Patients with type 2 diabetes mellitus (T2DM) have increased cancer risks. The authors reported nonlinear associations of cancer with triglyceride and other lipids in T2DM. Crosstalk between lipid ...metabolism and the renin-angiotensin system may increase cancer risk via activation of insulin-like growth factor-1 pathway in T2DM. In this analysis, the authors explored associations of cancer risk with high/low triglyceride in T2DM and possible modifying effects of statins on this risk association, if any.
A consecutive cohort of 5166 Chinese patients with T2DM, free of cancer at enrollment and not using statins at or before enrollment, was analyzed using Cox models. Biological interactions were estimated using relative excess risk because of interaction, attributable proportion because of interaction, and synergy index. Relative excess risk because of interaction > 0, attributable proportion because of interaction > 0, or synergy index > 1 indicates biological interaction.
During 5.25 years of follow-up (median), 4.7% (n = 243) patients developed cancer. Triglyceride < 1.70 mmol/L was associated with increased cancer risk in the entire cohort and in statin nonusers, but not in statin users. Patients with triglyceride < 1.70 mmol/L plus nonuse of statins during follow-up had 2.74-fold increased cancer risk compared with their counterparts with either triglyceride ≥ 1.70 mmol/L or use of statins or both. There was significant interaction between triglyceride < 1.70 mmol/L and nonuse of statins (relative excess risk because of interaction, 0.99; 95% confidence interval CI, 0.07-1.90 and attributable proportion because of interaction, 0.36; 95% CI, 0.02-0.70).
In Chinese T2DM patients, triglyceride < 1.70 mmol/L might be associated with increased cancer risk, which was attenuated in the presence of use of statins.
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. ...We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near
(rs9942471,
= 4.5 × 10
) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at
and
, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Increasing Severity of Cardiovascular Risk Factors With Increasing Middle Cerebral Artery Stenotic Involvement in Type 2 Diabetic
Chinese Patients With Asymptomatic Cerebrovascular Disease
G. Neil ...Thomas , PHD 1 ,
Jian Wen Lin , MB 1 2 ,
Wynnie W.M. Lam , FRCR 3 ,
Brian Tomlinson , FRCP 1 ,
Vincent Yeung , FRCP 1 ,
Juliana C.N. Chan , FRCP 1 ,
Roxanna Liu , MPH 1 and
Ka Sing Wong , MD, MPH 1
1 Department of Medicine and Therapeutics, the Chinese University of Hong Kong, the Prince of Wales Hospital, Shatin, Hong Kong
Special Administrative Region, People’s Republic of China
2 Department of Neurology, First Affiliated Hospital, Sun Yat-sen University of Medical Sciences, Guangzhou, People’s Republic
of China
3 Department of Diagnostic Radiology and Organ Imaging, the Chinese University of Hong Kong, the Prince of Wales Hospital, Shatin,
Hong Kong Special Administrative Region, People’s Republic of China
Address correspondence and reprint requests to Ka Sing Wong, Department of Medicine and Therapeutics, Prince of Wales Hospital,
Shatin, NT, Hong Kong SAR, People’s Republic of China. E-mail: ks-wong{at}cuhk.edu.hk
Abstract
OBJECTIVE —To identify determinants associated with increasing severity of middle cerebral artery (MCA) stenosis in asymptomatic Chinese
type 2 diabetic patients with and without MCA stenosis determined using transcranial Doppler. Conventional risk factors contribute
to the pathogenesis of ischemic stroke, and differences in the pattern of these may explain the heterogeneity of disease presentation
in different populations. In Chinese patients, MCA stenosis is the most commonly identified intracranial vascular lesion.
RESEARCH DESIGN AND METHODS —Anthropometric and fasting biochemical parameters were compared between type 2 diabetic patients with MCA stenosis in one
( n = 185) or both ( n = 200) vessels and 1,492 type 2 diabetic patients without evidence of stenosis.
RESULTS —Increasing MCA stenotic vascular involvement was associated with significantly increasing age, duration of diabetes, systolic
blood pressure, and LDL cholesterol, but with lower glucose levels. There was also an increased prevalence of hypertension,
dyslipidemia, and use of blood pressure–and glucose-lowering agents in the patients with MCA stenosis. Concomitant significant
increases in the prevalence of peripheral vascular disease and retinopathy were also observed in the patients with MCA stenosis.
CONCLUSIONS —Transcranial Doppler examination identified stenosis in one or both MCAs in over one-fifth of the Chinese type 2 diabetic
subjects without symptoms of cerebrovascular disease. A number of conventional cardiovascular risk factors were closely associated
with MCA stenosis. This technique may allow the identification of a particularly high-risk group, and further studies are
required to determine whether asymptomatic MCA stenosis is predictive of primary cerebrovascular events and whether intensive
treatment of risk factors would reduce the risk.
MCA, middle cerebral artery
Footnotes
G.N.T. is currently affiliated with the Department of Community Medicine, University of Hong Kong, Pokfulam, Hong Kong Special
Administrative Region, People’s Republic of China.
Accepted February 1, 2004.
Received October 28, 2003.
DIABETES CARE
β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout ...(Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells.
We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding.
In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice.
Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates the ATX-LPA pathway to reverse β cell dysfunction associated with glucolipotoxicity.
•Sirtuin 3 (Sirt3) deletion upregulates autotaxin/ATX, the enzyme converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA).•LPA induces dedifferentiation in β cell line and primary islet through LPA receptor-MAPK p38 and JNK signaling.•ATX knockdown ameliorates LPA induced β cell dedifferentiation and improves insulin secretion in obese Sirt3 knockout mice.
Abstract Aims/Introduction We analyzed patient‐reported outcomes of people with type 2 diabetes to better understand perceptions and experiences contributing to treatment adherence. Materials and ...Methods In the ongoing International Diabetes Management Practices Study, we collected patient‐reported outcomes data from structured questionnaires (chronic treatment acceptance questionnaire and Diabetes Self‐Management Questionnaire) and free‐text answers to open‐ended questions to assess perceptions of treatment value and side‐effects, as well as barriers to, and enablers for, adherence and self‐management. Free‐text answers were analyzed by natural language processing. Results In 2018–2020, we recruited 2,475 patients with type 2 diabetes (43.3% insulin‐treated, glycated hemoglobin (HbA 1c ) 8.0 ± 1.8%; 30.9% with HbA 1c <7%) from 13 countries across Africa, the Middle East, Europe, Latin America and Asia. Mean ± standard deviation scores of chronic treatment acceptance questionnaire (acceptance of medication, rated out of 100) and Diabetes Self‐Management Questionnaire (self‐management, rated out of 10) were 87.8 ± 24.5 and 3.3 ± 0.9, respectively. Based on free‐text analysis and coded responses, one in three patients reported treatment non‐adherence. Overall, although most patients accepted treatment values and side‐effects, self‐management was suboptimal. Treatment duration, regimen complexity and disruption of daily routines were major barriers to adherence, whereas habit formation was a key enabler. Treatment‐adherent patients were older (60 ± 11.6 vs 55 ± 11.7 years, P < 0.001), and more likely to have longer disease duration (12 ± 8.6 vs 10 ± 7.7 years, P < 0.001), exposure to diabetes education (73.1% vs 67.8%, P < 0.05), lower HbA 1c (7.9 ± 1.8% vs 8.3 ± 1.9%, P < 0.001) and attainment of HbA 1c <7% (29.7% vs 23.3%, P < 0.01). Conclusions Patient perceptions/experiences influence treatment adherence and self‐management. Patient‐centered education and support programs that consider patient‐reported outcomes aimed at promoting empowerment and developing new routines might improve glycemic control.
OBJECTIVE:--Triglyceride-rich lipoprotein particles may promote the progression of diabetic nephropathy. Patients with diabetic nephropathy have increased plasma triglycerides and reduced activity of ...hepatic lipase (HL), which hydrolyzes triglycerides. We hypothesized that the HL -514Crightwards arrowT polymorphism, which reduces HL expression, and its interactions with polymorphisms in apolipoprotein (apo) E and apoC3 increase the risk of diabetic nephropathy. RESEARCH DESIGN AND METHODS--In a case-control study involving 374 Chinese type 2 diabetic patients with and 392 without diabetic nephropathy, we genotyped the HL -514Crightwards arrowT, apoE exon 4, and apoC3 -482Crightwards arrowT polymorphisms. RESULTS:--HL -514T-containing genotypes (T+) were associated with diabetic nephropathy (OR = 1.7, P = 0.0009). Adjustment by multiple logistic regression for hypertension, triglycerides, sex, non-HDL cholesterol, BMI, smoking, and alcohol intake did not diminish the association (OR = 1.8, P = 0.003). The association between HL T+ genotypes and diabetic nephropathy appeared stronger in diabetic patients with apoC3 -482 non-TT genotypes (OR = 1.9, P = 0.003) or apoE var epsilon2 or var epsilon4 alleles (OR = 2.2, P = 0.005). Subjects with HL TT exhibited trends toward increased triglyceride and non-HDL cholesterol levels compared with CC carriers. CONCLUSIONS:--HL T+ genotypes might increase the risk of developing diabetic nephropathy by slowing clearance of triglyceride-rich remnant lipoproteins. In concert with other risk factors (e.g., hyperglycemia), lipid abnormalities may damage the kidneys and endothelium, where reduced binding sites for lipases may precipitate a vicious cycle of dyslipidemia, proteinuria, and nephropathy.
Drug interactions with warfarin can be dangerous and although common drug interactions are now well recognized those with Chinese herbs are not widely appreciated. ‘Danshen’ is a herbal medicine ...often used for various complaints, particularly cardiovascular, in the Chinese community. We report a case of danshen‐induced overcoagulation with severe and dangerous abnormalities of clotting in a patient with rheumatic heart disease.
Background: Obesity is a growing global health problem. Obesity‐associated inflammatory and metabolic consequences may vary in different ethnic populations, and data in Chinese adolescents are ...sparse. In this study, we analysed the clinical and biochemical factors associated with overweight and obesity in Chinese adolescents.
Methods: This is a cross‐sectional cohort study with 2102 Chinese adolescents randomly selected from 14 secondary schools in Hong Kong. Clinical and biochemical parameters including inflammatory markers, among different groups stratified by degrees of obesity, were compared by multivariate logistic regression analysis.
Results: The median age was 16 yr (interquartile range: 14–17 yr) (45.6% boys and 54.4% girls). Among the boys, 16.5% were overweight and 6.8% were obese. The respective percentages in girls were 8.2 and 5.8%. Compared with the group with normal weight in both boys and girls, high systolic blood pressure (SBP), increased insulin resistance (by homoeostasis model assessment, HOMA‐IR), elevated high‐sensitivity C‐reactive protein (hsCRP) level and low high‐density lipoprotein cholesterol (HDL‐C) level were independently associated with overweight/obesity. In boys, the respective odds ratio (95% CI) was 1.03 (1.01–1.05) for SBP, 21.0 (12.0–36.8) for HOMA‐IR, 3.65 (2.10–6.35) for hsCRP and 0.24 (0.11–0.51) for HDL‐C. In girls, the respective figures were 1.02 (1.00–1.04), 9.82 (5.65–17.1), 6.28 (3.12–12.6) and 0.18 (0.08–0.41). In girls, low‐density lipoprotein cholesterol was also independently associated with overweight/obesity 1.56 (1.09–2.24).
Conclusions: In Chinese adolescents, overweight/obesity is independently associated with SBP, insulin resistance, hsCRP and low HDL‐C. Early intervention in overweight and obese adolescents may potentially retard the development of these cardiovascular risk factors.
Human insulin-like growth factor-I (hIGF-I) is a growth factor which is highly resemble to insulin. It is essential for cell proliferation and has been proposed for treatment of various ...endocrine-associated diseases including growth hormone insensitivity syndrome and diabetes mellitus. In the present study, an efficient plant expression system was developed to produce biologically active recombinant hIGF-I (rhIGF-I) in transgenic rice grains.
The plant-codon-optimized hIGF-I was introduced into rice via Agrobacterium-mediated transformation. To enhance the stability and yield of rhIGF-I, the endoplasmic reticulum-retention signal and glutelin signal peptide were used to deliver rhIGF-I to endoplasmic reticulum for stable accumulation. We found that only glutelin signal peptide could lead to successful expression of hIGF-I and one gram of hIGF-I rice grain possessed the maximum activity level equivalent to 3.2 micro molar of commercial rhIGF-I. In vitro functional analysis showed that the rice-derived rhIGF-I was effective in inducing membrane ruffling and glucose uptake on rat skeletal muscle cells. Oral meal test with rice-containing rhIGF-I acutely reduced blood glucose levels in streptozotocin-induced and Zucker diabetic rats, whereas it had no effect in normal rats.
Our findings provided an alternative expression system to produce large quantities of biologically active rhIGF-I. The provision of large quantity of recombinant proteins will promote further research on the therapeutic potential of rhIGF-I.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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