General Nondiabetic Population Research Articles

The Association Between Metabolic Syndrome, Hyperfiltration, and Long-Term GFR Decline in the General Population

One-quarter of adults worldwide meet the criteria of metabolic syndrome (MetS). MetS increases the risk of diabetes, chronic kidney disease (CKD), and cardiovascular disease. However, the association between MetS, hyperfiltration, and long-term glomerular filtration rate (GFR) decline in the general population is unknown. In the Renal Iohexol Clearance Survey (RENIS), we investigated 1551 people aged 50 to 63 years; representative of the general population without diabetes, cardiovascular disease, or kidney disease. The GFR was measured using iohexol clearance at baseline and twice during 11 years of follow-up. Hyperfiltration at baseline was defined as an absolute GFR (ml/min) above the 90th percentile adjusted for sex, age, and height, because these variables correlate with nephron number. MetS was defined as increased waist circumference and 2 risk factors among hypertension, hyperglycemia, elevated triglycerides, and low high density lipoprotein (HDL)-cholesterol levels. The GFR decline rate was calculated using linear mixed models. MetS was associated with hyperfiltration at baseline (odds ratio [OR] 2.4; 95% CI: 1.7-3.5, P< 0.001) and a steeper GFR decline rate during follow-up (-0.30 [-0.43 to-0.16] ml/min per 1.73 m2/yr). Compared to those without MetS, GFR decline was-0.83 (95% CI:-1.13 to-0.53) ml/min per 1.73 m2/yr in those with MetS and baseline hyperfiltration and-0.15 (-0.30 to 0.00) in those MetS without hyperfiltration, P= 0.2 for interaction. In the nondiabetic general population, those with MetS had an increased OR of hyperfiltration and steeper long-term GFR decline. Randomized controlled trials are needed to explore whether treatment of hyperfiltration can prevent loss of GFR in persons with MetS.

Creatine kinase is associated with glycated haemoglobin in a nondiabetic population. The Tromsø study.

Creatine kinase (CK) has been associated with insulin resistance and identified as a risk marker of cardiovascular disease largely by its relationship with hypertension and increased body mass index. This study determined whether CK is a predictor of glycated haemoglobin (HbA1C) in a nondiabetic general population. Associations between CK and the outcome variable HbA1C (%) were performed by variance and multivariate analyses in 11662 nondiabetic subjects defined as HbA1C (%) <6.5 who participated in the population based Tromsø study (Tromsø 6) in Norway. Abnormal elevated CK was detected in 543/11662 participants (4.66%). Mean HbA1C (%) in the "high CK" group was 5.62 (SD = 0.33) compared to 5.52 (SD = 0.36) in the "normal CK" group, P <0.001. CK increased significantly and linearly with higher levels of HbA1C (%) quartiles in women (P <0.001) and non-linearly in men (P <0.001). In a multivariate analysis, CK was independently associated with HbA1C (%) after adjusting for age, sex, body mass index, blood pressure, glucose, lipids, C-reactive protein, creatinine, alanine transaminase and aspartate aminotransferase. A 1-unit increase in log CK was associated with a 0.17-unit increase in HbA1C (%). These data demonstrate a positive and independent association between CK and glycated haemoglobin in a nondiabetic general population.

Association of triglyceride–glucose index and traditional risk factors with cardiovascular disease among non-diabetic population: a 10-year prospective cohort study

BackgroundThe triglyceride–glucose (TyG) index is known as a reliable alternative marker of insulin resistance (IR), which has been regarded as a predictor of cardiovascular disease (CVD). However, whether TyG index can predict the risk and occurrence of CVD in non-diabetic population remains uncertain. The aim of this study was to explore the association between the TyG index and cardiovascular risk factors and to clarify the prognostic value of the TyG index for CVD, coronary heart disease (CHD) and stroke in non-diabetic general population in Eastern China.MethodsA total of 6095 cases without diagnosed diabetes and CVD were included. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2) and the participants were divided into 4 groups according to the TyG index quartiles (Q1, Q2, Q3, Q4). The primary outcome was CVD, including CHD and stroke. Cox proportional hazards regression analysis was used to investigate the association between the TyG index and the risk of CVD.ResultsDuring the 10-year follow-up, 357 (5.9%) participants of CVD, 224 (3.7%) participants of CHD and 151 (2.5%) participants of stroke were observed. The incidence of CVD increased with the TyG index quartiles. Multivariate Cox regression analysis showed that the hazard ratios [95% confidence interval (CI)] in Q4 group were respectively 1.484 (1.074–2.051) for CVD, 1.687 (1.105–2.575) for CHD and 1.402 (0.853–2.305) for stroke compared to Q1 group. Moreover, adding the TyG index to models with traditional risk factors yielded a significant improvement in discrimination and reclassification of incident CVD and CHD.ConclusionsThe TyG index is associated with cardiovascular risk factors and can be used as a useful, low-cost predictive marker for CVD and CHD risk in non-diabetic population.

PSUN312 Interaction Between Insulin Sensitivity Status and Cex in control of Gene Expression in Human iPS Cell-Derived Myoblasts

Abstract Insulin resistance is a major risk factor in the development of type 2 diabetes, metabolic syndrome, polycystic ovarian disease, and many other disorders. About 25% of people within the general non-diabetic population are insulin resistant, and this has been shown to increase the risk for type 2 diabetes and cardiovascular disease. The aim of this study was to uncover the nature of the cell autonomous differences in gene expression that contribute to differences in insulin sensitivity and disease risk using induced pluripotent stem cell (iPSC) derived from humans at both ends of the insulin sensitivity spectrum, i.e., top 20% of insulin resistance vs. top 20% of insulin sensitive. We find that iPSCs differentiated into myoblasts (iMyos) from non-diabetic individuals in the highest quintile of insulin resistance (I-Res) show impaired insulin signaling, defective insulin-stimulated glucose uptake, and decreased glycogen synthase activity compared to iMyos from the insulin sensitive individuals (I-Sen), indicating these cells mirror in vitro the alterations seen in vivo. Transcriptomic analysis of these iMyos revealed a major effect of insulin resistance on gene expression, but an even larger, and unexpected, effect of sex of the donor on gene expression ex vivo. Thus, in cells from male donors, there were 184 significantly up-regulated and 167 significantly down-regulated genes in iMyos from I-Res vs I-Sen donors. The I-Res up-regulated genes were mostly related to the extracellular matrix organization and integrin signaling pathways, while the down-regulated genes belonged to immuno-regulatory pathways (p&amp;lt;0.05). Interestingly, in cells from females, distinct genes expression differences marked insulin resistance. Thus, iMyos from females showed up-regulation of 69 genes in the I-Res subgroup linked to cellular senescence and response to stress (p&amp;lt;0.05). In addition, and more strikingly, we also observed over 1500 sex-specific changes in gene expression that were independent of the insulin sensitivity status, with 766 genes significantly higher in cells from male donors and 786 genes higher in cells from female donors (FDR&amp;lt;0.2). Chromosomal positional analysis of the most sex-biased genes (FC&amp;gt;1.5) showed that only 7% of the differentially expressed genes were encoded by the X- or Y-chromosomes, while the remainder were spread across the autosomes. Furthermore, a comparison of the RNA sequencing data from these cell lines at the iPS cell and iMyos stage showed that X chromosome inactivation during the myoblast differentiation process was normal and that the sex-specific changes were not due to differences in X chromosome dosage in males and females but represent either persistent epigenetic changes and/or crosstalk between X and Y encoded genes and autosomal genes. Thus, insulin sensitivity status and patient sex interact to produce changes in gene expression that can contribute to how insulin resistance and other diseases are manifest differently in men and women. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

1122-P: Subgroup Analysis to Evaluate Individuals at Risk for Incident Diabetes

Since type 2 diabetes (T2D) is a heterogenous disease, treatment of T2D appears to be better personalized depending on their underlining conditions. A recent attempt to classify adult-onset DM based on only 6 DM related variables (GAD antibodies, age at diagnosis, BMI, HbA1c, and HOMA2 indices) , showed that DM can be classified into 5 clusters, among them 4 represent T2D (Lancet Diabetes Endocrinol. 2018;6:361) . We here classified non-diabetic population to find risk cluster for incident DM, or to extend strategies for prevention of T2D. The participants were recruited from Iwaki study, a health promotion study of Japanese people. Among 1167 participants in 2014 (baseline) , 868 non-diabetic individuals who attended at least one time in 2015 to 20were included in this prospective study. A hierarchical cluster analysis was performed based on 5 variables (age, BMI, HbA1c, HOMA2-β, and HOMA2-IR) . The hazard ratios (HRs) for incident T2D of clusters observed were examined using Cox proportional hazards model. Traits (mean) of 5 clusters observed were as follows: age (clusters; 1: 60.1, 2: 58.7, 3: 63.6, 4: 36.1, 5: 48.3) , BMI (1: 20.8, 2: 24.2, 3: 22.9, 4: 20.7, 5: 27.7) , HbA1c (1: 5.54, 2: 5.67, 3: 6.01, 4: 5.41, 5: 5.73) , HOMA2-β (1: 82.8, 2: 101.8, 3: 78.5, 4: 101.4, 5: 143.1) , and HOMA2-IR (1: 0.53, 2: 0.79, 3: 0.73, 4: 0.57, 5: 1.16) . The HR for incident T2D was significantly higher in cluster 3 than in clusters 1, 2, and 4, even after adjustment for age and sex (HR (p) : 5.00 (0.005) , 4.90 (0.005) , and 10.4 (0.048) , respectively) . Accordingly, cluster 3 had significantly higher age and HbA1c than other clusters, lower HOMA2-β than clusters 2, 4, and 5, and lower HOMA2-IR and BMI than clusters 2 and 5. In summary, cluster analysis of a general non-diabetic population revealed a risk cluster for incident T2D, and, thus, individuals with characteristics representing the cluster (less insulin resistant but decreased insulin secretion, older age, and poor metabolic control) should be a target for prevention of incident T2D. Disclosure R.Ito: None. M.Daimon: None. S.Mizushiri: None. S.Ono: None. Y.Nishiya: None. A.Tamura: None. M.Murabayashi: None. A.Kamba: None.

MO433: Nitric-Oxide Precursors and Dimethylarginines as Risk Factors for Accelerated GFR Decline in the Non-Diabetic General Population

Abstract BACKGROUND AND AIMS Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, vasoconstriction, atherosclerosis and chronic kidney disease (CKD) [1]. Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. The worldwide prevalence of CKD is increasing and is a major contributor to morbidity and mortality. Differences in glomerular filtration rate (GFR) are only partly explained by conventional CKD risk factors [2]. Therefore, we investigated the association of serum levels of endogenous inhibitors of NO, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) and precursors of NO, arginine, citrulline and ornithine, with a decline in GFR and new-onset CKD. METHOD In a prospective cohort study of 1407 participants in the Renal Iohexol Clearance Survey (RENIS) without self-reported kidney disease, cardiovascular disease, or diabetes, GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years [3]. GFR decline rates were analysed using a linear mixed model, new-onset CKD (GFR &amp;lt; 60 ml/min/1.73 m2) with interval-censored Cox regression and accelerated GFR decline (the 10% with the steepest GFR decline) with logistic regression. RESULTS Neither ADMA nor arginine was associated with any outcomes. Higher SDMA was associated with a slower annual GFR decline and a lower arginine/dimethylarginine ratio with a steeper GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline with an odds ratio (OR) of 1.43 [95% confidential interval (CI) 1.16–1.76] per standard deviation (SD) higher citrulline and an OR of 1.23 (95% CI 1.01–1.49) per SD increase in ornithine (Table 1). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.31 (95% CI 1.05–1.63) per SD higher citrulline. CONCLUSION Associations between NO precursors and the outcomes suggest that NO-metabolism plays a significant role in the pathogenesis of age-related GFR decline, and the development of CKD in middle-aged people. Our findings warrant further investigation into the pathogenesis of NO-metabolism and the possible therapeutic targets and preventive measures.

White-coat hypertension and arterial stiffness

The objective of our work was to study the relationship between White-coat hypertension (WCT) and vascular dysfunction in a general non-diabetic population. We included patients between the ages of 30 and 70. They all benefited from a clinical and biological assessment. Blood pressure was measured in consultation, and at home by an ambulatory blood pressure monitoring (ABPM) by Tonoport V GE®. We performed a measurement of the carotido-femoral pulse wave velocity (cfPWV) (Sphygmocor®), a search for carotid atherosclerotic plaque (CAP), and an Ankle-Brachial Index (ABI). We have adopted the recommendations of the European Societies of Cardiology and High Blood Pressure to retain the diagnosis of WCT (a consultation BP ≥ 140/90 mmHg and an average BP of 24 hours < 135/85 mmHg). Statistics: SPSS 21.0 software. In total, 333 participants aged 46.8 ± 9.9 years were included [170 women (51.1%)]. The average consultation BP was 128.8 ± 17.7/77.7 ± 7.0 mmHg. In ABPM, the average 24-hour BP: 125.5 ± 11.90/117.4 ± 78.8 mmHg, daytime: 129.0 ± 12.1/82.1 ± 9.9 mmHg, and nocturnal: 115.9 ± 13.2/68.7 ± 9.6 mmHg; 16.8% ( n = 56) WCT, 43.5% ( n = 145) normo tension (NT), 25.2% ( n = 84) masked hypertension (MHT), 14.4% ( n = 48) confirmed hypertension (cHT). The average cfPWV of WCT patients (9.6 ± 2.4 m/s) was higher than that of the NT (8.5 ± 2.3 m/s), P = 0.007, and not statistically different from that of the MHT (9.36 ± 2.7 m/s, P = 0.5), and the cHT (10.7 ± 3.3 m/s, P = 0.06). CAPs were present at 6.9% NT, 26.8% WCT, 19% MHT, 20.8% cHT, respectively, P < 0.001. An ABI ≤ 0.9 was rated in 0.7% NT, 5.4% WCT, 6% MHT, and 16.7% cHT, P < 0.01. In multivariate analysis, MHT and fatty liver disease were the independent factors associated with high cfPWV (≥ 10 m/s). The results of our study suggest that people with WCT have higher cfPWV than normotensive people. However, this WCT does not appear to be an independent factor associated with high arterial stiffness.

Higher Frequency of Physical Activity Reduces the Risk of Kidney Function Loss in a General Non-Diabetic Population

Higher Frequency of Physical Activity Reduces the Risk of Kidney Function Loss in a General Non-Diabetic Population

Association of Metabolic Syndrome with Hyperfiltration in a General Non-Diabetic Population: The Renal Iohexol Clearance Survey

Association of Metabolic Syndrome with Hyperfiltration in a General Non-Diabetic Population: The Renal Iohexol Clearance Survey

Serum matrix metalloproteinase 7 and accelerated glomerular filtration rate decline in a general non-diabetic population.

BackgroundAge-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general non-diabetic population.MethodsIn the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1627 subjects aged 50–64 years without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 mL/min/1.73 m2/year) and incident CKD [GFR <60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol].ResultsHigher MMP7 levels (per standard deviation increase of MMP7) were associated with steeper GFR decline rates [−0.23 mL/min/1.73 m2/year (95% confidence interval −0.34 to −0.12)] and increased risk of accelerated GFR decline and incident CKD [odds ratios 1.58 (1.30–1.93) and 1.45 (1.05–2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors]. MMP2 and TIMP1 showed no association with GFR decline or incident CKD.ConclusionsThe pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population.

Association of High-Density Lipoprotein Cholesterol With GFR Decline in a General Nondiabetic Population

IntroductionAlthough lower high-density lipoprotein cholesterol (HDL-C) levels are considered a risk factor for cardiovascular disease (CVD), experimental evidence suggest that aging, inflammation, and oxidative stress may remodel HDL-C, leading to dysfunctional HDL-C. Population studies on HDL-C and loss of the glomerular filtration rate (GFR) reported inconsistent results, but they used inaccurate estimates of the GFR and may have been confounded by comorbidity.MethodsWe investigated the association of HDL-C levels with risk of GFR loss in a general population cohort; the participants were aged 50–62 years and did not have diabetes, CVD, or chronic kidney disease (CKD) at baseline. The GFR was measured using iohexol-clearance at baseline (n=1627) and at the follow-up (n=1324) after a median of 5.6 years. We also investigated any possible effect modification by low-grade inflammation, physical activity, and sex.ResultsHigher HDL-C levels were associated with steeper GFR decline rates and increased risk of rapid GFR decline (>3 ml/min per 1.73 m2 per year) in multivariable adjusted linear mixed models and logistic regression (–0.64 ml/min per 1.73 m2 per year [95% CI –0.99, –0.29; P < 0.001] and odds ratio 2.7 [95% CI 1.4, 5.2; P < 0.001] per doubling in HDL-C). Effect modifications indicated a stronger association between high HDL-C and GFR loss in physically inactive persons, those with low-grade inflammation, and men.ConclusionHigher HDL-C levels were independently associated with accelerated GFR loss in a general middle-aged nondiabetic population.

Declining mortality in older people with type 2 diabetes masks rising excess risks at younger ages: a population-based study of all-cause and cause-specific mortality over 13 years.

Excess mortality in people with vs without type 2 diabetes (T2DM) has fallen, but it is unclear whether men/women at all ages have benefited and which causes of death have driven these trends. All-cause and cause-specific mortality rates and excess mortality [by mortality rate ratios (MRRs) relative to the non-diabetic general population] were examined in 1268018 Australians with T2DM registered on the National Diabetes Services Scheme (2002-2014). Age-standardized mortality decreased in men (-2.2%/year; Ptrend < 0.001) and women with T2DM (-1.3%/year; Ptrend < 0.001) throughout 2002-14, which translated to declines in the MRRs (from 1.51 to 1.45 in men; 1.59 to 1.46 in women; Ptrend < 0.05 for both). Declining mortality rates in T2DM were observed in men aged 40+ years and women aged 60+ years (Ptrends <0.001), but not at younger ages. However, the only age group in which excess mortality declined relative to those without diabetes was 80+ years (Ptrends < 0.05); driven by reductions in excess cancer-related deaths in men and cardiovascular disease (CVD) in women. Among age groups <80 years, CVD and cancer MRRs remained similar or increased over time, despite falls in both CVD and cancer mortality rates. MRRs for non-CVD/non-cancer-related deaths increased in 60-79 year-olds, but were otherwise unchanged. Declining excess mortality attributable to T2DM from 2002-14 was driven entirely by reductions in those aged 80+ years. Declines in total mortality among those with T2DM were apparent in more age groups, but often to a lesser extent than in the general population, thereby serving to increase the excess risk associated with T2DM.

Profile of microalbuminuria in non-diabetic myocardial infarction

Background: Urinary albumin excretion between 20 to 200 mg per litre is defined as microalbuminuria (MAU). MAU acts as a marker for endothelial cell destruction and is associated with atherosclerosis in both diabetics and non-diabetics. This study aimed to assess the MAU prevalence in nondiabetic patients with myocardial infarction.Methods: A cross-sectional study was conducted at tertiary care hospital. Among non-diabetic patients with myocardial infarction. The study was conducted from October 2019 to March 2020. All patients were subjected to complete physical examination, electrocardiography (ECG) and echocardiography. Quantitative determination of MAU was done in a urine sample. Diagnostic coronary angiogram was performed for all patients. Appropriated statistical tests were applied.Results: Among 80 study participants, 73.75% were men, and 26.25% were women. Smoking habit was present among 60%, and 56.25% were hypertensive. The prevalence of microalbuminuria was 27.5%. A statistically significant difference was seen between TIMI scoring and presence of MAU (p&lt;0.001). The difference in vessels type between the microalbuminuria status was found to be significant (p=0.005).Conclusions: Evidence from this study shows that the presence of MAU had a strong association between myocardial infarction and its application as a risk factor of cardiovascular diseases in general non-diabetic population proves practical.

Association between insulin resistance and left ventricular diastolic dysfunction in non-diabetic general population

Abstract Background Insulin resistance due to visceral fat accumulation plays a central role in the development of diabetic mellitus and subsequent cardiovascular disease. Abdominal obesity and diabetic mellitus are associated with the progression of left ventricular diastolic dysfunction which is the major structural abnormality in patients with heart failure. However, whether insulin resistance influences left ventricular diastolic dysfunction in non-diabetic subjects is unclear. Purpose In this study, we aimed to clarify the association between insulin resistance and left ventricular diastolic dysfunction in non-diabetic general population. Methods We examined 2,572 non-diabetic subjects with preserved left ventricular systolic function (ejection fraction ≥50%) and without a past history of diabetic mellitus, heart failure, coronary artery disease, atrial fibrillation, stroke, moderate to severe valvular disease, who underwent medical check-ups at the University of Tokyo Hospital from January 2009 to December 2018. Diabetes mellitus was defined as fasting glucose level ≥126 mg/dL or a subject's use of oral antidiabetic medications or insulin. We calculated the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) score [HOMA-IR = fasting glucose (mg/dL) × insulin (μU/mL) / 405], and defined insulin resistance as HOMA-IR ≥2.5. Left ventricular diastolic function was assessed by echocardiography, using tissue doppler analysis (E/E' ratio in septal and lateral). Visceral adiposity was assessed as visceral fat volume measured by computed tomography scanner. Results Mean age was 53.3±9.8 years, and 1,746 subjects (67.9%) were male. Overall, HOMA-IR was 1.1 on average, and HOMA-IR ≥2.5 was observed in 5.0% of study population. BMI and the prevalence of obesity were higher in subjects with HOMA-IR ≥2.5 than in those without. There was no significant difference in left ventricular ejection fraction between HOMA-IR ≥2.5 and ≤2.5. E/E' ratio in septal and lateral were higher in subjects with HOMA-IR ≥2.5 than in those without. Multivariable logistic regression analysis demonstrated that obesity and waist circumference, visceral fat volume were independently associated with HOMA-IR ≥2.5, however, age, hypertension, hypercholesterolemia were not. Further, multiple regression analysis including insulin resistance, age, male gender, obesity, hypertension, hypercholesterolemia, cigarette smoking and visceral fat volume, showed that insulin resistance was an independent determinant of increasing E/E' in both septal and lateral, whereas visceral fat volume was not (Figure 1). Conclusion The results of the present study suggest that insulin resistance due to visceral fat accumulation might be associated with the development of left ventricular diastolic dysfunction in non-diabetic general population without overt cardiovascular disease. Figure 1 Funding Acknowledgement Type of funding source: None

Subclinical hypothyroidism is associated with albuminuria in Japanese nondiabetic subjects

Thyroid dysfunction is a risk factor of cardiovascular disease (CVD), and albuminuria is a predictor of CVD. For preventing the CVD, it is essential to clarify from which stage of thyroid dysfunction the risk of CVD starts developing. We thus investigated the association between subclinical thyroid dysfunction and albuminuria, focusing on a nondiabetic general population. We analyzed the data of 17,221 nondiabetic subjects who underwent annual health checkups by multivariate logistic regression analyses. Compared with the subjects with euthyroidism, those with subclinical hypothyroidism presented a higher prevalence of albuminuria. By a multivariate logistic regression analysis, subclinical hypothyroidism showed a significant and independent association with the high prevalence of albuminuria compared with euthyroidism (OR 1.64, 95% CI 1.21-2.21, p = 0.001). In accord with this result, the analysis in which the lowest quartile of thyroid stimulating hormone (TSH) concentration (<0.96 µIU/mL) was used as a reference revealed that the highest quartile (>2.07 µIU/mL) had a significant and independent association with the prevalence of albuminuria (OR 1.23, 95% CI 1.01-1.51, p = 0.04). One microliter unit per milliliter increase of the serum concentration of TSH also had a significant and independent association with the prevalence of albuminuria (OR 1.07, 95% CI 1.02-1.12, p = 0.006). The association between subclinical hyperthyroidism and the prevalence of albuminuria was not significant. Our data indicated that subclinical hypothyroidism was significantly and independently associated with the high prevalence of albuminuria.

Non-Alcoholic Fatty Liver Disease Treatment in Patients with Type 2 Diabetes Mellitus; New Kids on the Block.

Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population. The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures). Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified. Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.

1452-P: Association between Aging and Insulin Resistance and Secretion in a General Nondiabetic Population

Objective: Aging is one of the risks for abnormal glucose tolerance or diabetes. Although association between age and, insulin secretion and resistance has been reported in various cross sectional studies, few studies evaluated changes of insulin resistance and secretion along with aging. Research Design and Methods: Among participants of the population-based Iwaki study of Japanese, those participated consecutively from 2014 to 2017 and were nondiabetic were included in this study (Men/Women: 200/294; Age: 21-90 (54.2 ± 13.5)). The effects of aging on homeostasis model assessment indices for insulin resistance (HOMA-R) and β-cell function (HOMA-β) were examined. Results: During the 3-year periods, HOMA-R significantly increased (p&amp;lt;0.0001), while HOMA-β significantly decreased (p&amp;lt;0.0001). Repeatedly measures ANOVA with adjustments for possible confounding and/or intermediating factors showed that the increase in HOMA-R became insignificant after adjustment with factors related to adiposity such as BMI and leptin (p=0.564), while the decrease in HOMA-β stayed significant even after such adjustments (p=0.046). Despite the facts, stepwise multiple regression analysis showed significant association of leptin not only with increases in HOMA-R (p=0.022) but also with decreases in HOMA-β (p =0.003). Conclusion: Insulin resistance increases along with aging probably due to a simultaneous adiposity, while insulin secretion decreases along with aging at least in part independently of such adiposity. However, the association between leptin and decreases in HOMA-β may suggest that adiposity of β-cells may be in part blamed for the decreases. Further, leptin may be a marker to predict those at risk of decreasing insulin secretion. We are now examining such association in details in consideration with blood metabolites and amino acids levels. Disclosure T. Fujita: None. M. Daimon: None. H. Murakami: None. S. Mizushiri: None. Y. Matsuhashi: None. S. Osonoi: None. M. Murabayashi: None. K. Takahashi: None. Y. Nishiya: None.

Incidence and Risk Factors for Blindness in Adults With Diabetes: The Israeli National Diabetes Registry (INDR)

To estimate the 3-year incidence of blindness among diabetes patients aged ≥18 years; to compare blindness incidence rates of persons with and without diabetes; and to investigate risk factors associated with diabetic retinopathy (DR), age-related macular degeneration (ARMD), glaucoma, and cataract-related blindness. Cohort study. The Israeli National Diabetes Registry for 2012 was cross-linked with the database of blindness certifications obtained from the National Registry of the Blind. Blindness was defined as the receipt of an official certificate of blindness (a visual acuity of 3/60 or worse, or a visual field loss of <20 degrees in the better eye.) Incidence rates of blindness, overall and by main cause of blindness, were calculated for the years 2013-2015. Standardized morbidity ratios (SMRs) for 2013 were calculated, using the nondiabetic population as a reference. A multinomial logistic model was used to identify covariates associated with the incidence of blindness by main cause of blindness. The 3-year incidence rates were 31.0 and 8.4 per 10 000 for overall and DR-related blindness, respectively. The SMR for overall blindness in people with diabetes was significantly higher than in the general nondiabetic population (1.39; 95% confidence interval: 1.27-1.53); however, the SMRs for ARMD, glaucoma, and cataract were not statistically significant. Poor metabolic control, insulin treatment, long diabetes duration, and chronic kidney disease were associated with DR-related blindness. Low socioeconomic status (SES) was associated with both cataract and DR-related blindness. Optimum metabolic control of diabetes is important for prevention of DR-related blindness. SES-related disparities in blindness risk should be explored and reduced by directing efforts to provide appropriate treatment for all diabetic patients in order to prevent unnecessary blindness.

Abdominal fat deposits determined by magnetic resonance imaging in relation to leptin and vaspin levels as well as insulin resistance in the general adult population.

Various fat depots including visceral (VAT), subcutaneous adipose tissue (SAT) or liver fat content (LFC) were supposed to have different influences on various entities including adipokine levels as well as insulin resistance/sensitivity. Therefore, the aim of the study was to investigate the associations of SAT, VAT and LFC with the levels of leptin and vaspin as well as insulin resistance in a general non-diabetic population. In total, 1825 participants of the Study of Health in Pomerania were characterized according to body fat compartments and LFC determined by magnetic resonance imaging. Of those subjects, insulin resistance (HOMA-IR) and insulin sensitivity ([ISI(comp)) were determined in 981 participants and adipokines were assessed in 698 using enzyme-linked immunosorbent assay. Analyses of variance and linear regression models adjusted for age, sex, smoking, height, physical inactivity and alcohol consumption were used for analysis. Using the residual method to assess independently the effect of the various fat depots, a strong positive association of SAT (beta per standard deviation (s.d.) increase 0.54 (95% confidence interval (CI) 0.47-0.60)) but not VAT (beta 0.01 (95% CI -0.08 to 0.09)) and LFC (beta 0.01 (95% CI -0.06 to 0.08)) with log2-leptin levels was found independent of the HOMA-IR status. Moreover, a positive association of LFC (beta 0.17 (95% CI 0.07-0.26)) with log2-vaspin levels becomes apparent, which were mostly driven by subjects with a low HOMA-IR. With respect to HOMA-IR and ISI(comp) index, pronounced positive and inverse associations to all fat markers were revealed, respectively, with the strongest relation found for SAT and LFC. SAT and LFC were identified as predominant sites associated with leptin and vaspin levels, respectively. Residual analysis pointed towards a general adverse effect of disproportional triglyceride storage across physiological despots, in particular in ectopic sides such as the liver, with markers of insulin resistance.

Predicting glycated hemoglobin levels in the non-diabetic general population: Development and validation of the DIRECT-DETECT prediction model - a DIRECT study.

Aims/hypothesisTo develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors.MethodsData from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM.ResultsAt baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model’s intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort.Conclusions/interpretationIn the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent.