Causal Associations in Type 2 Diabetes Development

Abstract Context Obesity, glucose, insulin resistance [homeostatic model assessment, version 2, for insulin resistance (HOMA2-IR)], and insulin secretion (HOMA2-β) have been associated with type 2 diabetes (T2D) observationally. However, the causal, genetic contribution of each parameter to this risk is largely unknown and important to study because observational data are prone to confounding but genetic, causal data are free of confounding and reverse causation. Objective We examined the causal, genetic contribution of body mass index (BMI), glucose level, C-peptide level, HOMA2-IR, and HOMA2-β to the risk of T2D in 95,540 individuals from the Copenhagen General Population Study and estimated the absolute 10-year risks. Methods Cox regression analysis, instrumental variable analysis, and Poisson regression analysis were performed to estimate the observational hazard ratios, causal, genetic ORs, and absolute 10-year risks of T2D. Results For 1-SD greater level, BMI was associated with an observational 66% (95% CI, 62% to 72%) and causal, genetic 121% (95% CI, 25% to 291%) greater risk of T2D; glucose with an observational 44% (95% CI, 41% to 46%) and causal, genetic 183% (95% CI, 56% to 416%) greater risk of T2D; and HOMA2-IR with an observational 30% (95% CI, 18% to 44%) and causal, genetic 12% (95% CI, 2% to 22%) greater risk of T2D. In contrast, for 1-SD greater level, HOMA2-β was associated with an observational 14% (95% CI, 11% to 16%) and causal, genetic 21% (95% CI, 8% to 32%) lower risk of T2D. The upper tertiles of HOMA2-IR were associated with absolute 10-year diabetes risks of 31% and 37% in obese women and men, age >60 years, and a glucose level of 6.1 to 11.0 mmol/L. Conclusions BMI, glucose level, HOMA2-IR, and HOMA2-β are causally associated with T2D.

Download Full-text

Glycemic Control and Risk of Sepsis and Subsequent Mortality in Type 2 Diabetes

10.2337/figshare.16775743 ◽

2021 ◽

Author(s):

Anca Balintescu ◽

Marcus Lind ◽

Mikael Andersson Franko ◽

Anders Oldner ◽

Maria Cronhjort ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Analysis ◽

Cox Regression ◽

Cubic Spline ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Increased Risk

Objective To investigate the nature of the relationship between HbA1c and sepsis among individuals with type 2 diabetes and to assess the association of sepsis and all-cause mortality in such patients. Research design and methods We included 502,871 individuals with type 2 diabetes recorded in the Swedish National Diabetes Register and used multivariable Cox regression and restricted cubic spline analyses to assess the association between time-updated HbA1c values and sepsis occurrence between January 1, 2005 and December 31, 2015. The association between sepsis and death was examined using multivariable Cox regression analysis. Result Overall, 14,534 (2.9%) patients developed sepsis during the study period. On multivariable Cox regression analysis, compared with an HbA1c of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was 1.15 (95% CI 1.07-1.24) for HbA1c <43 mmol/mol (6.1%); 0.93 (0.87-0.99) for HbA1c 53-62 mmol/mol (7.0-7.8%); 1.05 (0.97-1.13) for HbA1c 63-72 mmol/mol (7.9-8.7%); 1.14 (1.04-1.25) for HbA1c 73-82 mmol/mol (8.8-9.7%); and 1.52 (1.37-1.68) for HbA1c >82 mmol/mol (9.7%). In the cubic spline model, a reduction of the adjusted risk was observed within the lower HbA1c range until 53 mmol/mol (7.0%), with a hazard ratio of 0.78 (0.73-0.82) per standard deviation, and increased thereafter (P for non-linearity <0.001). As compared to patients without sepsis, the adjusted hazard ratio for death among patients with sepsis was 4.16 (4.03-4.30). Conclusions In a nationwide cohort of individuals with type 2 diabetes, we found a U-shaped association between HbA1c and sepsis and a four-fold increased risk of death among those developing sepsis.

Download Full-text

Glycemic Control and Risk of Sepsis and Subsequent Mortality in Type 2 Diabetes

10.2337/figshare.16775743.v1 ◽

2021 ◽

Author(s):

Anca Balintescu ◽

Marcus Lind ◽

Mikael Andersson Franko ◽

Anders Oldner ◽

Maria Cronhjort ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Analysis ◽

Cox Regression ◽

Cubic Spline ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Increased Risk

Download Full-text

Trigger finger is associated with risk of incident cardiovascular disease in individuals with type 2 diabetes: a retrospective cohort study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002070 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002070

Author(s):

Yusuke Mineoka ◽

Michiyo Ishii ◽

Yoshitaka Hashimoto ◽

Hiroki Yuge ◽

Machiko Toyoda ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Analysis ◽

Cohort Study ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Cox Regression ◽

Trigger Finger ◽

Cox Regression Analysis

IntroductionTrigger finger is one of the complications affecting the upper extremity in patients with diabetes. Diabetes is also a well-known risk factor that predisposes individuals to cardiovascular diseases (CVDs). This retrospective cohort study aimed to establish the association between trigger finger and the patients with incident CVD with type 2 diabetes.Materials and methodsTrigger finger was diagnosed by palpating a thickened tendon during ﬂexion or on the manifestation of a locking phenomenon during extension or ﬂexion of either ﬁnger. The relationship between trigger finger and other clinical parameters or complications of diabetes was examined by a comparative analysis. Cox regression analysis was used to evaluate the association between trigger finger and incidence of CVD. We calculated the propensity scores using sex, body mass index, age, smoking status, duration of diabetes, estimated glomerular filtration rate, hypertension, dyslipidemia, and hemoglobin A1c as the number of patients with incident CVD during the follow-up period was low.ResultsAmong the 399 patients with type 2 diabetes, 54 patients had trigger finger. Patients with trigger finger were significantly older in age and had been suffering from diabetes for a longer duration. They also displayed worse renal function and glycemic control, along with a higher incidence of hypertension, neuropathy and nephropathy. During the average 5.66±1.12 years of follow-up, a total of 18 incidents occurred. According to the Cox regression analysis, trigger finger was shown to be associated with enhanced risk of the incidence of CVD after adjustment for the covariates (adjusted HR=3.33 (95% CI 1.25 to 8.66), p=0.017).ConclusionsTrigger finger is associated with the risk of incident CVD in patients with type 2 diabetes. Thus, clinicians must consider these factors at the time of diagnosis of such patients.

Download Full-text

Modelling ethnic differences in the distribution of insulin resistance via Bayesian nonparametric processes: an application to the SABRE cohort study

The International Journal of Biostatistics ◽

10.1515/ijb-2019-0108 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Marco Molinari ◽

Maria de Iorio ◽

Nishi Chaturvedi ◽

Alun Hughes ◽

Therese Tillin

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mcmc Methods ◽

Model Assessment ◽

Bayesian Nonparametric ◽

Nonparametric Prior ◽

Posterior Inference ◽

Regression Framework ◽

Analyse Data

AbstractWe analyse data from the Southall And Brent REvisited (SABRE) tri-ethnic study, where measurements of metabolic and anthropometric variables have been recorded. In particular, we focus on modelling the distribution of insulin resistance which is strongly associated with the development of type 2 diabetes. We propose the use of a Bayesian nonparametric prior to model the distribution of Homeostasis Model Assessment insulin resistance, as it allows for data-driven clustering of the observations. Anthropometric variables and metabolites concentrations are included as covariates in a regression framework. This strategy highlights the presence of sub-populations in the data, characterised by different levels of risk of developing type 2 diabetes across ethnicities. Posterior inference is performed through Markov Chains Monte Carlo (MCMC) methods.

Download Full-text

Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

Journal of International Medical Research ◽

10.1177/03000605211048293 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110482

Author(s):

Xiaoqin Ha ◽

Xiaoling Cai ◽

Huizhe Cao ◽

Jie Li ◽

Bo Yang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Effective Means ◽

Model Assessment ◽

High Concentration ◽

Obesity And Diabetes ◽

Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

Download Full-text

Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes

Acta Endocrinologica ◽

10.1530/eje-12-0374 ◽

2012 ◽

Vol 167 (4) ◽

pp. 569-578 ◽

Cited By ~ 34

Author(s):

Francisco J Ortega ◽

Mónica Sabater ◽

José M Moreno-Navarrete ◽

Neus Pueyo ◽

Patricia Botas ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Lipid Metabolism ◽

Inflammatory Markers ◽

Low Grade ◽

Model Assessment ◽

Glucose And Lipid Metabolism ◽

Obese Subjects

ObjectiveIncreased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance.DesignWe performed both cross-sectional and longitudinal (diet-induced weight loss) studies.MethodsCirculating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (SI, Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19).ResultsCirculating calprotectin was significantly increased in IGT–T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin withSIwas independent of BMI and age. In fact,SItogether with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR.ConclusionThese findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity.

Download Full-text

Correlation between markers of renal function and sight-threatening diabetic retinopathy in type 2 diabetes: a longitudinal study in an Indian clinic population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001325 ◽

Cited By ~ 1

Author(s):

Ramachandran Rajalakshmi ◽

Coimbatore Subramanian Shanthi Rani ◽

Ulagamathesan Venkatesan ◽

Ranjit Unnikrishnan ◽

Ranjit Mohan Anjana ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Serum Creatinine ◽

Cox Regression ◽

Tertiary Care ◽

Cox Regression Analysis ◽

Increased Risk ◽

New Onset

IntroductionPrevious epidemiological studies have reported on the prevalence of diabetic kidney disease (DKD) and diabetic retinopathy (DR) from India. The aim of this study is to evaluate the effect of DKD on the development of new-onset DR and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2D).Research design and methodsThe study was done on anonymized electronic medical record data of people with T2D who had undergone screening for DR and renal work-up as part of routine follow-up at a tertiary care diabetes center in Chennai, South India. The baseline data retrieved included clinical and biochemical parameters including renal profiles (serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria). Grading of DR was performed using the modified Early Treatment Diabetic Retinopathy Study grading system. STDR was defined as the presence of proliferative diabetic retinopathy (PDR) and/or diabetic macular edema. DKD was defined by the presence of albuminuria (≥30 µg/mg) and/or reduction in eGFR (<60 mL/min/1.73 m2). Cox regression analysis was used to evaluate the hazard ratio (HR) for DR and STDR.ResultsData of 19 909 individuals with T2D (mean age 59.6±10.2 years, mean duration of diabetes 11.1±12.1 years, 66.1% male) were analyzed. At baseline, DR was present in 7818 individuals (39.3%), of whom 2249 (11.3%) had STDR. During the mean follow-up period of 3.9±1.9 years, 2140 (17.7%) developed new-onset DR and 980 individuals with non-proliferative DR (NPDR) at baseline progressed to STDR. Higher serum creatinine (HR 1.5, 95% CI 1.3 to 1.7; p<0.0001), eGFR <30 mL/min/1.73 m2 (HR 4.9, 95% CI 2.9 to 8.2; p<0.0001) and presence of macroalbuminuria >300 µg/mg (HR 3.0, 95% CI 2.4 to 3.8; p<0.0001) at baseline were associated with increased risk of progression to STDR.ConclusionsDKD at baseline is a risk factor for progression to STDR. Physicians should promptly refer their patients with DKD to ophthalmologists for timely detection and management of STDR.

Download Full-text

Proinsulin to insulin ratio is associated with incident type 2 diabetes but not with vascular complications in the KORA F4/FF4 study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001425 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001425

Author(s):

Cornelia Then ◽

Christina Gar ◽

Barbara Thorand ◽

Cornelia Huth ◽

Holger Then ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Waist Circumference ◽

Vascular Complications ◽

Model Assessment ◽

Incident Type ◽

The Metabolic Syndrome ◽

Incident Type 2 Diabetes

IntroductionWe investigated the association of the proinsulin to insulin ratio (PIR) with prevalent and incident type 2 diabetes (T2D), components of the metabolic syndrome, and renal and cardiovascular outcomes in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006–2008)/FF4 study (2013–2014).Research design and methodsThe analyses included 1514 participants of the KORA F4 study at baseline and 1132 participants of the KORA FF4 study after a median follow-up time of 6.6 years. All-cause and cardiovascular mortality as well as cardiovascular events were analyzed after a median time of 9.1 and 8.6 years, respectively. The association of PIR with T2D, renal and cardiovascular characteristics and mortality were assessed using logistic regression models. Linear regression analyses were used to assess the association of PIR with components of the metabolic syndrome.ResultsAfter adjustment for sex, age, body mass index (BMI), and physical activity, PIR was associated with prevalent (OR: 2.24; 95% CI 1.81 to 2.77; p<0.001) and incident T2D (OR: 1.66; 95% CI 1.26 to 2.17; p<0.001). PIR was associated with fasting glucose (β per SD: 0.11±0.02; p<0.001) and HbA1c (β: 0.21±0.02; p<0.001). However, PIR was not positively associated with other components of the metabolic syndrome and was even inversely associated with waist circumference (β: −0.22±0.03; p<0.001), BMI (β: −0.11±0.03; p<0.001) and homeostatic model assessment of insulin resistance (β: −0.22±0.02; p<0.001). PIR was not significantly associated with the intima-media thickness (IMT), decline of kidney function, incident albuminuria, myocardial infarction, stroke, cardiovascular or all-cause mortality.ConclusionsIn the KORA F4/FF4 cohort, PIR was positively associated with prevalent and incident T2D, but inversely associated with waist circumference, BMI and insulin resistance, suggesting that PIR might serve as a biomarker for T2D risk independently of the metabolic syndrome, but not for microvascular or macrovascular complications.

Download Full-text

Decreased Plasma Maresin 1 Concentration Is Associated with Diabetic Foot Ulcer

Mediators of Inflammation ◽

10.1155/2020/4539035 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Tian Miao ◽

Bangliang Huang ◽

Niexia He ◽

Lihua Sun ◽

Guangsheng Du ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Diabetic Foot ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Model Assessment ◽

Homeostasis Model Assessment

Aims. To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. Methods. Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n=43), type 2 diabetes (T2DM, n=40), or diabetic foot ulcer (DFU, n=13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. Results. Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P<0.001) and were lowest in DFU patients among these 3 groups. (DFU vs. T2DM, P<0.05). Plasma MaR1 concentrations were negatively correlated with BMI, waist circumference (Wc), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-c, FPG, 2hPG, HbA1c, and homeostasis model assessment for insulin resistance (HOMA-IR) (all P<0.05) and were positively correlated with HDL-c, acute insulin response (AIR), area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and homeostasis model assessment for beta-cell function (HOMA-β) (all P<0.05). After adjusting for age and sex, Wc, WHR, TG, FPG, 2hPG, HbA1c, HOMA-IR, AIR, AUC, and HOMA-β remain statistically significant (all P<0.05). Conclusions. Plasma MaR1 concentration were decreased in T2DM with or without DFUs and were the lowest in DFU patients. The decreased plasma MaR1 strongly associated with obesity, impaired glucose and lipid metabolism, reduced first-phase of glucose-stimulated insulin secretion, and enhanced insulin resistance.

Download Full-text

Electroacupuncture and Rosiglitazone Combined Therapy as a Means of Treating Insulin Resistance and Type 2 Diabetes Mellitus: A Randomized Controlled Trial

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/969824 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Rong-Tsung Lin ◽

Huei-Chin Pai ◽

Yu-Chen Lee ◽

Chung-Yuh Tzeng ◽

Chin-Hsien Chang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Combined Therapy ◽

Hypoglycemic Activity ◽

Model Assessment ◽

Significant Difference ◽

Plasma Ffa

Aims.To evaluate the efficacy of rosiglitazone (TZD) and electroacupuncture (EA) combined therapy as a treatment for type 2 diabetes mellitus (T2DM) patients by randomized single-blind placebo controlled clinical trial.Methods.A total of 31 newly diagnostic T2DM patients, who fulfilled the study's eligibility criteria, were recruited. The individuals were randomly assigned into two groups, the control group (TZD,N=15) and the experimental group (TZD + EA,N=16). Changes in their plasma free fatty acid (FFA), glucose, and insulin levels, together with their homeostasis model assessment (HOMA) indices, were statistically compared before and after treatment. Hypoglycemic activity (%) was also compared between these two groups.Results.There was no significant difference in hypoglycemic activity between the TZD and TZD + EA group. The effectiveness of the combined therapy seems to derive from an improvement in insulin resistance and a significant lowering of the secreted insulin rather than the effect of TZD alone on T2DM. The combined treatment had no significant adverse effects. A lower plasma FFA concentration is likely to be the mechanism that causes this effect.Conclusion.This combined therapy seems to suppress endogenous insulin secretion by improving insulin resistance via a mechanism involving a reduction in plasma FFA. This trial is registered with ClinicalTrials.govNCT01577095.

Download Full-text