；r=0.634，P<0.05；r=0.517，P<0.05；r=0.480，P<0.05;r=0.572，P<0.05），与HDL3-C呈负相关（r=-0.374，P<0.05）。 结论： 肥胖2型DM患者血清E-选择素含量明显增加，氧化应激可能参与其变化。     

Acetylcholinesterase and its association with heparan sulphate proteoglycans in cortical amyloid deposits of Alzheimer's disease.

Previous studies have used a sensitive histochemical technique to demonstrate acetylcholinesterase and butyrylcholinesterase within the pathological lesions of Alzheimer's disease. In this study, we used this technique to show that acetylcholinesterase localized in either frozen or fixed neocortical tissue sections is removed after treatment with various glycosaminoglycans, heparinases or proteases. Heparan sulphate, heparinase lyase type I and to a lesser degree, heparin and chondroitin sulphate were effective in solubilizing a large part of the cholinesterase activity. At physiological concentrations, the protease papain or trypsin readily removed activity but collagenase or pronase were relatively less effective. Peptide protease inhibitors and divalent metals did not exhibit any clear effect. The specificity of these observations was shown by inhibition of activity with various anticholinesterases including diisofluorophosphate. Our results suggest that acetylcholinesterase is anchored to and may be released from the heparan sulphate glycosaminoglycans shown to be contained in the lesions. We further suggest that the localization of cholinesterases is closely associated with the accumulation of the glycosaminoglycans in amyloid plaques and neurofibrillary tangles.     

肝脂酶基因启动子-250G/A多态性与2型糖尿病合并冠心病易感性的相关研究

目的 探讨汉族人群肝脂酶(hepatic lipase,HL)基因启动子-250G/A多态性与2型糖尿病(type 2 diabetes mellitus,T2DM)合并冠心病(coronary heart disease,CHD)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性方法(polymerase chain reaction-restricted fragment length polymorphism,PCR-RFLP)检测364例T2DM+CHD组、357例T2DM组患者和356名健康对照者HL基因启动子-250G/A多态性,并分析其对脂类的影响.结果 T2DM组与对照组HL基因启动子-250G/A多态性基因型和等位基因频率差异无统计学意义(P>0.05);T2DM+CHD组GA+AA基因型频率低于对照组(0.431 vs 0.618,P=0.031);等位基因频率差异无统计学意义(P>0.05).调整混杂因素后,Spearman相关及线性回归分析,糖尿病患者(T2DM组和T2DM+CHD组),A等位基因与高密度脂蛋白胆固醇、载脂蛋白A1呈正相关;Logistic回归分析显示,A等位基因是冠心病发生的一个危险因素.结论 HL基因启动子-250G/A多态性与2型糖尿病合并冠心病的发生有关,并影响脂类代谢.     

Acetylcholinesterase and butyrylcholinesterase--important enzymes of human body

The serine hydrolases and proteases are a ubiquitous group of enzymes that is fundamental to many critical life-functions. Human tissues have two distinct cholinesterase activities: acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase functions in the transmission of nerve impulses, whereas the physiological function of butyrylcholinesterase remains unknown. Acetylcholinesterase is one of the crucial enzymes in the central and peripheral nerve system. Organophosphates and carbamates are potent inhibitors of serine hydrolases and well suited probes for investigating the chemical reaction mechanism of the inhibition. Understanding the enzyme's chemistry is essential in preventing and/or treating organophosphate and carbamate poisoning as well as designing new medicaments for cholinergic-related diseases like as Alzheimer's disease.     

The frequencies of apolipoprotein E genotypes in health and disease in the Croatian population--an overview of expectations and real results

The aim of the overview is to show the distribution of common apolipoprotein E (APOE) genotypes in the Croatian population, and to test whether it could serve as a new molecular biomarker in some clinical entities. The study included the following groups: patients with angiographically confirmed coronary artery disease, myocardial infarction, Alzheimer's dementia, vascular dementia, hyperlipidemias, diabetes mellitus, pancreatitis, and healthy subjects. Group comparisons of different clinical entities and control group were performed using Pearson's Chi2-test. There was no difference in APOE genotype frequencies between coronary artery disease neither myocardial infarction and control group. The ApoE genotype frequencies in patients with Alzheimer's disease were significantly different from those in the control group. APOE-4 allele tends to be a risk factor for the development of Alzheimer's disease. The frequencies were only marginally different in vascular dementia. Patients with hypercholesterolemia, those with inherited familial hypercholesterolemia, children with diabetes mellitus, and patients with pancreatitis of different etiology showed distributions of APOE genotypes that differed from the control group. It is concluded that the frequencies of APOE genotypes yielded no statistically significant result to confirm the association between APOE genotypes and any specific disease with the exception of Alzheimer's disease; APO-epsilon4 allell has become one of the important biomarkers in diagnosis of Alzheimer's dementia.     

Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy

Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.     

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.     

Increased urinary angiotensinogen precedes the onset of albuminuria in normotensive type 2 diabetic patients

It was previously reported that intrarenal renin angiotensin system (RAS) plays a pivotal role in the onset and progression of diabetic nephropathy (DN). Urinary angiotensinogen (UAGT) was employed as a special index of the intrarenal RAS status and enhanced significantly at a very early stage of chronic kidney disease and type 1 diabetes. On the basis of these findings, the present study was performed to test the hypothesis that UAGT levels are increase even before the development of DN in type 2 diabetic patients without hypertension. 102 patients with type 2 diabetes mellitus (T2DM) and 18 healthy volunteers were studied cross-sectionally. Clinical data were collected and morning spot urine samples were obtained from all participants. UAGT levels were detected by an enzyme-linked immunosorbent assay (ELISA). As a result, UAGT to creatinine ratio (UAGT/Cr) was significantly enhanced in T2DM patients before the appearance of urinary albumin (UALB) and further increased to a greater degree in albuminuric patients. UAGT/Cr levels were positively correlated with Log (UALB to creatinine ratio) and diastolic blood pressure, but negatively correlated with estimated glomerular filtration rate. These data indicate that elevated UAGT levels precede the onset of albuminuria in normotensive T2DM patients. UAGT might potentially serve as an early marker to determine intrarenal RAS activity and predict progressive kidney disease in T2DM patients without hypertension.     

Insulin as a primary autoantigen for type 1A diabetes

Type 1A diabetes mellitus is caused by specific and progressive autoimmune destruction of the beta cells in the islets of Langerhans whereas the other cell types in the islet (alpha, delta, and PP) are spared. The autoantigens of Type 1A diabetes may be divided into subgroups based on their tissue distributions: Beta-cell-specific antigens like insulin, insulin derivatives, and IGRP (Islet-specific Glucose-6-phosphatase catalytic subunit Related Peptide); neurendocrine antigens such as carboxypeptidase H, insulinoma-associated antigen (IA-2), glutamic acid decarboxylase (GAD65), and carboxypeptidase E; and those expressed ubiquitously like heat shock protein 60 (a putative autoantigen for type 1 diabetes). This review will focus specifically on insulin as a primary autoantigen, an essential target for disease, in type 1A diabetes mellitus. In particular, immunization with insulin peptide B:9-23 can be used to induce insulin autoantibodies and diabetes in animal models or used to prevent diabetes. Genetic manipulation of the insulin 1 and 2 genes reciprocally alters development of diabetes in the NOD mouse, and insulin gene polymorphisms are important determinants of childhood diabetes. We are pursuing the hypothesis that insulin is a primary autoantigen for type 1 diabetes, and thus the pathogenesis of the disease relates to specific recognition of one or more peptides.     

An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-kappaB ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-alpha to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-alpha. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.     

A Reappraisal of the Blood Glucose Homeostat which Comprehensively Explains the Type 2 Diabetes Mellitus–Syndrome X Complex

Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic α- and β-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.     

Prevention of cardiovascular disease in diabetes mellitus: by stressing the CARDS study

Recently, diabetes mellitus has become a global epidemic disease. There is a study indicating that type 2 diabetes mellitus (DM) is frequently found in children and teenager. Furthermore, in some countries, it is more frequent than type 1 diabetes mellitus.1 WHO stated that in the year of 2000, there were 177 million diabetes mellitus patient in the world and it is predicted that in the year of 2030, it will be increased to 366 million.2 This is very problematical for some countries such as India, People's Republic of China and Indonesia where the prevention and treatment facilities are still inadequate. To date, Indonesia has occupied the 4th rank, with predicted number of diabetes mellitus patient about 8.4 million and this number will be increased to 21.3 million in the year of 2030. There is no data about the number of patient with metabolic syndrome (MS) and insulin resistance syndrome (IR), but it should be higher than the number of diabetic patient. As we all have known, these conditions are the high-risk condition of diabetes mellitus development.2 One of reasons concerning why prevalence and pre-diabetic condition are increased (including the increased MS) is rising obesity frequency. In the United States, over 60% of recent adult population are overweight, which is defined as "body mass index" (BMI) 25; and about 30% of them have obesity, which is defined as BMI 30%.3 If diabetes mellitus occurred, cardiovascular disease (CVD) including coronary heart disease (CHD) also may occur. It is important to prevent the diabetes mellitus as well as to prevent the complication risk of CVD in diabetic patient.     

2型糖尿病伴冠心病及冠心病患者血清内脂素水平的研究

目的探讨血清内脂素在2型糖尿病伴冠心病及冠心病患者中的作用。方法采用酶联免疫法（EusA）对临床上确诊为2型糖尿病伴冠心病患者64例，冠心病患者85例及健康对照组30例，进行血清内脂素水平的测定。结果2型糖尿病伴冠心病组及冠心病组的血清内脂素水平明显高于正常对照组（P〈0．01），有统计学意义。结论血清内脂素在2型糖尿病的发生和发展中具有一定的生理作用，并可能对冠心病的发生和发展中也具有一定的生理作用。     

Change in serum cholinesterase activity in Jamaican diabetics.

This study investigates the alteration of serum cholinesterase levels in diabetics and its possible relationship to blood glucose, insulin, triglyceride, and cholesterol levels. Fourteen phasic insulin-dependent diabetes mellitus patients were compared with 10 insulin-dependent diabetes mellitus, 10 noninsulin-dependent diabetes mellitus, and 10 normal controls. Each group was matched for age, sex, body mass index, and duration of diabetes. Mean age was 56.7 +/- 2.5 years; mean body mass index, 24.0 +/- 0.8 kg/m2; and mean duration of diabetes, 14.2 +/- 2.2 years. Serum acetylcholinesterase, insulin, triglyceride, and cholesterol levels as well as fasting blood sugar were all assayed using standard techniques. Results suggest an associated increase of serum acetylcholinesterase with triglyceride levels in diabetics and may point to a possible association between increased serum acetylcholinesterase and vascular complications in Jamaican diabetics.     

Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease

Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, caloric restriction, or exercise training.