Tissue inhibitor matrix metalloproteinase 1 and risk of type 2 diabetes in a Chinese population

IntroductionThe non-invasive enhanced liver fibrosis (ELF) score—comprising tissue inhibitor of matrix metalloproteinases-1 (TIMP1), hyaluronic acid (HA) and amino-terminal propeptide of type III procollagen (PIIINP)—has been shown to accurately predict fibrosis stages among patients with non-alcoholic fatty liver disease (NAFLD). However, no study has examined whether the ELF score or its components would also be predictive of type 2 diabetes, which commonly coexists and shares the same pathogenic abnormalities with NAFLD. Therefore, we prospectively investigated their associations with type 2 diabetes risks for the first time.Research design and methodsThe ELF score was measured among 254 type 2 diabetes cases and 254 age-matched and sex-matched controls nested within the prospective Singapore Chinese Health Study. Cases had hemoglobin A1c (HbA1c) levels <6.5% at blood collection (1999–2004) and reported to have diabetes during follow-up II (2006–2010). Controls had HbA1c levels <6.0% at blood-taking and remained free of diabetes at follow-up II. Multivariable conditional logistic regression models were used to assess the ELF-diabetes association.ResultsHigher TIMP1 levels were associated with increased type 2 diabetes risk, and the OR comparing the highest versus lowest quartiles was 2.56 (95% CI 1.23 to 5.34; p trend=0.035). However, ELF score, PIIINP and HA were not significantly associated with type 2 diabetes risks.ConclusionsHigher TIMP1 levels, but not ELF score, PIIIMP and HA, were associated with increased type 2 diabetes risk in Chinese adults. Our results suggested that elevated TIMP1 levels may contribute to the type 2 diabetes development through pathways other than liver fibrosis.

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Hormonal factors and type 2 diabetes risk in women: a 22 year follow-up study on more than 83 000 women from the E3N cohort study

Endocrine Abstracts ◽

10.1530/endoabs.63.oc11.1 ◽

2019 ◽

Author(s):

Sopio Tatulashvili ◽

Gaelle Gusto ◽

Beverley Balkau ◽

Emmanuel Cosson ◽

Fabrice Bonnet ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cohort Study ◽

Diabetes Risk ◽

Hormonal Factors ◽

Follow Up Study

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Serum levels of mac-2 binding protein are associated with diabetic microangiopathy and macroangiopathy in people with type 2 diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001189 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001189

Author(s):

Yoshitaka Hashimoto ◽

Masahide Hamaguchi ◽

Ayumi Kaji ◽

Ryosuke Sakai ◽

Noriyuki Kitagawa ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Liver Fibrosis ◽

Proliferative Diabetic Retinopathy ◽

Binding Protein ◽

Protein Glycosylation ◽

Diabetic Microangiopathy ◽

Alcoholic Fatty Liver ◽

Increased Risk

IntroductionNon-alcoholic fatty liver disease is reportedly associated with type 2 diabetes and progressive liver fibrosis, as evaluated by transient elastography, and has been linked with micro- and macroangiopathy in people with type 2 diabetes. The purpose of this cross-sectional study was to investigate the association between serum mac-2 binding protein glycosylation isomer (M2BPGi) levels and diabetic complications in people with type 2 diabetes.Research design and methodsSerum M2BPGi levels were measured in terms of cut-off index (C.O.I.) units. Urinary albumin excretion (UAE) was calculated and nephropathy was graded as normoalbuminuria, microalbuminuria, or macroalbuminuria. Retinopathy was divided into three groups: no-diabetic retinopathy (NoDR), non-proliferative-diabetic retinopathy (NPDR), or proliferative-diabetic retinopathy (PDR) .ResultsThe mean age for the 363 studied subjects (212 males) was 66.4±10.6 years, the median serum M2BPGi level was 0.77 (0.57–1.04) C.O.I., and the median UAE was 22 (9–82.1) mg/g creatinine. M2BPGi levels in microalbuminuria (0.83 (0.61 to 1.18) C.O.I.) and macroalbuminuria (0.88 (0.67 to 1.22) C.O.I.) cases were higher than those in normoalbuminuria cases (0.71 (0.54 to 0.92) C.O.I.). M2BPGi levels in NPDR (0.93 (0.68 to 1.28) C.O.I.) and PDR (0.95 (0.71 to 1.31) C.O.I.) cases were higher than in cases with NoDR (0.73 (0.56 to 0.99) C.O.I.). Furthermore, M2BPGi levels in subjects with a history of cardiovascular diseases were higher than in those with no such history (0.82 (0.65 to 1.22) vs 0.76 (0.55 to 1.03) C.O.I., p=0.019). The logarithm of (M2BPGi+1) was associated with the logarithm of UAE values after adjusting for covariates (standardized β=0.107, p=0.031).ConclusionsThis study reveals a close association between serum M2BPGi levels and diabetic microangiopathy and macroangiopathy in people with type 2 diabetes. The results also show that liver fibrosis, evaluated by M2BPGi, is independently associated with an increased risk of albuminuria.

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Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Nature Communications ◽

10.1038/s41467-021-26536-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chuanyan Wu ◽

Yan Borné ◽

Rui Gao ◽

Maykel López Rodriguez ◽

William C. Roell ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Genome Wide Association Study ◽

Regulatory Protein ◽

Alcoholic Fatty Liver ◽

Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

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Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Diabetologia ◽

10.1007/s00125-019-05001-w ◽

2019 ◽

Vol 62 (12) ◽

pp. 2298-2309 ◽

Cited By ~ 16

Author(s):

Ari V. Ahola-Olli ◽

Linda Mustelin ◽

Maria Kalimeri ◽

Johannes Kettunen ◽

Jari Jokelainen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Young Adults ◽

Fasting Glucose ◽

Diabetes Risk ◽

Increased Risk ◽

Metabolic Biomarkers ◽

Incident Cases ◽

Future Diabetes

Abstract Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.

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Variability in estimated glomerular filtration rate and the incidence of type 2 diabetes: a nationwide population-based study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001187 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001187

Author(s):

You-Bin Lee ◽

Da Hye Kim ◽

Eun Roh ◽

So-Hyeon Hong ◽

Jung A Kim ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Filtration Rate ◽

Estimated Glomerular Filtration Rate ◽

Diabetes Risk ◽

Incident Type ◽

Incident Type 2 Diabetes

ObjectiveVariability in estimated glomerular filtration rate (eGFR) has been associated with adverse outcomes in patients with diabetes or chronic kidney disease (CKD). However, no previous study has explored the relationship between eGFR variability and type 2 diabetes incidence.Research design and methodsIn this nationwide, longitudinal, cohort study, we investigated the association between eGFR variability and type 2 diabetes risk using the Korean National Health Insurance Service datasets from 2002 to 2017. eGFR variability was calculated using the variability independent of the mean (eGFR-VIM), coefficient of variation (eGFR-CV), standard deviation (eGFR-SD) and average real variability (eGFR-ARV).ResultsWithin 7 673 905.58 person-years of follow-up (mean follow-up: 3.19 years; n=2 402 668), 11 981 cases of incident type 2 diabetes were reported. The HRs and 95% CIs for incident type 2 diabetes increased according to advance in quartiles of eGFR-VIM (HR (95% CI): Q2, 1.068 (1.009 to 1.130); Q3, 1.077 (1.018 to 1.138); Q4, 1.203 (1.139 to 1.270)) even after adjusting for confounding factors including mean eGFR and mean fasting plasma glucose levels. The subgroup analyses according to risk factors as well as analyses using eGFR-CV, eGFR-SD and eGFR-ARV showed consistent results. The association between increased eGFR variability and type 2 diabetes risk was more prominent in men, individuals with dyslipidemia and those with CKD as shown in the subgroup analysis (p for interaction <0.001).ConclusionsIncreased eGFR variability may be an independent predictor of type 2 diabetes and might be useful for risk stratification of individuals without diabetes.

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Low-, medium- and high-glycaemic index carbohydrates and risk of type 2 diabetes in men

British Journal Of Nutrition ◽

10.1017/s000711451000485x ◽

2010 ◽

Vol 105 (8) ◽

pp. 1258-1264 ◽

Cited By ~ 19

Author(s):

Minna E. Similä ◽

Liisa M. Valsta ◽

Jukka P. Kontto ◽

Demetrius Albanes ◽

Jarmo Virtamo

Keyword(s):

Type 2 Diabetes ◽

Glycaemic Index ◽

Diabetes Risk ◽

Glycaemic Load ◽

Nutrient Density ◽

Cox Proportional Hazard ◽

Diet History Questionnaire ◽

Diet History

Findings on dietary glycaemic index (GI) and glycaemic load (GL) as risk factors for type 2 diabetes have been controversial. We examined the associations of dietary GI and GL and the associations of substitution of lower-GI carbohydrates for higher-GI carbohydrates with diabetes risk in a cohort of Finnish men. The cohort consisted of 25 943 male smokers aged 50–69 years. Diet was assessed, at baseline, using a validated diet history questionnaire. During a 12-year follow-up, 1098 incident diabetes cases were identified from a national register. Cox proportional hazard modelling was used to estimate the risk of diabetes, and multivariate nutrient density models were used to examine the effects of substitution of different carbohydrates. Dietary GI and GL were not associated with diabetes risk; multivariate relative risk (RR) for highest v. lowest quintile for GI was 0·87 (95 % CI 0·71, 1·07) and for GL 0·88 (95 % CI 0·65, 1·17). Substitution of medium-GI carbohydrates for high-GI carbohydrates was inversely associated with diabetes risk (multivariate RR for highest v. lowest quintile 0·75, 95 % CI 0·59, 0·96), but substitution of low-GI carbohydrates for medium- or high-GI carbohydrates was not associated with the risk. In conclusion, dietary GI and GL were not associated with diabetes risk, and substitutions of lower-GI carbohydrates for higher-GI carbohydrates were not consistently associated with a lower diabetes risk. The associations of dietary GI and GL with diabetes risk should be interpreted by considering nutritional correlates, as foods may have different properties that affect risk.

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Cytokeratin-18 and enhanced liver fibrosis scores in type 1 and type 2 diabetes and effects of two different insulins

Journal of Investigative Medicine ◽

10.1136/jim-2017-000609 ◽

2017 ◽

Vol 66 (3) ◽

pp. 661-668 ◽

Cited By ~ 1

Author(s):

Arun Sanyal ◽

Kenneth Cusi ◽

Mark L Hartman ◽

Shuyu Zhang ◽

Edward J Bastyr ◽

...

Keyword(s):

Type 2 Diabetes ◽

Liver Fibrosis ◽

Liver Fat ◽

Phase Iii ◽

Cytokeratin 18 ◽

Alcoholic Fatty Liver ◽

Link Type ◽

Group Population

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

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MON-644 Prevalence of Non-Alcoholic Fatty Liver Disease and Liver Fibrosis in Patients with Type 2 Diabetes Mellitus

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1748 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Nada Fanous ◽

Fernando Bril ◽

Eddison Godinez Leiva ◽

Srilaxmi Kalavalapalli ◽

Kenneth Cusi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Liver Disease ◽

Liver Fibrosis ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Severe Fibrosis

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The more severe form is non-alcoholic steatohepatitis (NASH) which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NASH is more common in patients with type 2 diabetes mellitus (T2DM). However, its true prevalence in unselected patients with T2DM in the United States remains unknown. In 2019, the American Diabetes Association recommended screening for NASH and liver fibrosis in all patients with T2DM with steatosis and/or elevated ALT. Screening focuses on liver fibrosis as associated with increased risk of cirrhosis and HCC. Still, a liver biopsy remains the gold standard to accurately assess the severity of liver disease. The aim of this study was to determine the prevalence of liver fibrosis in unselected patients with T2DM presenting to primary care or endocrinology clinics at a university hospital in the US. Secondary outcomes were to assess the prevalence of steatosis controlled attenuation parameter (CAP) and performance of vibration-controlled transient elastography (VCTE) as a non-invasive tool to identify patients with significant liver fibrosis. Patients with T2DM between ages of 21-79 and without a history of alcohol intake or other causes secondary causes of NAFLD were recruited for the study. Participants underwent screening for NAFLD at the time of their clinic visit by means of point-of-care CAP and VCTE. Initial evaluation also included obtaining patient demographics, routine chemistries, and fasting samples (on visit #2 if not fasting initially) for metabolic measurements and fibrosis biomarkers. Liver biopsies were offered to patients with a liver stiffness measurement (LSM) ≥8.0 kPa (i.e., highly likely to have moderate-to-severe fibrosis or ≥F2), or those with ≥7 kPa if AST ≥20 and had an APRI and/or FIB-4 score suggestive of being at high-risk of liver fibrosis (i.e., at least mild-to-moderate fibrosis or ≥F1). A total of 469 patients were recruited (age 59±12; 56% females; 60% non-Hispanic whites, 30% African Americans, 4% Asian; BMI 33±6 Kg/m2; A1c 7.5±1.7%; FPG 143±60 mg/dL; AST 22±11 U/L; ALT 24±17 U/L; triglycerides 156±151 mg/dL; LDL-C 88±37 mg/dL; HDL-C 47±13 mg/dL). The prevalence of NAFLD by CAP (≥280) was 67% with a mean CAP of 305±3. The prevalence of any fibrosis was 24% patients. Among those with fibrosis, 15% had moderate-to-severe fibrosis or ≥F2. In those that underwent a liver biopsy, 61% had moderate-to-severe fibrosis (F2-3). Our ongoing study demonstrates the high prevalence of liver steatosis and fibrosis in patients with T2DM. NASH is a common but under-recognized complication of T2DM that requires greater awareness among clinicians taking care of patients with diabetes. While the optimal screening strategy remains unclear, an approach based on plasma biomarkers and CAP/VCTE deserves further exploration moving forward.

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Non-alcoholic fatty liver disease, cytokeratin-18, and risk of type 2 diabetes mellitus: A cohort study

10.21203/rs.2.16214/v1 ◽

2019 ◽

Author(s):

Ruofan Hu ◽

Shaoyong Xu ◽

Han Shen ◽

Ce Jing ◽

Aihua Jia ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cohort Study ◽

Fatty Liver Disease ◽

Cytokeratin 18 ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Abstract Background & Aims: Although many studies have shown that non-alcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM), no cohort study has explored the relationship between the histopathological grade of NAFLD and the risk of T2DM in NAFLD patients. We aimed to explore whether a higher concentration of cytokeratin-18 (CK-18), as a reliable marker of hepatic fibrosis, was associated with a greater risk of T2DM in patients with NAFLD. Methods: The population-based cohort study was based on China National Diabetes and Metabolic Disorders Survey with a follow-up of five years. NAFLD was determined by ultrasonography. T2DM were diagnosed based on oral glucose tolerance test. Serum CK-8 was measured using the M30 Apoptosense ELISA kit. Results: 457 subjects were enrolled and three groups were analyzed: a non-NAFLD group (n=363), a low-CK-18 NAFLD group (n=46), and a high-CK-18 NAFLD group (n=48). 20 (3.9%) developed diabetes during follow-up. The incidence of T2DM was 2.5%, 8.7%, and 12.5% in the non-NAFLD, low-CK-18 NAFLD, and high-CK-18 NAFLD groups, respectively. Cox proportional hazard regression showed that, compared with the non-NAFLD group, the adjusted relative risks of T2DM were 3.37 (95% CI: 1.05-10.86, P =0.042) and 4.71 (95% CI: 1.71-12.99, P =0.003), respectively, in the low-CK-18 NAFLD and high-CK-18 NAFLD groups. Conclusions: Higher CK-18 level in ultrasound-diagnosed NAFLD patients is associated with higher risk of T2DM. We recommend screening for NAFLD using ultrasound in the first instance, with, if possible, CK-18 assay being subsequently used to screen individuals at higher risk of diabetes.

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The Association between Sleep Quality and Type Two Diabetes at 20 Year Follow-up in the Southall And Brent REvisited (SABRE) Cohort: a Tri-ethnic Analysis

10.1101/2020.08.23.20157073 ◽

2020 ◽

Author(s):

Zhen Ling Ong ◽

Nishi Chaturvedi ◽

Therese Tillin ◽

Caroline Dale ◽

Victoria Garfield

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Sleep Quality ◽

South Asians ◽

Diabetes Risk ◽

Poor Sleep ◽

Falling Asleep ◽

Traditional Risk Factors

Objective: The risk of developing type 2 diabetes associated with poor sleep quality is comparable to that of traditional risk factors (e.g. overweight, physical inactivity). In the United Kingdom, these traditional risk factors could not explain the two to three-fold excess risks in South Asian and African Caribbean men compared to Europeans. This study investigates the (i)the association between mid-life sleep quality and later-life type 2 diabetes risk and (ii)a potential modifying effect of ethnicity. Research Design and Methods: The Southall and Brent REvisited (SABRE) cohort comprised Europeans, South Asians, and African Caribbeans (median follow-up = 19 years). Complete case analysis was performed on 2190 participants without diabetes at baseline (age= 51.7 ± 7SD). Competing risks regressions were used to estimate the hazard ratios (HRs) of developing type 2 diabetes associated with four self-reported baseline sleep exposures (difficulty falling asleep, early morning waking, waking up tired and snoring) while adjusting for confounders. Modifying effects of ethnicity were analysed by (i) testing for interactions and (ii) performing ethnicity-stratified analysis. Results: Snoring was strongly associated with increased type 2 diabetes risk but only among South Asians in a fully-adjusted model (HR 1.42, 95%CI=1.08-1.85, P=0.011). Our results revealed no elevated risk for any of the sleep exposures across all three ethnic groups. Conclusions: The association between snoring and type 2 diabetes appeared to be modified by ethnicity, with South Asians at greatest risk.

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