Type 2 Diabetes Group Research Articles

Clinical Observation of Macular Vessel Density in Type 2 Diabetics with High Myopia

Introduction: The aim of this study was to compare the macular retinal vessel density (VD) of diabetics with high myopia, diabetics without high myopia, and healthy controls. Methods: This cross-sectional study recruited type 2 diabetic (T2D) people with no history of ocular treatment in our hospital. Thirty T2D people with high myopia (30 eyes) were included in group A, while 30 T2D people (30 eyes) without myopia were included in group B. Another 30 healthy volunteers (30 eyes) were included in group C. The superficial and deep capillary plexuses VD of the macula were measured in all subjects by optical coherence tomography angiography. In T2D people with high myopia, the correlation between VD in macular regions and baseline data was investigated. Results: (1) Overall comparison of the 3 groups: no statistically significant differences in macular central superficial vessel density (SVD) were found in the three groups (p > 0.05). There were significant differences in the temporal, superior, nasal, inferior SVD between the 3 groups (p < 0.05). There were significant differences in macular central, temporal, superior, nasal, and inferior deep vessel density (DVD) between the three groups (p < 0.05). (2) Comparison of B (no myopia, T2D group) and C (healthy control group): inferior SVD in group B was lower than that in group C (p < 0.05). Temporal, superior, nasal, and inferior DVD in group B were lower than those in group C (p < 0.05). (3) A (high myopia group, T2D) compared with B (no myopia, T2D group), A group compared with C (healthy control group): temporal, superior, nasal, inferior SVD and DVD in group A were all lower than those in group B and C (p < 0.05), DVD in group B was lower than those in group C (p < 0.05). (4) The mean SVD and DVD were not correlated with age, IOP, anterior chamber depth, corneal curvature, but they were negatively correlated with axial length and duration of diabetes in the T2D people with high myopia. Conclusion: Myopia and diabetes are two important factors affecting macular retinal VD. Comparing with the eyes of T2D people without high myopia, the VD in macular regions shows a higher decline in the eyes of T2D people with high myopia.

Elevated IgG and IgM Autoantibodies to Advanced Glycation End Products of Vascular Elastin in Hypertensive Patients with Type 2 Diabetes: Relevance to Disease Initiation and Progression.

The increased glycation of elastin is an important factor in vascular changes in diabetes. Using the ELISA method, we determined serum levels of IgM and IgG autoantibodies to advanced glycation end products of vascular elastin (anti-AGE EL IgM and anti-AGE EL IgG) in 59 hypertensive patients with type 2 diabetes (T2D) and 20 healthy controls. Serum levels of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and the C-reactive protein (CRP) were also determined. The levels of anti-AGE EL IgM antibodies in the T2D group were similar to those in the control group, while those of anti-AGE EL IgG antibodies were significantly higher (p = 0.017). Significant positive correlations were found between the levels of anti-AGE EL IgM antibodies and MMP-2 (r = 0.322; p = 0.013) and between the levels of anti-AGE EL IgG antibodies and CRP (r = 0.265; p = 0.042). Our study showed that elevated anti-AGE EL IgG antibody levels may be an indicator of the enhanced AGE-modification and inflammatory-mediated destruction of vascular elastin in hypertensive patients with T2D. Anti-AGE EL IgM antibodies may reflect changes in vascular MMP-2 activity, and their elevated levels may be a sign of early vascular damage.

IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes.

Enteroviruses (EV) are among the leading environmental triggers of childhood-onset type 1 diabetes (T1D). Our aim was to determine the prevalence of antibodies against EV and their association with T1D in different age groups (n = 62), including young adults, and to compare these data with results from HLA-matched control participants (n = 62). IgA, IgG, and IgM antibodies against EV were detected. IgA EV antibodies were present in 46.8% of participants with T1D (median level 10.9 EIU) and in 11.3% of controls (median level 3.4 EIU). IgA EV positivity and higher level of IgA EV antibodies were both significant risk factors for T1D (odds ratio (OR) 8.33; 95% confidence interval (CI) 2.52–27.6; p = 0.0005 and OR 1.04; 95% CI 1.01–1.06; p = 0.0105, respectively). Importantly, the prevalence of IgA EV antibodies in the subgroups of both children and young adults was also significantly different between participants with T1D and their matched controls (p = 0.0089 and p = 0.0055, respectively). Such differences were not seen for IgG and IgM EV antibodies. However, IgG EV antibodies were associated with 65 kDa glutamic acid decarboxylase antibodies, but not with zinc transporter 8 and protein tyrosine phosphatase IA2 antibodies. The genotype frequency of PTPN22 (rs2476601) and IFIH1 (rs1990760) was not associated with EV positivity. This study showed that EV infections may be an important disease-promoting factor of T1D not only in childhood-onset but also in adult-onset T1D. However, to further confirm this association, direct virological studies are needed in the latter T1D group.

Ectopic fat is associated with cardiac remodeling-A comprehensive assessment of regional fat depots in type 2 diabetes using multi-parametric MRI.

BackgroundDifferent regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls.MethodsFrom the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects (35% female, mean age 59.5 ± 4.6 years): 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function (end-diastolic volume, mass, concentricity, ejection fraction), as well as regional body composition (liver proton density fat fraction, visceral adipose tissue, abdominal subcutaneous adipose tissue, thigh muscle fat infiltration, fat tissue-free thigh muscle volume and epicardial adipose tissue).ResultsCompared to the control group, the T2D group had increased: visceral adipose tissue volume index (P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass (St Beta −0.23, P < 0.05) as well as LV end-diastolic volume (St Beta −0.27, P < 0.05) was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) (St Beta 0.24, P < 0.05; St Beta 0.34, P < 0.01, respectively). In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01 (95% CI 1.28–7.05, P < 0.05) per L/m2 increase in visceral adipose tissue volume.ConclusionsEctopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue.

Association Between Dietary Fiber Intake and Risk of Depression in Patients With or Without Type 2 Diabetes.

Depression and type 2 diabetes (T2D) are both serious public health problems, with morbidity and mortality in people increasing year by year, resulting in a heavy economic burden. A correlation between dietary fiber and both has been reported. Nevertheless, few data are available concerning dietary fiber and the risk of depression with or without T2D, which deserve further attention. We assessed the relationship between dietary fiber intake and risk of depression with or without T2D in the 2007-2014 National Health and Nutrition Examination Survey (NHANES) population. A 24-h dietary review was used to assess fiber intake. The Patient Health Questionnaire-9 was used to assess depression. Stability of the results was assessed using restricted cubic spline models and logistic regression, as well as sensitivity analyses. A total of 17,866 adults aged 20 years and older with a mean age of 49.3 ± 17.7 years were included in this study, of whom 49.5% were male. After adjusting for covariates, the association of dietary fiber intake with the risk of depression appeared to differ between non-T2D group and T2D group (OR, 0.987; 95% CI, 0.979-0.995 vs. OR, 1.003; 95% CI, 0.988-1.017). Furthermore, when dietary fiber was converted to a categorical variable, there was evidence of interaction between T2D status and fiber intake on decreasing the prevalence of depression (P-value for interaction = 0.015). Sensitivity analysis showed stable results. Our findings indicated that whether a patient has T2D may affect the relationship between dietary fiber intake and the risk of depression, which still needs to be confirmed by further randomized controlled trials.

COVID-19 Lockdown and Lifestyle Changes in Saudi Adults With Types 1 and 2 Diabetes.

ObjectiveWe aimed to evaluate and compare the impact of COVID-19 lockdown on lifestyle changes and other common related effects of the lockdown in Saudi adults with diabetes mellitus (DM), both type 1 (T1D) and type 2 diabetes (T2D).Methods265 T1D and 285 T2D individuals were included in this cross-sectional survey during lockdown using an online questionnaire and compared with 297 participants without DM. Variables included demographics, treatment changes, use of supplements, change in sleeping habits and physical activity, dietary changes, social and mental health, and education and awareness during COVID-19 lockdown.ResultsThe COVID-19 lockdown was associated with more treatment doses in people with T1D but not in those with T2D (p = 0.003). More participants with T1D and T2D than the control group reported that they felt symptoms of depression during lockdown (ORs of 1.83, p = 0.008 and 2.2, p = 0.001, respectively) and that lockdown affected them psychologically (ORs of 1.64, p = 0.019 and 1.85, p = 0.005, respectively). More participants with T1D than controls reported that their physical activity decreased during lockdown (OR of 2.70, p = 0.024). Furthermore, significantly lesser participants in both DM groups than controls agreed that the health education regarding COVID-19 covered everything (ORs of 0.41, p < 0.001 and 0.56, p < 0.001, respectively for T1D and T2D groups). Regarding dietary habits, the DM groups reported more changes in either the number of daily meals, meal content, or mealtimes than the control group.ConclusionsCOVID-19 lockdown-associated lifestyle changes were more prevalent in individuals with T1D and T2D compared to control. Findings may assist public health authorities in outlining their responses in pandemics and promote healthy lifestyle adaptations in this high-risk cohort to limit adverse effects in future lockdowns.

Artemisia annua L. Extracts Improved Insulin Resistance via Changing Adiponectin, Leptin and Resistin Production in HFD/STZ Diabetic Mice.

ObjectivesInsulin resistance (IR) is major cause of type 2 diabetes (T2D), and adipokines (e.g., adiponectin, leptin, and resistin) play an important role in insulin sensitivity. Medicinal plants are frequently used for T2D treatment. This study investigates the effect of Artemisia annua L. (AA) extracts on adipokines in mice with high-fat-diet (HFD)/streptozotocin (STZ)-induced T2D.MethodsWe divided 60 mice into 12 groups (n = 5 per group) control, untreated T2D, treated T2D, and 9 other groups. T2D was induced in all groups, except controls, by 8 weeks of HFD and STZ injection. The treated T2D group was administered 250 mg/kg of metformin (MTF), while the nine other groups were treated with 100, 200, and 400 mg/kg of hot-water extract (HWE), cold-water extract (CWE), and alcoholic extract (ALE) of AA (daily oral gavage) along with 250 mg/kg of MTF for 4 weeks. The intraperitoneal glucose tolerance test (IPGTT) was performed, and the homeostasis model assessment of adiponectin (HOMA-AD) index and blood glucose and serum insulin, leptin, adiponectin, and resistin levels were measured.ResultsSimilar to MTF, all three types of AA extracts (HWEs, CWEs, and ALEs) significantly (p < 0.0001) decreased the area under the curve (AUC) of glucose during the IPGTT, the HOMA-AD index, blood glucose levels, and serum insulin, leptin, and resistin levels and increased serum adiponectin levels in the MTF group compared to the T2D group (p < 0.0001). The HWEs affected adipokine release, while the CWEs and ALEs decreased leptin and resistin production.ConclusionWater and alcoholic AA extracts have an antihyperglycemic and antihyperinsulinemic effect on HFD/STZ diabetic mice. In addition, they decrease IR by reducing leptin and resistin production and increasing adiponectin secretion from adipocytes.

Relationship between the Level of Amylinemia and Albuminuria Categories in Patients with Latent Autoimmune Diabetes in Adults

BACKGROUND: β-cells of islets of Langerhans produce not only insulin but another hormone – amylin, whose role in the development and progression of chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is not known for certain. AIM: The aim of the study was to determine the relationship between amylinemia and albuminuria categories in patients with latent autoimmune diabetes in adults (LADA) and CKD. METHODS: 89 patients with DM and CKD were examined, as well as 15 representatives of the control group. The patients were divided into three groups by the types of DM: 36 patients with LADA, 25 patients with classical type 1 diabetes mellitus (T1D), and 28 patients with type 2 diabetes (T2D). Serum amylin levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: In the group of patients with LADA, the amylin content was 9.0 times higher than in control (p &lt; 0.01) and 6.8 times higher compared to classical T1D (p &lt; 0.01); at the same time, it was 17.3% lower than in T2D group (p &lt; 0.05). In patients with T1D, the level of amylinemia did not change, whereas in T2D group it was 10.8 times significantly higher compared to the control and 8.3 times higher than in the group of patients with classical T1D. The highest indicator was registered in patients with LADA2 phenotype. The level of amylin was increasing in proportion to the categories of albuminuria. Positive correlations were found between the content of amylin and insulin, C-peptide, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index and creatinine. CONCLUSION: Serum amylin level significantly increases progrediently to the albuminuria categories in patients with LADA (especially in LADA2 phenotype) and T2D.

Knockdown of IFNAR2 reduces the inflammatory response in mouse model of type 1 diabetes

Backgroundand Purpose: To investigate the biological role of interferon α/β receptor 2 (IFNAR2) in type 1 diabetes (T1D). MethodsFirst, IFNAR2 mRNA and protein expression levels in serum of T1D patients and healthy controls were detected by RT-qPCR and Western blot. For experimental studies, 80 male C57BL/6 mice were randomly divided into 4 groups with 20 mice in each group: the control group, the T1D group, the T1D + ad-con group and the T1D + ad-si-IFNAR2 group. The T1D mouse model was generated by multiple intraperitoneal injections of small doses of streptozotocin (STZ). Body weight and blood glucose levels were measured weekly until 6 weeks. After 6 weeks, all mice were sacrificed and the levels of insulin (Ins), tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), IL-6, and type I interferon γ (IFN-γ), IFNAR2 protein expression, the number of dendritic cells (DCs), and changes in islet β cells were assessed. ResultsIFNAR2 mRNA and protein expression levels in serum of T1D patients were significantly higher than those in healthy controls (P < 0.05). Furthermore, IFNAR2 protein expression, number of DCs, and IFNAR2 mRNA, blood glucose, TNF-α, and IFN-γ levels were significantly upregulated in T1D mice compared with the control group (P < 0.05), while weight, and Ins, IL-6, and IL-4 levels were decreased (P < 0.05). However, knockdown of IFNAR2 reversed these trends. There was no significant difference in markers between the T1D + ad-con group and the T1D group (P > 0.05). ConclusionsKnockdown of IFNAR2 reduced the inflammatory response and improved islet function of T1D mice.

653-P: Post-Breakfast Glycemic Profiles in Hispanic/Latino Adults with or at Risk of Type 2 Diabetes

Hispanic/Latinos in the U.S. bear an excess burden of type 2 diabetes (T2D) . In type 1 diabetes and insulin-treated T2D, continuous glucose monitoring (CGM) is an established technology to guide therapy, yet CGM use and studies are rare in people with/at-risk of non-insulin treated T2D and ethnic minorities. In this study, CGM was used to assess breakfast glycemic response in free-living adults with or at risk of non-insulin treated T2D. For 9-14 days, 35 Hispanic/Latino adults (28 female, median HbA1c 6.0% [IQR 5.5%, 6.8%]) wore blinded Abbott Freestyle Libre CGM and logged food via the MyFitnessPal app. Start and peak time of glycemic responses associated with a glucose rise ≥20 mg/dL between 5-a.m. were manually annotated. Median variation between annotated and logged time was 39 [20, 78] minutes. Participants were stratified using HbA1c into at risk for T2D, pre-T2D, and T2D. Median starting glucose (SG) ; maximum glucose rise (Max GR) ; time-to-peak (TTP) ; and incremental area under the curve over 2, 3, and 4 hours (iAUC2hr, iAUC3hr, iAUC4hr) were computed (Table 1) . The T2D group had significantly higher post-breakfast glycemic measures than the at-risk group for all measures. The T2D group also had higher measures than pre-T2D for all but Max GR. Increases in response from at-risk to pre- to T2D in Hispanic/Latino adults suggest post-breakfast glycemic profiles may potentially be used to monitor diabetes progression. Disclosure A.Pai: Employee; Apple. R.F.Santiago: Research Support; Abbott. W.C.Bevier: Research Support; Abbott Diabetes. N.M.Glantz: Research Support; Abbott. S.Barua: None. A.Sabharwal: None. D.Kerr: Advisory Panel; Abbott Diabetes, Novo Nordisk A/S, Sanofi, Consultant; Evidation Health, Research Support; Novo Nordisk A/S, Stock/Shareholder; Glooko, Inc., Hi.Health. Funding Elsevier Foundation

1465-P: Metabolic Remodeling in Pancreatic Beta Cells in Japanese Patients with Type 2 Diabetes

Background and Aims: It has been shown that metabolic remodeling from oxidative phosphorylation to glycolysis via activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) occurs in pancreatic beta cells in non-Asians with diabetes, resulting in impaired beta cell function. We used multiple autopsy pancreatic sections to investigate whether such changes occur in Japanese patients with type 2 diabetes (T2D) , and if so, which clinical and pathological features of islets relate to this remodeling. Methods: Autopsy pancreatic sections from patients with T2D and non-diabetic donors (ND) were stained with antibodies against PFKFB3, insulin, and glucagon. The PFKFB3-positive ratio of pancreatic beta cells and alpha cells between T2D and ND were compared. Next, the relationships between PFKFB3-postive beta cell ratio, patient background factors and pathological features of the islets were explored. Results: In total, 36 cases (18 cases each for T2D and ND) were enrolled and 50-100 islets/case were evaluated. Mean age was 70.6 ± 7.7 vs. 64.3 ± 12.8 years and body mass index (BMI) 22.4 ± 4.2 vs. 23.3 ± 4.5 kg/m2, respectively. T2D duration was 9.8 ± 9.9 years. The PFKFB3-positive beta cell ratio was significantly higher in T2D (29.7 ± 18.6% vs. 11.1 ± 8.7%, p&amp;lt;0.05) , whereas the PFKFB3-positive alpha cell ratio did not differ between groups. A negative correlation between PFKFB3-positive beta cell ratio and BMI was found only in the T2D group (r=-0.65, p&amp;lt;0.05) . No correlation was observed between PFKFB3-positive beta cell ratio and age/disease duration in the T2D group. Thioflavin T staining revealed a positive correlation between amyloid deposition in the islets of T2D and PFKFB3 positivity in beta cells (r=0.67, p&amp;lt;0.05) . Conclusion: Our results indicate that intracellular metabolic remodeling mediated by upregulation of PFKFB3 occurs in pancreatic beta cells of Japanese patients with T2D. Low BMI and amyloid deposition may affect PFKFB3 expression in beta cells from patients with T2D. Disclosure R.Izumihara: None. H.Nomoto: None. K.Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science , MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H.Kameda: None. K.Cho: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. H.Mizukami: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL &amp; BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding JSPS KAKENHI Grant Number JP20281167.Japan Diabetes Society Junior Scientist Development Grant.MSD Life Science Foundation, Public Interest Incorporated Foundation.

Activation of inflammatory pathways in PBMCs linking type 2 diabetes in older adults without obesity.

The mechanism that underlies the dysregulation of glucose metabolism in older adults without obesity has yet to be thoroughly understood. This study investigated the risk of developing Type 2 diabetes (T2D) in older adults without obesity (BMI: 18.5 to <25kg/m2). Data on glucose levels (measured by an oral glucose tolerance test), body composition, physical activity level, lipid profile, inflammatory cytokines, and nuclear factor kappa B (NF-κB) and Sirtuin 1 (SIRT1) signaling pathways in peripheral blood mononuclear cells (PBMCs) in older adults with normal glucose tolerance (NGT, n=17) and those with prediabetes (n=20) or T2D (n=8) were gathered. As expected, participants with T2D exhibited higher insulin resistance; β-cell dysfunction; and higher levels of triglycerides and tumor necrosis factor-α (TNF-α) than those with NGT. No differences in physical activity, lean mass, body fat, or cholesterol were observed between the NGT, prediabetes, and T2D groups. Downregulation of SIRT1 and activation of NF-κB signaling in PBMCs were observed in the T2D group. Increased phosphorylation of NF-κB and low SIRT1 protein expression in PBMCs were associated with insulin resistance and β-cell dysfunction. NF-κB and its upstream inhibitor IκBα were positively and inversely correlated with TNF-α, respectively. SIRT1 expression was positively correlated with IL-10. Activation of NF-κB signaling pathways and downregulation of SIRT1 in PBMCs were associated with the inflammatory milieu in older adults without obesity.

986-P: Children with Type 2 Diabetes (T2D) Have Altered Arginine Metabolism

To investigate arginine metabolism in pediatric T2D, we measured fasting amino acid levels in 28 children (T2D: n=13, healthy controls [H/C]: n=15) . In the T2D group, the mean HbA1c was 8.5 ± 3.4%, with mean diabetes duration of 2.7 ± 2.4 years, and mean BMI percentile higher (98.5 ± 1) than in H/C (71.5 ± 32.6, p=0.006) . There were no statistical differences between T2D and H/C in age (16.4 ± 0.8 years) , sex (46% female) , race/ethnicity (61% Hispanic, 21% Black, 18% non-Hispanic White) , or protein intake in the preceding day (64 ± 30.5 gram) . We found lower fasting arginine (77 ± 21.9 vs. 97.2 ± 15.9 μmol/L, p=0.01) , citrulline (a precursor of arginine) (21.1 ± 7.3 vs. 27.8 ± 5.5 μmol/L, p=0.01) , and glutamine (a precursor of citrulline) (424.6 ± 64.7 vs. 539.5 ± 76.3, p=&amp;lt;0.001) levels in children with T2D vs. H/C. The difference in fasting arginine levels was even more significant (72.6 ± 15.6 in the T2D group vs. 97.2 ± 15.9 μmol/L in controls, p&amp;lt;0.001) after removal of a T2D group outlier identified by Grubb’s test (outlier: 130 vs. the rest: 72.6 ± 15.6 μmol/L) . There were no differences in ornithine, proline, and ADMA levels between the groups (Figure 1) . In conclusion, children with T2D have a unique metabolomic signature in regard to arginine metabolism. Since arginine plays important roles in regulating both insulin secretion and sensitivity, our findings may provide mechanistic insight into T2D pathophysiology and opportunities for precision therapy. Disclosure M. Tosur: Advisory Panel; Provention Bio, Inc. S. Deen: None. M.J. Redondo: Advisory Panel; Provention Bio, Inc. F. Jahoor: None. A. Balasubramanyam: None. Funding Texas Children's Hospital Pilot Grant

100-OR: Association of Recent Myocardial Infarction with Insulin Resistance and Fatty Liver Disease in Type 2 Diabetes

Insulin resistance and nonalcoholic fatty liver disease (NAFLD) frequently associate with type 2 diabetes (T2D) and cardiovascular disease and worsen their prognosis. We hypothesized that people with recent myocardial infarction (MI) have lower left ventricular ejection fraction (EF) and higher degree of insulin resistance (IR) , hepatocellular lipid content (HCL) and risk of hepatic fibrosis than matched people without MI. Thus, participants of the “DIabetes and ST-Elevation MI (DISTEMI) Study” were examined 6-12 weeks after MI (MI+; n=53, 28% T2D) and compared to age-, sex-, BMI-matched people without MI (MI-; n=48, 31% T2D) . Insulin sensitivity was assessed during fasting (Homeostasis Model Assessment (HOMA) 2-IR) and hyperinsulinemic-euglycemic clamps (M-value) . EF, HCL and liver stiffness, associated with fibrosis stages, were quantified by 1H-magnetic resonance imaging, spectroscopy and elastography, respectively. MI+ had a lower EF (47±2 vs. 58±1 %, p&amp;lt;0.0001) and M-value (7.3±0.4 vs. 8.2±0.4 mg*kg-1*min-1, p&amp;lt;0.05) compared to MI-, which was mainly due to a difference between the T2D groups (EF: 39±6 vs. 52±2 %, p&amp;lt;0.001; M-value: 4.2±0.5 vs. 6.1±0.6 mg*kg-1*min-1, p&amp;lt;0.05) . HCL (3.4±0.8 vs. 5.8±0.9 %) and liver stiffness (2.2±0.1 vs. 2.3±0.1 kPa) were comparable between MI+ and MI-. HCL correlated negatively with M-value (r=-0.95, p&amp;lt;0.05) and positively with systolic blood pressure (r=0.91, p&amp;lt;0.05) in MI+ with T2D. In MI+ without T2D, HCL correlated positively with HOMA2-IR (r=0.58, p&amp;lt;0.01) and BMI (r=0.53, p&amp;lt;0.01) . In conclusion, recent myocardial infarction in people with type 2 diabetes associates with decreased ejection fraction and increased insulin resistance. The correlation between insulin resistance and liver fat content suggests that HCL can serve as a non-invasive cardiovascular marker and may identify persons with a worse outcome after myocardial infarction. Disclosure C.Möser: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. O.P.Zaharia: n/a. F.C.Michlotti: None. Y.Kupriyanova: None. V.Schrauwen-hinderling: None. P.Bobrov: None. V.Burkart: None. M.Kelm: Board Member; DGIM-Deutsche Geselleschaft für Innere Medizin, DGK-Deutsche Gesellschaft für Kardiologie, DSHF-Deutsche Stiftung für Herzforschung, ESC- European Society of Cardiology, Other Relationship; Abiomed , Bayer AG, diaplan, Kel Con GmbH, Research Support; Abiomed Europe GmbH, B.Braun, Edwards Lifesciences Corporation, European Union, IPP Med GmbH - Institut für Pharmakologie u. präventive Medizin GmbH, Mars Scientific Advisory Council (MSAC) , Medicure Inc., Microvision Medical. J.M.Szendroedi: Consultant; Boehringer Ingelheim International GmbH. Funding Research Network SFB 1116 of the German Research Foundation

1095-P: Clusters of Prediabetes and Type 2 Diabetes Stratify All-Cause Mortality in a Cohort of Participants Undergoing Invasive Coronary Diagnostics

Risk for complications and mortality among patients with type 2 diabetes (T2D) is heterogenous. Different trajectories can be identified in the prediabetic state, which comprises heterogenous metabolic clusters. It is not known whether such pathophysiologic clusters of prediabetes and diabetes affect survival in at-risk persons being evaluated for coronary heart disease. The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56-70) who have since been followed-up for a median of 14.5 (IQR 9.6-17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n=794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analyzed using Cox regression. Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR) 1.42) , 5 (HR 1.43) and 6 (HR 1.46) age-, BMI-, HbA1c- and sex-adjusted. In the T2D group, 5were assigned to mild age-related diabetes (MARD) , 183 to severe insulin-resistant diabetes (SIRD) , 84 to mild obesity-related diabetes (MOD) , to severe insulin-deficient diabetes (SIDD) . Compared to the low-risk nondiabetes group, crude mortality was not different in MOD. An increased mortality was found for MARD (HR 2.2) , SIRD (HR 2.2) and SIDD (HR 2.5) . Metabolic clustering successfully stratifies survival even among persons already undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are in danger of increased mortality Disclosure K.Prystupa: None. G.Delgado: None. A.P.Moissl: None. M.E.Kleber: Employee; SYNLAB Holding Deutschland GmbH. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. A.L.Birkenfeld: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. W.Maerz: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding German Federal Ministry of Education and Research (BMBF) (01GI0925)

830-P: The Pan-PPAR Agonist Lanifibranor Improves Nonalcoholic Steatohepatitis (NASH) and Glycemic Control

Lanifibranor therapy resulted in both NASH resolution and fibrosis reduction in the phase 2b NATIVE study in patients with non-cirrhotic NASH, compared to placebo. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D) . We evaluated the association between the effect of lanifibranor on glycemic control (GC) and NASH markers. Methods: NATIVE included 247 patients, randomized to lanifibranor 800, 1200 mg/d or placebo for 24 weeks of treatment; 228 patients completed the trial. Efficacy in NASH was measured with SAF score (primary endpoint) and NASH-CRN grading and fibrosis staging. Biomarkers for insulin resistance (IR) , GC, lipid metabolism, inflammation, liver enzymes and imaging of hepatic steatosis by continuous attenuation parameter (CAP) were analyzed at baseline (BL) and end of treatment (EOT) . Correlations between HbA1c (≤6, &amp;gt;6 - ≤7 and &amp;gt;7%) at BL and HbA1c change from BL to EOT with improvement in biomarkers and histologic features of NASH at EOT were assessed. Results: T2D was present in 103 (42%) patients. The composite endpoint of NASH resolution and fibrosis improvement in the overall and T2D group for lanifibranor (pooled data) versus (vs) placebo was 26% vs. 7% (p&amp;lt;0.001) , and 26% vs. 3% (p=0.003) , respectively. Irrespective of T2D status, lanifibranor improved fasting glucose (FG) , IR, lipid metabolism, C-reactive protein, and liver enzymes. In contrast to placebo, lanifibranor improved mean HbA1c from BL in the overall and T2D group, -0.41% and -0.66%, respectively. In the lanifibranor group, BL HbA1c correlated with BL NASH activity and fibrosis; HbA1c decrease at EOT correlated with improvement of FG, insulin, IR, liver enzymes, HDL-cholesterol, triglycerides, ApoB, ApoB/ApoA1, CAP and histologic improvement of steatosis and ballooning. Conclusion: GC correlates with NASH severity. The improvement of metabolic markers of NASH and hepatic steatosis with lanifibranor treatment is consistent with its beneficial effect on GC. Disclosure M.P.Cooreman: Employee; Inventiva Pharma. S.Francque: None. L.Dzen: Employee; Inventiva Pharma. P.Huot-marchand: Employee; Inventiva Pharma. J.L.Junien: None. P.Broqua: None. M.F.Abdelmalek: Advisory Panel; Akero Therapeutics, Inc., Bristol-Myers Squibb Company, Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Akero Therapeutics, Inc., Allergan, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Celgene, DURECT Corporation, Enanta, Enyo Pharma, Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Poxel SA, TARGET PharmaSolutions, Inc., Viking Therapeutics.

1331-P: Associations between Insulin Resistance and Plasma Lipids and Metabolomics in Women with and without Type 1 Diabetes

Insulin resistance (IR) increases risk for cardiovascular disease and mortality in people with type 1 diabetes (T1D) . We previously found associations between plasma lipids, metabolites and IR; whether these associations differ in people with and without T1D is not well understood. We analyzed targeted plasma lipidomics and untargeted plasma metabolomics in 25 premenopausal women aged 18-45 yrs (12 with T1D and 13 without diabetes [non-DM]) who had a hyperinsulinemic euglycemic clamp to measure glucose infusion rate (GIR) . After stratifying by diabetes, women were classified by tertiles of GIR. We used sparse partial least-squares discriminant analysis to predict and moderated t-tests to compare most IR vs. most insulin sensitive (IS) tertile. Among women with T1D, 3 lipids, 4 amino acids, 3 peptides, 3 xenobiotics, 1 carbohydrate, and 1 nucleotide were lower and 1 lipid and 1 fatty acid were higher in the most IS tertile (Table) . Among non-DM women, 4 lipids, 1 cofactor, 1 fatty acid, and 1 phosphatidylethanolamine were lower and 1 nucleotide and 1 lipid were higher in the most IS tertile. None of the top features were the same in the T1D and non-DM groups. Plasma lipids and metabolites were differentially associated with IR in women with and without T1D. Future work should validate these findings in a larger sample of women and men, and explore how these biomarkers relate to IR and metabolism in T1D. Disclosure T.B.Vigers: None. L.Pyle: None. I.E.Schauer: None. B.C.Bergman: Research Support; Eli Lilly and Company. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. Funding American Diabetes Association (7-13-CD-10) ; National Heart, Lung, and Blood Institute (grant HL61753 and HL113029) , JDRF Diabetes Foundation (grant 17-2013-313) , DERC Clinical Investigation Core (grant P30 DK57516) , NIH-M01-RR00051, NIH P30-DK116073

Circulating Ism1 Reduces the Risk of Type 2 Diabetes but not Diabetes-Associated NAFLD.

PurposeTo examine the association of serum Ism1, a new adipokine that can regulate glucose uptake, with type 2 diabetes (T2D) in a Chinese population. Considering high prevalence of Nonalcoholic Fatty Liver Disease in patients with type 2 diabetes and the regulating role of Ism1 on glucose uptake of peripheral tissues, we further explored the association between Ism1 and diabetes-associated nonalcoholic fatty liver disease.MethodsA total of 120 newly diagnosed T2D patients and 60 control subjects with normal glucose were recruited in the case-control study. Serum Ism1 concentrations were determined by ELISA. Multivariate logistic regression analysis was used to evaluate the independent association of serum Ism1 concentration with the risk of T2D. The 120 newly diagnosed T2D patients were divided into uncomplicated T2D group and diabetes-associated NAFLD group according to the FLI score.ResultsThe Ism1 level of normoglycemic controls was higher than that of T2D patients (3.91 ± 0.24 ng/ml vs 3.01 ± 0.16 ng/ml, P=0.001). Based on quartile analysis of Ism1 level, the proportion of high circulating Ism1 levels in the control group increased while T2D group decreased, and the distribution difference was statistically significant (P=0.015). Logistic regression analysis indicated that the serum Ism1 level was an independent protective factor of type 2 diabetes (OR=0.69, 95%CI: 0.54-0.89). The decrease of Ism1 level did not increase the risk of non-alcoholic fatty liver disease in diabetic patients by Binary logistic regression analysis (OR=1.08, 95% CI: 0.69-1.69).ConclusionsThe increase of serum Ism1 was associated with a decreased risk of diabetes, and it did not reduce the risk of non-alcoholic fatty liver disease in diabetic patients.

Effects of continuous subcutaneous insulin infusion on the microstructures, mechanical properties and bone mineral compositions of lumbar spines in type 2 diabetic rats

BackgroundContinuous subcutaneous insulin infusion (CSII) for the treatment of type 2 diabetes (T2D) can improve the structure and strength of femur of rats, but the effect of CSII treatment on the lumbar spine of T2D rats is unknown. The purpose of this study is to investigate the effects of CSII on the microstructure, multi-scale mechanical properties and bone mineral composition of the lumbar spine in T2D rats.MethodsSeventy 6-week-old male Sprague–Dawley (SD) rats were divided into two batches, each including Control, T2D, CSII and Placebo groups, and the duration of insulin treatment was 4-week and 8-week, respectively. At the end of the experiment, the rats were sacrificed to take their lumbar spine. Microstructure, bone mineral composition and nanoscopic-mesoscopic-apparentand-macroscopic mechanical properties were evaluated through micro-computed tomography (micro-CT), Raman spectroscopy, nanoindentation test, nonlinear finite element analysis and compression test.ResultsIt was found that 4 weeks later, T2D significantly decreased trabecular thickness (Tb.Th), nanoscopic-apparent and partial mesoscopic mechanical parameters of lumbar spine (P < 0.05), and significantly increased bone mineral composition parameters of cortical bone (P < 0.05). It was shown that CSII significantly improved nanoscopic-apparent mechanical parameters (P < 0.05). In addition, 8 weeks later, T2D significantly decreased bone mineral density (BMD), bone volume fraction (BV/TV) and macroscopic mechanical parameters (P < 0.05), and significantly increased bone mineral composition parameters of cancellous bone (P < 0.05). CSII treatment significantly improved partial mesoscopic-macroscopic mechanical parameters and some cortical bone mineral composition parameters (P < 0.05).ConclusionsCSII treatment can significantly improve the nanoscopic-mesoscopic-apparent-macroscopic mechanical properties of the lumbar spine in T2D rats, as well as the bone structure and bone mineral composition of the lumbar vertebrae, but it will take longer treatment time to restore the normal level. In addition, T2D and CSII treatment affected bone mineral composition of cortical bone earlier than cancellous bone of lumbar spine in rat. Our study can provide evidence for clinical prevention and treatment of T2D-related bone diseases.

The Kynurenine Pathway in Obese Middle-Aged Women with Normoglycemia and Type 2 Diabetes.

We examined the relationships of tryptophan (Trp) and the metabolites of the kynurenine pathway (KP) to the occurrence of type 2 diabetes (T2D) and metabolic risk factors in obese middle-aged women. The study included 128 obese women divided into two subgroups: a normoglycemic group (NG, n = 65) and a T2D group (n = 63). The concentrations of serum tryptophan (Trp), kynurenine (Kyn), 3-hydroxykynurenine (3HKyn), quinolinic acid (QA), and kynurenic acid (Kyna) were analyzed using ultra-high-performance liquid chromatography coupled with electrospray ionization/triple quadrupole mass spectrometry. Blood biochemical parameters and anthropometric parameters were measured. The women with T2D had significantly higher Trp, Kyna, Kyna/QA ratio, and Kyna/3HKyn ratio values than the NG women. Logistic regression analysis showed that the concentrations of Trp and Kyna and the values of the Kyna/3HKyn ratio were most strongly associated with T2D occurrence, even after controlling for confounding factors. The model with Trp level and Kyna/3HKyn ratio accounted for 20% of the variation in the presence of T2D. We also showed a different pattern of correlations between kynurenines and metabolic factors in the NG and T2D women, which was mostly reflected in the stronger relationship between BMI and KP metabolites in the NG obese women. An increase in Trp and Kyna levels with an accompanying increase in Kyna/3HKyn ratio value is associated with the occurrence of T2D in obese middle-aged women.