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  • KELSEY, MEGAN M.  (5)
  • PYLE, LAURA  (5)
  • 1
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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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  • 2
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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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  • 3
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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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  • 4
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    Longitudinal Predictors of Insulin Sensitivity and Secretion during Puberty
    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: All youth experience a transient reduction in Si during puberty, but little is known about the associated physiology. We previously demonstrated cross-sectionally that insulin-like growth factor 1 (IGF-1) and leptin are associated with Si early in puberty. We now aim to evaluate longitudinal predictors of Si and acute insulin response to glucose (AIRg) during puberty. Methods: Forty-five (47% female) normal-weight (mean BMI %ile 44±22%) ethnically mixed youth entered the study in early puberty (Tanner [T] 2-3). Study visits, including an IV glucose tolerance test (IVGTT), fasting laboratory studies, and DXA, were performed at T2-3, T4, and T5, based on breast development and testicular volume. Physical activity (PA) was assessed by the 3DPAR (3-Day PA Recall). Repeated measures models were used to test if changes over time in potential predictors (IGF-1, leptin, estradiol, total testosterone, dehydroepiandrosterone-sulfate, PA, and urinary gonadotropins) were associated with changes over time in the outcomes, with and without adjustment for sex and % body fat. Results: Si (p=0.04) decreased and AIRg increased (p=0.12) from T2/3-T5. IGF-1 and leptin were the only significant predictors of change in Si and AIRg over time. IGF-1 was associated with both Si (β=-0.016, p=0.0004) and AIRg (β=1.40, p=0.002), and remained so after adjusting for sex and % fat (p=0.0007 and 0.004, respectively). Leptin was associated with Si in univariate analysis (p=0.003) and with both Si (β=-0.238, p=0.003) and AIRg (β=38.4, p=0.043) after adjustment for sex and % fat. Conclusions: This is the first study to show a longitudinal relationship between leptin and Si and AIRg during puberty independent of sex and body fat, and confirms previous reports of associations between IGF-1 and Si and AIRg. These results suggest that leptin and IGF-1 may be driving factors for changes in Si and AIRg during puberty. Knowledge of normal pubertal metabolism may contribute to understanding of diseases of pubertal onset, such as type 2 diabetes. Disclosure M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp.. L. Pyle: None. A.M. Hilkin: None. A. Johnson: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Daiichi Sankyo Company, Limited, Merck & Co., Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Boehringer Ingelheim GmbH.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1348-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 5
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    1342-P: Development of Type 2 Diabetes (T2D) in Obese Adolescent Girls with Polycystic Ovary Syndrome (PCOS)
    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: PCOS is a common endocrine disorder that starts in adolescence and, when accompanied by obesity, is associated with a 4-fold risk of T2D. Adolescent onset of T2D carries significant morbidity and decreased life expectancy; rates of T2D are 12.5 cases/100,000/year in the general youth population. The incidence and prevalence of T2D in teen girls with PCOS and obesity are unknown. We conducted a retrospective chart review at a large tertiary care center. Using ICD9/10 codes for PCOS, girls aged 11-21 years with clinic visits between 7/1/2013-8/15/2018 and a BMI %ile & gt; 85th were identified. Diagnosis of PCOS and T2D were confirmed using Endocrine Society and ADA guidelines, respectively. Key demographic and diagnostic information, including time of T2D diagnosis relative to PCOS diagnosis, was extracted. Prevalence of T2D in the PCOS cohort was calculated 1) from the entire T2D cohort and 2) only the incident T2D cases, as our site may have excess new T2D diagnosis referrals. We identified 600 cases of PCOS (15.2 ± 1.8 years, BMI %ile 96.2 ± 12.1) and 54 of these also had T2D, of whom 23 were diagnosed with PCOS prior to T2D (incident cohort). The prevalence of T2D in girls with PCOS and overweight/obesity was 4% including only incident cases and 9% with inclusion of all T2D. The incidence of T2D among adolescents with obesity and PCOS is 129 cases/1000/year and T2D presents 26 ± 19 months after PCOS diagnosis. Girls with T2D were more likely to be Hispanic (67% vs. 49%; p & lt;0.0001) have obstructive sleep apnea (32% vs. 17%; p=0.01) and a 1st-degree relative with T2D (56% vs. 22%; p & lt;0.001) than those who didn’t develop T2D. Girls with PCOS and obesity are at high-risk for developing T2D in adolescence, with 1 in 23 developing T2D within 2 years of diagnosis with PCOS. Girls at higher risk include those with a strong family history of T2D and Hispanic ethnicity. Further work is needed to confirm these rates in the overall adolescent population and to develop strategies for prevention of T2D in these high-risk youth. Disclosure J. Hudnut-Beumler: None. J. Kaar: None. L. Pyle: None. M.M. Kelsey: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. M. Cree-Green: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K23DK107871)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1342-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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