Circulating osteogenic precursor cells in type 2 diabetes mellitus

Context: Type 2 diabetes mellitus (T2D) is associated with an increased risk of fractures and low bone formation. However, the mechanism for the low bone formation is not well understood. Recently, circulating osteogenic precursor (COP) cells, which contribute to bone formation, have been characterized in the peripheral circulation. Objective: Our objective was to characterize the number and maturity of COP cells in T2D. Patients, Design, and Setting: Eighteen postmenopausal women with T2D and 27 controls participated in this cross-sectional study at a clinical research center. Main Outcome Measures: COP cells were characterized using flow cytometry and antibodies against osteocalcin (OCN) and early stem cell markers. Histomorphometric (n = 9) and molecular (n=14) indices of bone turnover and oxidative stress were also measured. Results: The percentage of OCN(+) cells in peripheral blood mononuclear cells was lower in T2D (0.8 ± 0.2 vs. 1.6 ± 0.4%; P < 0.0001), whereas the percentage of OCN(+) cells coexpressing the early marker CD146 was increased (OCN(+)/CD146(+): 33.3 ± 7 vs. 12.0 ± 4%; P < 0.0001). Reduced histomorphometric indices of bone formation were observed in T2D subjects, including mineralizing surface (2.65 ± 1.9 vs. 7.58 ± 2.4%, P = 0.02), bone formation rate (0.01 ± 0.1 vs. 0.05 ±0.2 μm(3)/um(2) · d, P = 0.02), and osteoblast surface (1.23 ±0.9 vs. 4.60 ± 2.5%, P = 0.03). T2D subjects also had reduced molecular expression of the osteoblast regulator gene Runx2 but increased expression of the oxidative stress markers p66(Shc) and SOD2. Conclusions: Circulating OCN(+) cells were decreased in T2D, whereas OCN(+)/CD146(+) cells were increased. Histomorphometric indices of bone formation were decreased in T2D, as was molecular expression of osteoblastic activity. Stimulation of bone formation may have beneficial therapeutic skeletal consequences in T2D.     

Apolipoprotein (a) levels in type 1 and type 2 diabetes mellitus

Type 1 and type 2 diabetes mellitus are both characterized by increased cardiovascular mortality and morbidity. Since several reports have indicated that apolipoprotein (a) [apo (a)] levels are positively associated with an increased risk of macrovascular disease, we investigated whether apo (a) levels are elevated in both types of diabetes mellitus and may thus represent an independent risk factor for atherosclerotic disease. Apo(a) concentrations in type 1 diabetic patients were not significantly different from matched controls (276±78 vs 149±46 units/l). Type 2 diabetic patients had considerably higher levels of apo (a) than matched controls (471±89 vs 221±61 units/l,P=0.06), though the difference was not statistically significant. However, concentrations of apo (a) were above 300 units/l in 36% of type 1 and 67% of type 2 diabetic patients, but in only 14% and 25% respectively of matched control subjects. Plasma triglycerides were positively and independently correlated with apo (a) levels in both diabetic and non-diabetic subjects. On the other hand, no significant correlation was found between apo (a) levels and glycosylated haemoglobin, total cholesterol or high density lipoprotein cholesterol in any of the groups studied. In conclusion, apo (a) levels are not significantly elevated either in type 1 or type 2 diabetic patients without proteinuria and in moderate metabolic control; however, levels above 300 units/l were 2.6 times more frequent in both types of diabetes mellitus than in carefully age-, sex-, and weight-matched control subjects.     

Interrelationship between coagulation factor VII and obesity in diabetes mellitus (type 2)

We explored the interrelationships of coagulation FVII activity levels with obesity, leptin and insulin resistance in diabetes mellitus (DM Type 2) and in non-diabetic control subjects. We found FVII hypercoagulant activity levels in DM not associated with obesity, leptin levels or insulin resistance. It was found independently associated with hypertriglyceridemia.     

基因-膳食交互作用与2型糖尿病

基因变异与膳食因素间交互作用对2型糖尿病的影响已经引起人们的关注.研究显示膳食中碳水化合物的质量和数量变化、膳食脂肪摄入增加可以与2型糖尿病基因变异产生交互作用,增加2型糖尿病风险.全基因组关联性研究(genome-wide association,GWA)表明遗传变异本身具有调节膳食结构与2型糖尿病之间关联性的作用.     

Both DQA1 and DQB1 genes are implicated in HLA-associated protection from type 1 (insulin-dependent) diabetes mellitus in a British Caucasian population

Summary Inherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus is partly determined by HLA genes. It has been suggested that protection from disease may be conferred by HLA-DQB1 genes which encode molecules with aspartate at position 57. We investigated the contributions of HLA-DRB1, DQA1 and DQB1 genes to protection from disease. Restriction fragment length polymorphism and sequence specific oligonucleotide analysis in 156 British Caucasian Type 1 diabetic and 116 control subjects showed protection from disease was associated with DR2, DRw6 and DR7 haplotypes. The most protective DQA1 allele was DQA1*0102 which occurred on both DR2 and DRw6 haplotypes. The DQB1 alleles DQB1*0303, DQB1*0602 and DQB1*0603 were associated with protection, as was DQB1*0604, which encodes an Asp-57 negative DQmolecule. Heterozygosity for both protective and predisposing HLA markers was reduced in diabetic compared with control subjects. We conclude that both DQA1 and DQB1 genes are implicated in HLA-associated protection from Type 1 diabetes in this British Caucasian population. The overall structure of the DQ heterodimer is critical and DQ-Asp 57 is of secondary importance in determining protection from disease. The effect of protective HLA types may predominate over that of predisposing markers.     

Lipids,lipoproteins and apolipoproteins in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus

Summary Total plasma cholesterol, triglycerides, VLDL-C, VLDL-TG, HDL-C and the apoproteins A-I, A-II, B and D were measured in 111 male non-obese diabetic patients and in 90 male control subjects of similar age and body weight distribution. Forty-eight patients had Type 1 (insulin-dependent diabetes) and 63 had Type 2 (non-insulin-dependent diabetes); all were in stable metabolic control while following an appropriate diet and therapy with insulin or oral hypoglycemic agents. HDL-C, apoA-I, apoB and the apoA-I/apoA-II ratio were significantly increased in the Type 1 patients, whereas the VLDL-C/VLDL-TG and LDL-C/apoB ratios were decreased significantly. Type 2 diabetics showed low HDL-C and low apoA-I/apoA-II ratio, while the values of apoA-I, A-II, D and the VLDL-C/VLDL-TG ratio were significantly higher than in controls. Type 1 diabetics in ‘fair’ metabolic control presented higher values of TG, VLDL-C, VLDL-TG and apoB than patients in ‘good’ control: lower values of apoA-I and of the ratios apoA-I/apoA-II, apoA-I/apoB and LDL-C/apoB were recorded in the same subgroup. In Type 2 diabetics no significant differences were observed according to metabolic control, with the exception of a higher apo-D value in subjects in ‘fair’ control. The data obtained support the view that good metabolic control may be important for the prevention of a relevant derangement of lipoprotein components, particularly in Type 1 patients. Partially supported by grant No. 83.02521.56 fromConsiglio Nazionale delle Ricerche (CNR), Roma, Italy (Progetto Finalizzato di Medicina Preventiva e Riabilitativa).     

转录因子7样2与2型糖尿病

转录因子7样2(TCF7L2)基因是2型糖尿病最重要的易感基因之一,其基因变异体与2型糖尿病有强相关性,是目前2型糖尿病多因子遗传学领域中最引人注目的基因之一.这一结果在许多人种中都得以证实,而在我国关于该基因的研究刚刚起步.TCF7L2基因位于染色体10q25,共编码619个氨基酸,其产物是Wnt信号通路中一种转录因子.该因子通过对胰高血糖素样肽-1(GLP-1)水平调节,在糖代谢中起重要作用.另外,该信号通路与胰腺和胰岛的正常发育密切相关.     

TCF7L2基因多态性与合肥地区人群2型糖尿病的关联性研究

探讨TCF7L2基因多态性与合肥地区人群2型糖尿病遗传易感性的关系.结果 显示TCF7L2基因的微卫星(DG10S478)多态性与合肥地区人群2型糖尿病发病风险无明显相关(P>0.05),在该地区人群2型糖尿病的发病中并非主效基因.     

Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus

Objective  Six known genes responsible for maturity-onset diabetes of the young (MODY) were analysed to evaluate the prevalence of their mutations in Thai patients with MODY and early-onset type 2 diabetes.
Patients and methods  Fifty-one unrelated probands with early-onset type 2 diabetes, 21 of them fitted into classic MODY criteria, were analysed for nucleotide variations in promoters, exons, and exon–intron boundaries of six known MODY genes, including HNF-4α , GCK , HNF-1α , IPF-1 , HNF-1β , and NeuroD1/β2 , by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. Missense mutations or mutations located in regulatory region, which were absent in 130 chromosomes of non-diabetic controls, were classified as potentially pathogenic mutations.
Results  We found that mutations of the six known MODY genes account for a small proportion of classic MODY (19%) and early-onset type 2 diabetes (10%) in Thais. Five of these mutations are novel including GCK R327H, HNF-1α P475L, HNF-1α G554fsX556, NeuroD1 –1972 G > A and NeuroD1 A322N. Mutations of IPF-1 and HNF-1β were not identified in the studied probands.
Conclusions  Mutations of the six known MODY genes may not be a major cause of MODY and early-onset type 2 diabetes in Thais. Therefore, unidentified genes await discovery in a majority of Thai patients with MODY and early-onset type 2 diabetes.     

Pancreatic volume in type 1 und type 2 diabetes mellitus

We measured pancreatic volume (PV) using helical computed tomography (CT) in 26 patients with type 1 diabetes mellitus (DM), 29 patients with type 2 DM, and 22 healthy individuals. We also evaluated the relationship between PV and the body surface area (BSA), established the pancreatic volume index (PVI) by dividing PV by BSA to correct PV for the body build, and examined its relationships with the duration of illness, serum C-peptide immunoreactivity level (CPR), and serum immunoreactive trypsin level (IRT). BSA and PV were correlated significantly (p<0.0001, r=0.645) in healthy individuals, and they were correlated also in the diabetic patients, (p=0.0023, r=0.563 in type 1 DM; p=0.0346, r=0.392 in type 2 DM). PV was significantly smaller in the type 1 DM group than in the healthy group and type 2 DM group (p<0.001 for both). PVI was also significantly smaller in the type 1 DM group than in the healthy group and type 2 DM group p<0.001 for both). PVI and IRT were significantly correlated in both DM groups (p<0.0001, r=0.732 in type 1 DM; p=0.0469, r=0.731 in type 2 DM). PVI was not correlated with the duration of illness or CPR. Helical CT was useful for the measurement of the pancreatic volume, and the pancreatic volume was reduced particularly in the patients with type 1 DM. A strong correlation was observed between PV and exocrine pancreatic function in type 1 DM, but the correlation between PV and exocrine pancreatic function was weak in type 2 DM. Received: February 2001 / Accepted in revised form: July 2001     

Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus

Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The plasma levels of lipoprotein cholesterol and triglycerides are largely influenced by the degree of glycaemic control. With poor metabolic control, plasma cholesterol and triglycerides are frequently elevated. In contrast, in well-regulated patients without micro- and macrovascular complications lipid levels are generally normal or even favourable, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. With the development of diabetic nephropathy the cardiovascular risk increases markedly and this complication is associated with increased concentrations of cholesterol and of the atherogenic lipoprotein species, lipoprotein(a), and low levels of high-density lipoprotein cholesterol. The rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in non-diabetic populations. It is hoped that with increased recognition of dyslipidaemia and aggressive therapeutic measures the overkill in diabetes mellitus from macrovascular diseases will be reduced.     

Overcoming obstacles in risk factor management in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by progressively worsening hyperglycemia that leads to microvascular and macrovascular complications. Optimal management of T2DM aims to simultaneously control hyperglycemia, hypertension, and dyslipidemia to reduce the overall risk. However, a large proportion of patients in clinical practice do not reach treatment targets. Some of the obstacles to achieving treatment targets include high medication costs, costs associated with health insurance, poor patient adherence to medication, patient fear of potential adverse effects, improper patient education, and failure by health care providers to appropriately initiate or intensify therapy (clinical inertia). Possible causes of clinical inertia include the influence exerted on physicians by reluctant patients and the influence of media-driven attention and the negative spin of clinical trial results on physicians' prescribing behavior and on patients' attitudes towards treatment. This negative publicity can be disproportionate to the overall body of scientific evidence and may, therefore, prove to be unfounded in the long-term. There is clear evidence of the benefits of the effective management of T2DM to achieve goals. Overcoming the obstacles to achieving treatment targets may include use of strategies such as early intensive treatment and combination therapy with drugs with complementary mechanisms of action.     

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

OBJECTIVE: To determine the relation between plasma leptin concentrations and metabolic control in human diabetes mellitus. DESIGN AND SUBJECTS: Cross sectional study consisting of 156 patients with diabetes mellitus type 1 (n=42), type 2 (n=114), and non-diabetic subjects (n=74). RESULTS: Plasma leptin concentrations were lower (P<0.05) in type 1 (8.3+/-1.7 ng/ml) and type 2 diabetic (14.9+/-1.8 ng/ml) than in non-diabetic humans (18.3+/-1.9 ng/ml). Only female type 1 and type 2 diabetic subjects also had decreased leptin/BMI ratios (P<0.05 vs non-diabetic females). The log rank test identified age-adjusted correlation of plasma leptin concentration with sex (P<0.0004) and body mass index (P<0.0218), but not with glycosylated haemoglobin A1c (P>0.5) in all groups. Plasma leptin was correlated with age (P<0.0058) and serum triglycerides (P<0.0199) in type 1 diabetic patients, and with serum cholesterol (P<0.0059) and LDL (P<0.0013) in type 2 diabetic patients. CONCLUSIONS: Defective leptin production and/or secretion might be present independently of metabolic control in female patients with type 1 or type 2 diabetes mellitus.     

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer’s disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic–euglycaemic clamp. Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.