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  • 1
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    9-OR: Insulin Resistance (IR) and Kidney Oxidative Metabolism in People with Type 1 Diabetes (T1D)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: IR has been linked to kidney injury in T1D. Animal models show that IR associates with impaired TCA cycle turnover and oxidative phosphorylation, collectively termed oxidative metabolism, but little is known about this relationship in humans with T1D. Thirty young adults with T1D (age: 23±3 years, diabetes duration: 13±5 years, 53% female, HbA1c: 7.9±1.1%, BMI: 25±3 kg/m2, UACR: 5 [3, 8] mg/g) and 20 healthy controls (HC) (age: 25±3, 50% female, HbA1c: 5.2±0.3%, BMI: 23±2 kg/m2, UACR: 5 [3, 9] mg/g) underwent hyperinsulinemic-euglycemic clamps to assess whole-body insulin sensitivity (IS), and MRI to assess kidney perfusion. A subset underwent voxel-wise and region-of-interest (ROI) pharmacokinetic (PK) 11C-acetate PET analyses (n=16 T1D; n=10 HC) to quantify kidney cortical oxidative metabolism (k 2), and research kidney biopsies with single-cell RNA sequencing (n=28 T1D; n=13 HC). Compared to HC, participants with T1D exhibited lower IS (7.8±2.6 vs. 14.3±4.0 mg/kg/min, p & lt;0.0001), cortical perfusion (196±68 vs. 243±46 ml/min/100g, p=0.01) and lower cortical k 2 (0.16±0.02 vs. HC 0.18±0.02 min-1, p=0.04) in voxel-wise models, although significance was not reached in the ROI PK analyses. IS associated with cortical k 2 (r:0.43, p=0.03) and the associations remained significant after adjusting for age, sex, and HbA1c (p=0.04). No significant interaction observed between T1D and HC for IS and cortical k2 (p=0.78). Proximal tubular transcripts of the enzymes catalyzing the proximal steps of the TCA cycle (e.g., ACO1, IDH1, SUCLG1) were lower in T1D vs. HC (all FDR-adjusted p & lt;0.0001). Kidney oxidative metabolism is impaired in young people with T1D and is linked to lower whole-body IS. Statistical differences in k 2 from ROI and voxel-wise analyses suggest regional variations in kidney oxidative metabolism that may not be apparent in global analysis. Spatial metabolomic analyses of kidney tissue in a subset of these participants are shown in abstract #2023-A-3407-Diabetes. Disclosure G.Richard: None. S.Gross: None. V.N.Shah: Advisory Panel; LifeScan Diabetes Institute, Medscape, Consultant; DKSH, Research Support; Novo Nordisk, Tandem Diabetes Care, Inc., Dexcom, Inc., Insulet Corporation, JDRF, National Institutes of Health, Speaker's Bureau; Dexcom, Inc., Insulet Corporation. L.Pyle: None. T.B.Vigers: None. J.K.Snell-bergeon: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. L.Li: None. P.V.Prasad: None. P.E.Ladd: None. C.Birznieks: None. B.B.Chin: None. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. P.J.Mccown: None. F.Alakwaa: None. M.Kretzler: Research Support; Lilly, Boehringer Ingelheim Inc., Traveere Pharmaceuticals, Novo Nordisk, certa, Chinook Therapeutics Inc., Janssen Research & Development, LLC, AstraZeneca, Moderna, Inc., Gilead Sciences, Inc., Regeneron, Ionis Pharmaceuticals, Angioin, Renalytix. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. F.C.Brosius: Advisory Panel; Gilead Sciences, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. G.Zhang: None. L.Driscoll: None. K.L.Tommerdahl: None. J.A.Schaub: None. A.Naik: Advisory Panel; CareDx. V.Nair: None. A.A.Macdonald: None. Funding JDRF; National Institute of Diabetes and Digestive and Kidney Diseases
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-9-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 2
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    319-OR: Effect of Vertical Sleeve Gastrectomy (VSG) on the Kidney Transcriptome of Youth with Type 2 Diabetes (T2D)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Introduction: VSG attenuates early diabetic kidney disease (DKD) in youth with T2D, yet the molecular mechanisms of VSG on kidney health are unknown. We analyzed single-cell RNA sequencing data from paired kidney biopsies obtained from youth with T2D before and 1-year after VSG. Methods: Data from 5 youths with T2D who underwent kidney biopsies before and after VSG were included in this analysis (pre-VSG:17±2 years, HbA1c 7.5±2.6%, BMI 41±3 kg/m2, 40% with albuminuria (UACR≥30mg/g). A total of 23598 cells were profiled from the five paired kidney biopsies, with 19735 cells from 12 HC. Cell selective differentially expressed genes in disease (T2D vs. HC) were computed. Disease genes that reversed directionality post-VSG were termed "suppressed by VSG" or "upregulated by VSG," depending on the direction of the reversal. Results: VSG resulted in the normalization of HbA1c and UACR in all cases at 12 months. Post VSG, 73% of proximal tubule (PT) genes that were upregulated in T2D vs. HC were suppressed in VSG vs. T2D. These suppressed genes were enriched for glycolysis, gluconeogenesis, and TCA cycle pathways (Figure). Gene and pathway changes in the PT were similar to what was recently demonstrated with SGLT2i in T2D youth. Conclusion: VSG, like SGLT2i, is associated with reduced central carbon metabolism in the PT and other nephron segments. Disclosure A.Naik: Advisory Panel; CareDx. K.N.Z.Fuller: None. P.E.Ladd: None. D.A.Sandoval: Consultant; Metis Therapeutics. S.Gross: None. P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. K.J.Nadeau: None. J.R.Ryder: None. T.Inge: None. J.B.Hodgin: None. F.C.Brosius: Advisory Panel; Gilead Sciences, Inc. F.Alakwaa: None. R.G.Nelson: None. M.Kretzler: Research Support; Lilly, Boehringer Ingelheim Inc., Traveere Pharmaceuticals, Novo Nordisk, certa, Chinook Therapeutics Inc., Janssen Research & Development, LLC, AstraZeneca, Moderna, Inc., Gilead Sciences, Inc., Regeneron, Ionis Pharmaceuticals, Angioin, Renalytix. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. J.A.Schaub: None. P.J.Mccown: None. V.Nair: None. S.Eddy: None. L.Pyle: None. T.B.Vigers: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc., Lilly. Funding Boettcher Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (K23116720, R01DK129211); JDRF (2-SRA-2019-845-S-B)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-319-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 3
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    406-P: Spatial Metabolomics of Human Kidney Tissues Reveal Impaired Tricarboxylic Acid (TCA) Cycle Turnover in Type 1 Diabetes (T1D)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: In abstract 2023-A-3497-Diabetes, we show impaired TCA cycle turnover using 11C acetate PET and lower proximal tubular transcripts of TCA cycle enzymes by single-cell RNA sequencing of kidney biopsies in young adults with T1D vs. healthy controls (HC). Spatial metabolomics analyses of the kidney tissue were conducted to further explore perturbations in kidney oxidative metabolism in T1D. Matrix-assisted laser desorption/ionization-mass spectrometry imaging-based spatial metabolomics was used to analyze metabolites in situ (spatial resolution: 20 μm) in kidney tissues from 8 participants with T1D and preserved kidney function and 5 HC. Univariate analysis (t-test or Wilcoxon Mann Whitney test) demonstrated that 36 of 456 METASPACE annotated metabolites were altered (P & lt;0.05) in T1D vs. HC. Partial least squares-discriminant analysis (PLS-DA) and heatmaps showed clearly separated clusters of metabolites. To identify the most significant discriminators for T1D, a variable importance in projection (VIP) plot from PLS-DA model was applied. Of the top 15 metabolites, two TCA cycle intermediates, succinic acid (m/z 117.0193, -H; P = 0.016) and malic acid (m/z 133.0142, -H; P = 0.026), were reduced in kidney tissues of participants with T1D. Pathway analysis revealed that the TCA cycle, mitochondrial electron transport chain, glutamate metabolism, malate-aspartate shuttle, and purine pathway were the dominant metabolic pathways perturbed in T1D kidney tissue. Spatial metabolomics comparing T1D kidney biopsies vs. HC reveal alterations of TCA cycle intermediates indicating mitochondrial dysfunction in the subclinical stages of diabetic kidney disease. The spatial metabolomics data are consistent with the data from transcriptomics and stable isotope tracing analysis in a subset of same participants. Further analysis with pathologic features will identify potential pathways linked to disease development. Disclosure G.Zhang: None. C.Birznieks: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. J.A.Schaub: None. K.J.Nadeau: None. V.Nair: None. F.Alakwaa: None. P.J.Mccown: None. A.Naik: Advisory Panel; CareDx. L.Pyle: None. D.Blondin: None. L.Liu: None. G.Richard: None. M.Kretzler: Research Support; Lilly, Boehringer Ingelheim Inc., Traveere Pharmaceuticals, Novo Nordisk, certa, Chinook Therapeutics Inc., Janssen Research & Development, LLC, AstraZeneca, Moderna, Inc., Gilead Sciences, Inc., Regeneron, Ionis Pharmaceuticals, Angioin, Renalytix. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. I.M.Tamayo: None. N.Garcia ponce de leon: None. T.B.Vigers: None. K.L.Tommerdahl: None. R.G.Nelson: None. P.E.Ladd: None. T.Alexandrov: None. Funding National Institutes of Health (UH3DK114920); JDRF (2-SRA-2019-845-S-B); Diabetes Research Center (P30DK116073)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-406-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 4
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    1266-P: Puberty Is Associated with a Rising HbA1c, Even in Healthy Normal Weight Youth
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Objective: ADA definitions of prediabetes are applied to children, yet little is known about the impact of the transient insulin resistance of puberty on glycemia. We aimed to evaluate the longitudinal trajectory of hemoglobin A1c (HbA1c) in youth with normal weight and with obesity as they progressed through puberty. Methods: Youth with normal weight (n=47, 49% female) or obesity (n=37, 62% female) of mixed race/ethnicity (Non-Hispanic White 34%, Hispanic 45%, Non-Hispanic Black 13%) entered the study in Tanner stage 2-3 (T2-3) and were followed until T5. Study visits were done at T2-3, T4, and T5 and included an IV glucose tolerance test, DXA, and fasting laboratory studies. HbA1c was measured by high-performance liquid chromatography and insulin sensitivity (Si), acute insulin response to glucose (AIRg), and disposition index (DI) were calculated. Group differences in HbA1c over time and time-dependent predictors of HbA1c were evaluated by mixed models, with and without adjusting for sex, race/ethnicity, and DXA %Fat. Results: Mean HbA1c was higher in youth with obesity (5.30±0.08%) vs. normal weight (5.10±0.06%, p=0.04) at baseline and each subsequent time point; differences were attenuated by adjusting for %Fat. HbA1c increased from T2/3 to T5 in the whole cohort (0.16±0.05%, p=0.004), and in youth with obesity (+0.18±0.08%, p=0.08), or normal weight (+0.14±0.05%, p=0.02); findings were similar after adjusting for sex, race/ethnicity, and %Fat. In a multivariate model adjusted for sex and race/ethnicity, HbA1c was associated with leptin (β=0.005, p=0.01) and adiponectin (β=-0.01p=0.02); these associations are similar after adjusting for %Fat. HbA1c was not associated with Si, AIRg or DI. Conclusions: Obesity is associated with higher HbA1c than normal weight during puberty. However, HbA1c increased during puberty, independent of body weight and composition. This increase in HbA1c is associated with changes in adipokines, but not with typical predictors of progression to diabetes (Si, DI). Disclosure M.M. Kelsey: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. A.M. Hilkin: None. C. Severn: None. L. Pyle: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Merck & Co., Inc. Funding American Diabetes Association (1-11-JF-23 to M.M.K.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD057022-04); University of Colorado Center for Women’s Health Research; Children’s Hospital Colorado Research Institute; National Institute for Diabetes and Digestive and Kidney Diseases (DK048520-13); National Center for Advancing Translational Sciences (UL1TR001082)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1266-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    Serum Uromodulin (SUMOD) Inversely Correlates with Aortic Stiffness in Type 1 Diabetes (T1D) Youth
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Lower SUMOD correlates with decreasing kidney function and atherosclerosis in adults with T1D, but its relationship with markers of arterial stiffness in youth with T1D is unknown. We sought to evaluate the relationship between SUMOD and central arterial stiffness in youth with T1D. Participants (n=49, 12-21 years old, 51% female, BMI 25.2±4.6 kg/m2, mean HbA1c8.6±1.4) were enrolled in EMERALD, a randomized controlled trial of metformin in youth with T1D. Post-hoc SUMOD was measured using Euroimmun ELISA kits from serum from the baseline visit. Ascending (AA) and descending aortic (DA) stiffness (pulse wave velocity [PWV] and strain) were determined by MRI at baseline and 3 months of follow-up. SUMOD positively correlated with AA strain (r: 0.37, p=0.04) and negatively with AA PWV (r: -0.41, p=0.03). According to SUMOD tertiles, participants in the lower tertile had higher AA PWV vs. the middle and high tertiles (Figure). Lower baseline SUMOD also predicted worsening in AA PWV over 3 months (β±SE: -0.04±0.01, p=0.03) adjusting for age, sex, baseline AA PWV, treatment group (metformin vs. placebo) and estimated glomerular filtration rate. In T1D youth, decreased SUMOD is associated with increased aortic stiffness. Further research is needed in T1D youth to understand the pathogenesis of SUMOD in cardiovascular disease. Disclosure P. Wiromrat: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. C. Roncal-Jimenez: None. M. Schäfer: None. A. Baumgartner: None. L. Pyle: None. M. Cree-Green: None. Y. Garcia Reyes: None. L. Browne: None. R. Johnson: Board Member; Self; XORT Therapeutics. Stock/Shareholder; Self; Colorado Research Partners LLC. Consultant; Self; Danone Research Foundation. K.J. Nadeau: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-431-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 6
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    216-OR: Cardiovascular (CV) Impact of BMI in Youth with Type 1 Diabetes (T1D)
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Insulin resistance (IR) and obesity are independently associated with T1D and are known risk factors for CV disease, the leading cause of mortality in T1D. We evaluated the impact of BMI on CV outcomes in T1D youth and compared obese T1D (OT1D) youth to youth with type 2 diabetes (T2D). Pubertal youth aged 12-21 years with T1D and T2D were recruited from the RESistance to InSulin in type 1 and type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with type 1 Diabetes (EMERALD) cohorts. Participants were stratified as lean (LT1D), overweight, or obese T1D or T2D (Table). CV outcomes included resting heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), leptin, hsCRP, and adiponectin. T1D participants performed bicycle ergometry for peak oxygen consumption (VO2peak), brachial artery (BA) distensibility by Dynapulse, and aortic MRI. HR, SBP, DBP, mean arterial pressure, and prevalence of hypertension were higher and BA distensibility, descending aorta oscillatory shear index, VO2peak, leptin, and hsCRP were worsened in OT1D vs. LT1D. Beyond hypertension prevalence in OT1D vs. T2D, which was worse in OT1D, T2D did not differ significantly from OT1D. Higher BMI, which is increasingly prevalent in T1D, is associated with a worsened CV profile in T1D youth, nearly approximating the CV phenotype of T2D youth. Closer attention to lifestyle management in T1D youth is needed to help reduce CV risk. Disclosure K.L. Tommerdahl: None. K.V. Baumgartner: None. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. A. Baumgartner: None. L. Pyle: None. J.G. Regensteiner: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. K.J. Nadeau: None. Funding American Diabetes Association (7-11-CD-08 to K.J.N.); JDRF (11-2010-343); National Institutes of Health (1R56DK088971-01)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-216-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 7
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    183-LB: The Gut Microbiome and Puberty in Girls at Risk for Type 2 Diabetes (T2D)
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Objectives: Pediatric-onset T2D is twice as common in girls vs. boys and is tightly linked with puberty and obesity. Alterations in gut microbiota, specifically the Firmicutes:Bacteroidetes ratio (F:B), may be associated with insulin sensitivity (Si) and may play a role in the pathophysiology of T2D. We aimed to evaluate associations between gut microbiome composition and Si and insulin secretion in obese prepubertal (PP) vs. late-pubertal (LP) girls. Methods: Obese PP (N=9, age 8.5 ±0.8 year, BMIz 2.0±0.5) and LP (Tanner 4-5, N=9, age 13.0±2.0 year, BMIz 2.0±0.5) obese girls underwent stool collection and intravenous glucose tolerance testing after an overnight fast. High-throughput sequencing of the bacterial 16S rRNA gene V3-V4 region was used to profile fecal bacterial communities. Bergman's minimal model was used to estimate Si and insulin secretion (acute insulin response to glucose, AIRg) and disposition index (DI). T-tests assessed group differences in Si, AIRg and DI. Spearman’s correlation examined relationships between microbiota relative abundance (%RA) and Si, AIRg and DI. Results: PP vs. LP girls had significantly higher Si (8.0±1.0 vs. 2.0±0.5 x10-4/min-1/μIU/ml, p & lt;0.001) and DI (3,525 ± 636 vs. 1,687 ± 385 x10-4/min-1, p=0.03). AIRg was not different between PP and LP girls (568 ± 132 vs. 840 ± 174 μIU/ml, p=0.23). F:B ratio related to insulin secretion and DI, (r=-0.32, p=0.20; r=-0.39, p=0.11) but not Si. At the genus level, Si was correlated to Ruminococus and Lachnospira %RA (r=0.53, p=0.02; r=0.50, p=0.036). AIRg was correlated to Peptostreptococcaceae %RA (r=-0.48, p=0.045). DI was correlated with Prevotella and Bifidobacterium %RA (r=0.57, p=0.01; R=- 0.54, p=0.02). Conclusion: These pilot study results suggest possible relationships among the gut microbiome, glucose metabolism, and puberty in girls at risk for T2D that merit further exploration. Disclosure B. Jobira: None. D.N. Frank: None. L. Pyle: None. S. Gross: None. D. Ir: None. W. Pendleton: None. C.E. Robertson: None. K.J. Nadeau: None. M.M. Kelsey: None. Funding University of Colorado Center for Women’s Health; National Institutes of Health/Colorado Clinical Translational Science Award (UL1TR002535)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-183-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 8
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    1746-P: Obese Youth with Type 1 Diabetes (T1D) Have Worse Hepatic Insulin Resistance (IR) Than Youth with Type 2 Diabetes (T2D)
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Background: The epidemic of obesity is growing in the U.S. due to changes in diet and lifestyle. Similar trends are also now occurring in T1D youth and may worsen IR and associated cardiovascular risk. However, the impact of obesity on IR in each tissue is unknown in T1D. Thus, we evaluated adipose, hepatic and muscle IR in obese youth with T1D, compared to BMI-similar control or T2D youth. Methods: 20 youth with T1D (age 16.0±2.3 years; % female 55; BMI%ile 95th [97, 98]; HbA1c 8.7±1.6%), 20 youth with T2D (age 15.4±2.3; % female 52; BMI%ile 95th [98, 99] ; HbA1c 8.5±2.4%) and 16 controls (age 14.8±1.8; % female 55; BMI%ile 97th [98, 99]) were included. In those with diabetes, glucose was controlled overnight by IV insulin to a target of ∼100 mg/dL. A 4-phase hyperinsulinemic-euglycemic clamp (basal, 10, 16 and 80 mU/m2/min of insulin [I] ) with isotopic tracers was performed the following AM to assess adipose, hepatic and muscle IR, respectively. Free fatty acids (FFA), glucose rate of disappearance (Rd) and glycerol and glucose rate of appearance (Ra) and %suppression (basal to 80 phase) were calculated. Results: Participant age, sex, BMI and Tanner stage were similar between groups. HbA1c was similar in groups with diabetes. During the basal phase, glycerol Ra/I and glucose Ra/I were similar between groups, but FFA/I was highest in obese controls (p & lt;0.001). At phase 10, glycerol Ra/I was similar between groups but FFA/I at phase 10 and 16 were similarly higher in T1D and T2D vs. controls (p=0.004, p & lt;0.001). At phase 16, glucose Ra/I and glycerol Ra/I were highest in T1D (p & lt;0.001, p & lt;0.001). At phase 80, T1D vs. T2D had similarly lower %glycerol Ra suppression than controls (p & lt;0.001) but higher glycerol Ra/I and glucose Rd in T1D vs. T2D (p=0.003, p=0.042). T1D youth and controls had similar glucose Rd (p=0.25). Conclusion: Obese youth with T1D have similar to worse adipose, worse hepatic, and less muscle IR than those with T2D. Treatment targeting obesity and IR is critically needed in T1D youth. Disclosure P. Wiromrat: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. B.C. Bergman: Consultant; Spouse/Partner; Novo Nordisk Inc., Sanofi US. Research Support; Self; Eli Lilly and Company. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. K.L. Tommerdahl: None. A. Baumgartner: None. L. Pyle: None. K.J. Nadeau: None. Funding American Diabetes Association (7-11-CD-08 to K.J.N.); National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; JDRF
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1746-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 9
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    404-P: Relationships among Triglyceride (TG) Concentrations across Lipoprotein Subclasses, Intraglomerular Hemodynamics, and Kidney Oxygen Availability in Adolescents with Type 1 Diabetes (T1D)
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D. Disclosure M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. Funding MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-404-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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    306-OR: A Metabolic Mismatch between Renal Oxygenation and Glomerular Filtration Rate in Type 1 Diabetes
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Glomerular filtration rate (GFR) is a major determinant of renal energy expenditure. Animal models support a mismatch between renal oxygenation (RO2) and energy expenditure in diabetic kidney disease (DKD). The objective of this study was to compare the ratio of RO2 to GFR (RO2:GFR) in adolescents with and without type 1 diabetes (T1D) and correlate the ratio with albuminuria, effective renal plasma flow (ERPF), blood pressure, trunk mass and renal oxygen consumption. RO2 was measured by blood oxygenation level dependent (BOLD) MRI before and after 20 mg of I.V. furosemide, trunk mass by DXA, GFR by iohexol clearance, ERPF by p-aminohippurate clearance and albuminuria by urine albumin-to-creatinine ratio (UACR) in 50 adolescents with T1D (mean age 16.1±3.0 yrs, trunk mass 44.8±2.2%, HbA1c 8.6±1.2%, GFR 189±40 ml/min) and 20 non-obese controls (mean age 16.1±2.9 yrs, trunk mass 44.9±2.2%, HbA1c 5.2±0.2%, GFR 136±22 ml/min). The RO2:GFR (s/ml/min*1000) was calculated as renal oxygenation (T2*, s) divided by GFR (ml/min), and furosemide-suppressible oxygenation (FSOC) as change in RO2 in responses to furosemide. Relationships were evaluated by correlation and multivariable generalized linear regression models. RO2:GFR was 25% lower in adolescents with T1D vs. controls (mean±SD: 0.24±0.04 vs. 0.32±0.04, p & lt;0.0001). In adolescents with T1D, lower RO2:GFR was associated with higher UACR (r=-0.31, p=0.03), diastolic blood pressure (r=-0.33, p=0.02), ERPF (r=-0.52, p=0.0009) and trunk mass (r=-0.39, p=0.006). Lower RO2:GFR was also associated with elevated FSOC after adjustments for age, sex and HbA1c (β±SE: -10.5±3.2, p=0.002). For the first time, we demonstrate an imbalance between RO2 and GFR in adolescents with T1D compared with healthy non-obese controls. Additionally, low RO2:GFR independently associated with albuminuria, central adiposity and elevated renal oxygen consumption. These data suggest a potential role of relative renal hypoxia in the development of early DKD. Disclosure C.L. Vinovskis: None. K.J. Nadeau: None. K.L. Tommerdahl: None. P.V. Prasad: None. L. Li: None. L. Pyle: None. M. Rewers: None. M. Pragnell: None. F.H. Mahmud: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Sanofi. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. R. Nelson: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma. Funding JDRF (2-SRA-2018-627-M-B); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK116720)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-306-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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