bluuebunny/crossref_metadata_2025 huggingface dataset:
242-OR: Bilateral Dorsolateral Prefrontal Cortex High-Definition Transcranial Direct-Current Stimulation (HD-tDCS) Improves Time-Trial Performance in Elite Cyclists with Type 1 Diabetes (T1D)
Authors: CODELLA ROBERTO , FILIPAS LUCA , GALLO GABRIELE , LUZI LIVIO
Published: May 2022

HD-tDCS is capable to increase the focality of neuromodulation and has been recently applied to improve endurance performance in healthy subjects. Here, in a double-blind, counterbalanced, randomized order, elite cyclists (27 ± 4.3 years; BMI: 20.2 ± 1.2 kg/m2; VO2peak: 67.5 ± 1.2 mL/min/kg) with T1D (no complications) underwent either HD-tDCS (F3, F4) or control (SHAM) and completed a constant-load trial at 75% of the 2nd ventilatory threshold plus a 15-km cycling time-trial (TT) . After HD-tDCS, the total time to cover the TT was 3.8 % faster (P<.01) and associated with higher mean power output (P<.01) and a lower rate of perceived exertion/power at iso-time (F=5.7; P<.01) than the SHAM condition. Cadence, lactate, glycemia, heart rate did not differ in both conditions. These findings suggest that upregulation of the prefrontal cortex could safely enhance endurance performance in elite cyclists with T1D, without altering physiological and perceptual responses at moderate intensity. Present data open to future applications of HD-tDCS to a wider population of active T1D-subjects.

Disclosure

R.Codella: None. L.Filipas: None. G.Gallo: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk.
25-LB: Peripheral Neuropathy and Associated Factors in Patients with Type 2 Diabetes Mellitus in Vietnam—A Cross-Sectional Study
Authors: TRANG NGUYEN T.T. , FONG TSORNG-HARN , DO TUNG D.
Published: May 2022

Peripheral neuropathy and associated factors in patients with type 2 diabetes mellitus in Vietnam: A cross-sectional study Diabetes peripheral neuropathy (DPN) is the most common complication associated with diabetes mellitus. We aimed to establish the characteristic and associated factors of DPN in Vietnam. In total, 140 patients with type 2 diabetes mellitus (T2DM) were screened and enrolled consecutively over a six month period at the endocrinology department in 103 Military hospital. Questionnaires, demographic details, clinical examination, and blood tests were used to collect data from all patients. DPN was evaluated using diabetes neuropathy symptom score and nerve conduction study. Potential factors related to DPN were explored including body mass index, years with disease (<10 vs. ≥10 years) , glycemic control (HbA1C <7.5% vs. ≥ 7.5%) , glomerular filtration rate (GFR) , lipid profile. The prevalence of DPN was 43.5% (61/140) in the number of patients with T2DM. The main manifestation of peripheral nerve damage in subject is numbness 54,1%, decreased rough touch 52,56%. The majority of patients did not have movement disorders 95.08% and normal sense of deep sensation 93,4%. The percentage of patients with a burning sensation, reduction in raw tactile and movement disorders was higher in the group with duration of disease over 10 years (n=23) , compared to the group less than 10 years (n=38) (p <0.05) . The neurotransmitter index in the group of patients with HbA1C ≥ 7.5% (n=17) was significantly different compared to the group with HbA1C < 7.5% (n=44) (p < 0.05) . The group with GFR <70 ml/ph/1.73m2 (n=12) showed the significant change in nerve conduction parameters compared to the group with GFR ≥ 70 ml/ph/1.73m2 (n=49) (p < 0.05) . DPN is highly frequent among patients with T2DM in Vietnam. Associated factors to DPN included duration of disease, HbA1C level and GFR index. The good glycemic control and early clinical manifestation as well as evaluating the kidney function would play an important role in this problem.

Disclosure

N. T. T. Trang: None. T. Fong: None. T. D. Do: None.
251-OR: Maternal Diabetes during Pregnancy and Incidence of Depression and Anxiety in Offspring from Childhood to Young Adulthood
Authors: XIANG ANNY , CARTER SARAH A. , LIN JANE C. , CHOW TING , MARTINEZ MAYRA P. , ALVES JASMIN M. , PAGE KATHLEEN A. , MCCONNELL ROB , NEGRIFF SONYA
Published: May 2022

Many mental health disorders have roots in childhood; diabetes during pregnancy may play a role. We assessed risks of depression and anxiety in offspring associated with maternal pre-existing type 1 (T1D) , type 2 (T2D) , and gestational diabetes (GDM) with and without antidiabetic medications during pregnancy. The cohort included 439,590 singletons born in 1995-2015; followed up to Dec. 2020. Mother’s diabetes status during pregnancy, covariates, and child’s first clinical diagnosis of depression and/or anxiety since age 5 were obtained from electronic medical records. Cox regression was used to assess the associations for all ages and separately for ages 5-12, >12 to 18, and >18 to 26 years. During follow-up, 6.8% of offspring had a clinical diagnosis of depression and 13.4% had a diagnosis of anxiety. Figure 1 shows cumulative incidence of depression and anxiety by maternal diabetes exposure and covariate adjusted hazard ratios for diabetes types relative to unexposed. T1D, T2D, GDM requiring medications were all significantly associated with depression and anxiety in offspring (p<0.for all) ; whereas GDM without medications was not (p>0.5) . The significant associations were observed for ages 5-12 and >12-18 years. These data suggest that severity of diabetes during pregnancy may increase offspring’s vulnerability for depression/anxiety during childhood and adolescence.

Disclosure

A.Xiang: None. S.A.Carter: None. J.C.Lin: None. T.Chow: None. M.P.Martinez: None. J.M.Alves: None. K.A.Page: None. R.Mcconnell: None. S.Negriff: None.
255-LB: Defining Functional Phenotype in Human Islets across Endocrine Cell Composition, Donor Age, Sex, and Ancestry
Authors: BRISSOVA MARCELA , DURAI HEATHER H. , MEI SHAOJUN , COLDREN ANASTASIA , DAVIS COREY , REIHSMANN CONRAD , HOPKIRK ALEXANDER L. , GIBSON DANNIELLE , ARAMANDLA RADHIKA , POFFENBERGER GREG , SAUNDERS DIANE C. , POWERS ALVIN C. , NILAND JOYCE C. , EVANS-MOLINA CARMELLA
Published: May 2022

The Integrated Islet Distribution Program (IIDP) is currently the largest source of human islets for research in the U.S. The IIDP Human Islet Phenotyping Program (HIPP) provides standardized islet assessment and makes these data available to researchers. Since 2016, HIPP has phenotyped 337 islet samples from nondiabetic organ donors (40%F / 60%M, 45±12 years, BMI 29.0±5.4; 52% European, 26% Latino, 8% African, 3% Asian, and 11% other ancestry) . To define the islet structure-function relationships, we integrated physiological profiling of hormone secretion with islet cell composition measured by immunohistochemistry­. We found that % β cells varied significantly (range 34 - 92%; CV 21%) and had a strong negative correlation with % α (range 3 - 59%; CV 33%; r -0.95; p<1.78E-163) and % δ cells (range 1 - 19%; CV 44%; r -0.32, p=2.69E-09) . This variation did not impact basal insulin secretion at 5.6 mM glucose, but insulin secretory responses stimulated by high 16.7 mM glucose, cAMP-evoked potentiation, and KCl-mediated depolarization, were all negatively correlated with % α and δ cells. By contrast, glucagon response to basal 5.6 mM glucose had the strongest negative correlation with % β cells (r -0.31, p=4.25E-09) , but not % δ cells (r 0.03, p=0.63) . Furthermore, the β cell composition did not correlate with age or BMI, but was higher in males vs. females (59.1±12.2% vs. 55.7±11.0%, p=0.0107) and in islets from donors of Asian ancestry (71.2±14.7%, p<0.01) . Finally, we noted that insulin response to KCl-mediated depolarization was significantly lower in islets from donors of African vs. European or Asian ancestry (8.3±4.0 vs. 16.5±8.8 and 13.0±7.0ng/IEQ; p<0.01) . Thus, these data highlight the importance of endocrine cell composition in islet hormone secretion possibly influencing β-α cell paracrine interactions and setpoint of glucagon secretion in response to low glucose. In addition, they suggest that β cell composition and insulin secretion are influenced by sex and ancestry.

Disclosure

M. Brissova: None. G. Poffenberger: None. D. C. Saunders: None. A. C. Powers: None. J. C. Niland: None. C. Evans-molina: Advisory Panel; Avotres Inc., DiogenX, Isla Technologies, MaiCell Therapeutics, Provention Bio, Inc., Other Relationship; Astellas Pharma Inc., Dompé, Lilly, Research Support; BMS, Nimbus Therapeutics. H. H. Durai: None. S. Mei: None. A. Coldren: None. C. Davis: None. C. Reihsmann: None. A. L. Hopkirk: None. D. Gibson: None. R. Aramandla: None.
256-LB: GABA and Sitagliptin Prevent Impairment of ß-Cell Function Caused by High-Fat Diet
Authors: WANG ZHIHONG , FAN LINLING , NI YUNZHI , MA ANRAN , WU DI , CUI QIAOLI , ZHOU YUE , LOU YAN-RU , PRUD'HOMME GERALD J. , WANG QINGHUA
Published: May 2022

Excessive loss of islet beta cells is a major cause for the development of type 2 diabetes (T2D) , and seeking an effective method to enhance beta cell proliferation is a promising therapeutic strategy for T2D. In this study, we examined whether combined therapy of GABA and sitagliptin is effective in promoting beta cell proliferation and ameliorating the impairment of beta-cell function caused by high-fat diet (HFD) feeding in mice. Male C57BL/6J mice were fed with normal chow diet, HFD, or HFD combined with GABA, sitagliptin, or both drugs. Daily oral drug administration was initiated one week before HFD and maintained for two weeks. After two weeks of intervention, we found that GABA or sitagliptin administration ameliorated the impairment of glucose tolerance induced by HFD. This was associated with improved insulin secretion in vivo. Notably, combined administration of GABA and sitagliptin significantly enhanced these effects as compared to each of the monotherapies. Combined GABA and sitagliptin was superior at increasing beta-cell mass, and associated Ki67+ and PDX-1+ beta-cell counts. In addition, we found that HFD-induced compensatory beta-cell proliferation was associated with increased activation of unfolded protein response (UPR) , as indicated by BiP expression. This could be an important mechanism of compensatory beta-cell proliferation, and beta cells treated with GABA and sitagliptin showed greater UPR activation. Our results suggest that the combined use of these agents produces superior therapeutic outcomes.

Disclosure

Z. Wang: None. Q. Wang: None. L. Fan: None. Y. Ni: None. A. Ma: None. D. Wu: None. Q. Cui: None. Y. Zhou: None. Y. Lou: None. G. J. Prud'homme: None.

Funding

The National Natural Science Foundation of China (No.81630020, 81570518, and 81800751) , the Ministry of Science and Technology (No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001) , and Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2017-64-G-R to G P, QW, and T J; and 2-SRA-2015-64 to Q W, G P and T J) .
258-OR: Sustainability of HbA1c Control of Tirzepatide vs. Insulin Glargine in People with Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)
Authors: PEARSON EWAN , DEL PRATO STEFANO , PAVO IMRE , FRANCO DENISE R. , YANG ZHENGYU , WIESE RUSSELL , KAHN STEVEN E.
Published: May 2022

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist in development for glucose-lowering in T2D. The open-label SURPASS-4 trial examined TZP vs. insulin glargine (iGlar) in adults with T2D inadequately controlled on oral medications. Participants (N=1989) with baseline HbA1c 7.5-10.5% and BMI ≥25 kg/m2 were randomized 1:1:1:3 to once weekly TZP (5, 10, 15 mg) or iGlar (100 U/mL) titrated to <100 mg/dL fasting glucose. This post hoc analysis evaluated the sustainability of glycemic control after the 52-week (wk) primary endpoint (last on-treatment visit post-52 wks, up to 1wks) , (median=85 wks) . After achieving the 52-wk HbA1c targets of <7%, ≤6.5%, or <5.7%, a participant was considered to have sustained long-term HbA1c control if the final, post-52-wk, on-treatment HbA1c measurement increased ≤0.2% from the 52-wk HbA1c target (Table) . More participants in all 3 TZP dose groups maintained each of the 3 HbA1c targets beyond 52 wks vs. iGlar (all TZP, p<0.05) . Thus, even for the lowest TZP dose (5 mg) , 59% of participants achieved an HbA1c ≤6.5% at 52 wks, with 75% of these having ≤0.2% increase at their last visit. In contrast, for iGlar, 29% achieved an HbA1c ≤6.5%, with 66% of these having ≤0.2% increase.

In conclusion, TZP treatment results in improved long-term HbA1c control for a significantly greater percentage of adults with T2D compared to iGlar.

Disclosure

E.Pearson: Speaker's Bureau; Sanofi. S.Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. I.Pavo: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. D.R.Franco: Advisory Panel; Abbott Diabetes, Medtronic, Novo Nordisk, Sanofi, Research Support; Eli Lilly and Company, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Medtronic, Roche Diabetes Care, Sanofi. Z.Yang: Employee; Eli Lilly and Company. R.Wiese: Employee; Eli Lilly and Company. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc.
26-LB: Risk Factors of Retinal Oxygen Metabolism and Hemodynamics for Retinopathy in Diabetes
Authors: JIN ZI , ZHOU ZIXIA , ZHANG BIN , WANG FEI , CHEN JIABAO , LIAO DINGYING , LU YUFEI , YANG YUETING , LI JINYING , ZHOU CHUANQING , REN QIUSHI
Published: May 2022

Purpose: Alterations in retinal oxygen metabolism and hemodynamics are signs of impending diabetic retinopathy (DR) . The study aimed to investigate risk factors of the retinal oxygen metabolism and hemodynamics for non-proliferative DR (NPDR) .

Method: The study included 166 eyes from 50 age-matched healthy subjects, 80 diabetic patients without DR (Non-DR) , and 36 NPDR. Each subjects underwent basic medical history and dilated fundal examinations including colour fundus photography, and custom-built multimodal ophthalmic device with function of retinal oximetry and laser speckle flowgraphy. Retinal metabolism was evaluated by retinal arteriolar (SO2a) , and venular (SO2v) oxygen saturation, while retinal hemodynamics was evaluated by related parameters such as diastolic duration, flow acceleration index (FAI) and resistance index (RI) . Continuous variables were analyzed by one-way analysis of variance, and categorical variables were analyzed by the chi-square test for three groups. The logistic regression model was used to obtain the risk factors of Non-DR developing into NPDR.

Result: The SO2a and SO2v of NPDR and Non-DR were higher significantly than controls (p<0.05) . There were significant difference among three groups in hemodynamics parameters, including diastolic duration, FAI, blowout score, and RI. The greatest risk factors of Non-DR developing into NPDR descending order were higher RI (odds ratio (OR) =5.84, 95% confidence interval (CI) =1.32-25.78) , shorter diastolic duration (OR= 3.46, 95% CI=1.35-8.87) , higher glycosylated hemoglobin A1c (OR=1.82, 95% CI=1.15-2.88) , lower body mass index (OR=1.74, 95% CI=1.19-2.55) , longer duration of diabetic mellitus (OR=1.21, 95% CI=1.05-1.39) , smaller age (OR=1.17, 95% CI=1.04-1.32) , higher SO2v (OR=1.16, 95% CI=1.00-1.34) , higher systolic blood pressure (OR=1.05, 95% CI=1.00-1.10) .

Conclusion: Both NPDR and Non-DR show abnormality in retinal oxygen metabolism and hemodynamics. Diastolic duration, RI, and SO2v are independent risk factors in NPDR.

Disclosure

Z. Jin: None. C. Zhou: None. Q. Ren: None. Z. Zhou: None. B. Zhang: None. F. Wang: None. J. Chen: None. D. Liao: None. Y. Lu: None. Y. Yang: None. J. Li: None.

Funding

Guangdong Basic and Applied Basic Research Foundation (2021A1515110747) .
263-OR: Glycemic Gap Predicts Mortality in a Large Multicenter Diabetes Cohort Hospitalized with COVID-19
Authors: MCDONNELL MARIE E. , SIMONSON DONALD C. , GOPALAKRISHNAN GEETHA , GARG RAJESH , MITRI JOANNA , WEINSTOCK RUTH S. , GREENFIELD MARGARET , PALERMO NADINE E. , RADHAKRISHNAN RAMYA , WESTCOTT GREGORY P.
Published: May 2022

While diabetes and admission blood glucose (BG) are established risk factors for adverse outcomes during hospitalization for COVID-19, reports on the impact of prior glycemic control have been variable. We examined the relationship between acute and chronic glycemia on risk of ICU admission, mechanical ventilation (MV) , and mortality among 1,786 patients with diabetes or hyperglycemia (BG > 180 mg/dl twice during any 24-hr period during hospitalization) admitted from March 2020 to February 2021 with COVID-at 5 large university hospitals in the eastern U.S. The cohort was 51.3% male, 53.3% White, 18.8% Black, 29.3% Hispanic, with age = 64.8 ± 13.8 y, BMI = 31.5 ± 7.9 kg/m2, admission BG = 216 ± 134 mg/dl, and HbA1c = 8.1 ± 2.2%. During hospitalization, 38.9% were admitted to the ICU, 22.9% received MV, and 10.6% died. In multivariate regression analysis, among demographic factors, age was the strongest risk factor for in-hospital mortality (OR = 1.per year [95% CI: 1.04, 1.06]) , and Hispanic ethnicity was the greatest risk factor for ICU admission (OR = 1.45 [95% CI: 1.16, 1.80]) and intubation (OR = 1.64 [95% CI: 1.28, 2.10]) . Higher BMI (p = 0.005) and admission BG (p = 0.014) were associated with increased risk of mortality, but HbA1c was not. The glycemic gap (GG) , defined as admission BG minus estimated average BG based on HbA1c, was a stronger predictor of mortality than either admission BG or HbA1c alone. Mortality rate was 5.7% for GG < -20 mg/dl; 12.2% for GG = -20 to < 20 mg/dl; 12.4% for GG = 20 to < 100 mg/dl; and 16.1% for GG ≥ 100 mg/dl (p for trend < 0.001) . Conclusion: Among patients with diabetes or hyperglycemia admitted for COVID-19, in addition to previously established risk factors for poor outcomes (age, Hispanic ethnicity, and BMI) , we found that GG is a stronger predictor of in-hospital mortality than blood glucose alone. This suggests that relative hyperglycemia, as measured by the admission GG, is an important marker of disease severity in COVID-and potentially other serious illnesses.

Disclosure

M.E.Mcdonnell: Advisory Panel; Everlywell, Inc., Research Support; Lilly, Stock/Shareholder; Abbott Diabetes. G.P.Westcott: None. D.C.Simonson: Stock/Shareholder; GI Windows, Phase V Technologies, Inc. G.Gopalakrishnan: Research Support; Eli Lilly and Company, Spruce Biosciences. R.Garg: None. J.Mitri: Consultant; dairy management, Lnutra. R.S.Weinstock: Research Support; Boehringer Ingelheim International GmbH, Dexcom, Inc., Diasome, Eli Lilly and Company, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Medtronic, Novo Nordisk, Tandem Diabetes Care, Inc., Tolerion, Inc. M.Greenfield: None. N.E.Palermo: Research Support; Dexcom, Inc. R.Radhakrishnan: None.

Funding

Brigham-TechFoundation, Cambridge, MA 2021
265-OR: Impact of the COVID-Pandemic on Diabetes Screening from 20to 2021 in Ontario, Canada
Authors: FAZLI GHAZAL S. , MOINEDDIN RAHIM , LING VICKI , BOOTH GILLIAN L.
Published: May 2022

Diabetes incidence is expected to increase following the COVID-pandemic due to widespread changes in physical activity, diet, and access to health care services. We used administrative health care databases from Ontario, Canada to examine monthly changes in diabetes screening during the pandemic (Mar 2020-Feb 2021) compared to the pre-pandemic period (Mar 2019-Feb 2020) among adults aged 20-85 without prior diabetes. The eligible population was 9,599,079 in Mar 20 and 9,941,336 in Feb 2021. Overall, the number of people screened for diabetes was 25.3% lower in the pandemic (N=4,060,348) versus pre-pandemic (N=5,437,284) period. However, the number of people screened each month declined by 65.6% between February and April 2020 (Figure 1; 1.53 vs. 4.44 per 100, -2.91 per 100) . Screening rates recovered by July 2020 (3.88 per 100) but remained 15.6% lower than in the pre-pandemic period. Similar patterns were observed in all age groups but declines in screening rates between February and April 2020 were greatest in adults aged 35-49 (-69.4%) and 50-64 (-69.5%) . Findings were also consistent across income groups.

In summary, we observed a sudden decline in diabetes screening in Ontario, Canada, where laboratory tests and other health care services are universally insured. This may lead to delays in prediabetes and diabetes diagnosis, resulting in missed opportunities for diabetes prevention and early management.

Disclosure

G.S.Fazli: None. R.Moineddin: None. V.Ling: None. G.L.Booth: None.

Funding

Canadian Institute for Health Research
271-OR: Hepatic Glucagon Resistance in Mice with Nonalcoholic Fatty Liver Disease
Authors: CEUTZ FREDERIK R. , CHRISTENSEN EMILIE E. , WINTHER-SOERENSEN MARIE , VILSTRUP HENDRIK , HOLST JENS J. , WEWER ALBRECHTSEN NICOLAI J.
Published: May 2022

Patients with nonalcoholic fatty liver disease (NAFLD) have elevated fasting levels of glucagon (gcg) and amino acids (AA) . Gcg regulates hepatic AA catabolism by augmenting ureagenesis. We hypothesized that hepatic steatosis causes gcg resistance and impaired gcg-induced hepatic ureagenesis. To address this, we developed an isolated liver perfusion model in mice and used it to investigate gcg’s direct effect on hepatic glucose production (HGP) and ureagenesis in 9 male mice with hepatic steatosis (NAFLD mice) (B6.Vlepob/ob/JRj) and healthy controls (CON) (C57bl6/JRj) . NAFLD mice had higher body mass (50 vs. 26 g, P<0.0001) and higher hepatic fat triglycerides (1vs. µmol/g, P<0.0001) compared to CON. Catheters were place in the portal vein and the inferior vena cava and the liver was perfused with Krebs Henseleit buffer with and without 5 mM AA mixture (Vamin) , nM gcg or both. Samples were collected every minute and analyzed for urea and glucose concentrations. Results were normalized to liver tissue protein content. AA administration increased hepatic urea production from baseline in both groups within six minutes (NAFLD mice: 2.4 vs. 5.3 mmol/min × µg protein, P=0.01) , (CON: 3.4 vs. 7.4 mmol/min × µg protein, P=0.02) . Gcg increased the AA-stimulated ureagenesis compared to AA administration alone in CON (7.4 vs. 9.4 mmol/min × µg protein, P<0.0001) but not in NAFLD mice (5.3 vs. 5.1 mmol/min × µg protein, P=0.66) . During the gcg administration (50 minutes) the total HGP was far greater in CON compared to NAFLD mice (309.5 vs. 195.5 µmol/min/µg protein, P=0.03) . The difference in glucose output could not be explained by hepatic glycogen content, as the NAFLD mice showed higher glycogen content than CON (1.7 vs. 0.8 µg/mg liver mass, P=0.02) . Our data support 1) that glucagon acutely increases the substrate-induced ureagenesis and 2) that hepatic steatosis causes resistance to the acute metabolic actions of glucagon on ureagenesis.

Disclosure

F.R.Ceutz: None. E.E.Christensen: None. M.Winther-soerensen: None. H.Vilstrup: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Merck & Co., Inc., Mercodia AB.

Funding

Nicolai J. Wewer Albrechtsen were financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.
282-OR: The Emotional Burden of Diabetes during Emerging Adulthood: “Cost. Everything Else Is Secondary.”
Authors: VITALE REBECCA J. , WENTZELL KATHERINE , LAFFEL LORI M.
Published: May 2022

Emerging adults (EA) with type 1 diabetes (T1D) have multiple developmental stage-specific challenges in diabetes management, including the transition to financial independence. The recently validated Problem Areas in Diabetes-EA (PAID-EA) survey is the first measure of diabetes distress (DD) in EA to include financial concerns. A sample of 287 participants with T1D ages 18-30 years completed an online survey including the 25-item PAID-EA, measures of DD and depressive symptomology, and clinical and demographic questions. To evaluate content validity, 2 open-ended questions asked for the most important worry mentioned and what worries were missed in the questions. Responses were analyzed using directed qualitative content analysis. As cost emerged as a major contributor to DD, responses to the PAID-EA item 21 (“I worry about the cost of diabetes”) were analyzed using Chi-square or Fisher’s exact test to assess participant factors associated with cost-related DD. Most participants (89%) provided open-ended responses (78% female, mean age 24 years) . Cost was the most frequent code in the qualitative analysis: 15% reported DD related to cost and 6% to insurance. Responses included worries about aging out of parents’ insurance and limitations on career choices to ensure payment for diabetes supplies. In all survey respondents, 90% replied “Agree” or “Somewhat agree” to PAID-EA item 21. Responses to this item did not differ by gender, age (< vs. >=25) , continuous glucose monitor use (Y/N) , insulin pump use (Y/N) , student status (full time vs. part time vs. no) , income (< vs ≥$75k) , or insurance status (parent vs. own vs. uninsured) . A greater proportion of those with HbA1c ≥ 7% endorsed worry about cost than with HbA1c < 7% (94% vs. 87%, p = 0.008) . Diabetes cost was a major contributor to DD in this sample of EA with T1D. Worry about diabetes costs was endorsed by nearly all participants, especially those not meeting glycemic targets. Managing the cost of diabetes care for EA may be an avenue to reduce DD.

Disclosure

R.J.Vitale: None. K.Wentzell: None. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc.

Funding

NIH T32DK007260NIH T32DK007529NIH P30DK036836
29-LB: Investigating the Molecular Basis of the Microbiota-Mediated Regulation of Postprandial Chylomicron Production
Authors: ABDALQADIR NYAN H.S. , ADELI KHOSROW
Published: May 2022

Obesity and insulin resistance have been identified as major global health concerns. They are associated with increased intestinal chylomicron production and subsequent remnant lipoprotein accumulation which lead to postprandial dyslipidemia. Dietary composition influences metabolic output of the gut microbiota by digesting dietary nutrients and producing various metabolites, which affects host metabolism. Understanding the mechanistic roles of the microbiota in regulating host lipid metabolism is therefore critical in addressing the pathogenesis of dyslipidemia. In this study, we aimed to investigate the effects of microbiota on lipid and lipoprotein metabolism in Syrian golden hamsters which is a more relevant animal model to human. Microbiota depletion was induced in male and female hamsters given either standard chow or a low fat/high fructose (HF) diet via antibiotic oral gavage administration. The results showed that feeding a HF diet increased plasma triglyceride (TG) and cholesterol (CH) levels while substantially reduced microbiota in antibiotic-administered groups led to significant reduction in circulating TG and CH in both diets. Then, we intended to look at the role of dysbiosis on postprandial lipid accumulation. Interestingly, in both sexes postprandial and TRL-TG levels were dramatically reduced after antibiotic administration; the effect was associated with significantly decreased ApoB48 protein levels. These changes appear to be due to a modulation of genes involved in farnesoid X receptor (FXR) receptor signaling in the ileum. Additionally, some critical genes implicated in lipid synthesis and absorption were also altered in the jejunum, with the most remarkable discovery being the extremely substantial down regulation of Scavenger Receptor Class B type 1“SR-B1” at both the mRNA and protein levels in all antibiotic-treated groups independent of sex and diet.

In summary, our results suggest a novel role for the gut microbiota in regulating lipid and lipoprotein metabolism in the gut, urging further studies to determine the underlying mechanisms.

Disclosure

N. H. S. Abdalqadir: None. K. Adeli: None.

Funding

Canadian Institutes of Health Research
29-OR: Impact of Carbohydrate-Restricted Nutrition Therapy Delivered via Continuous Remote Care on Metabolic Markers in Veterans with Type 2 Diabetes: A Nationwide, Real-World Study
Authors: VANTIEGHEM MICHELLE , MCKENZIE AMY L. , RATNER ROBERT E.
Published: May 2022

Type 2 Diabetes (T2D) affects one in four Veterans and often occurs with dyslipidemia, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD) . In a pilot program, the Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via continuous remote care to Veterans to reverse T2D by reducing glucose and dependence on medication, as demonstrated in prior research. This retrospective analysis assessed the 1- and 2-year effects on lipids and renal and hepatic markers in a real-world sample of Veterans with T2D using medical record data. Changes in metabolic markers from enrollment to 1- and 2-years (E, 1y, 2y) were assessed with paired t-tests with Holm-Bonferroni correction for multiple comparisons. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . HDL-C (E: 42±16, 1y: 46±12, 2y: 44±11 mg/dl; ps<0.001) and triglycerides (E: 205±168, 1y: 186±184, 2y: 160±119 mg/dl; 2y p<0.05) improved. Total cholesterol (E: 165±46 mg/dl) and nonHDL-C (E: 124±46 mg/dl) were unchanged. Serum creatinine (E: 1.0±0.3 mg/dl) and eGFR (E: 85±18 ml/min/1.73m2) were stable; BUN increased (E: 17.3±6.1; 1y: 19.6±8.4, 2y: 18.9±7.6 mg/dl, ps<0.05) but remained within normal limits. Liver enzymes (ALP at E: 77.8±24.6 U/L; ALT at E: 32.3±17.1 U/L) were within normal limits and unchanged except AST decreased (E: 26.6±14.1, 1y: 21.7±8.7, 2y: 21.8±9.3 U/L, 2y p<0.05) . Veterans with T2D who underwent two years of diabetes reversal treatment improved atherogenic dyslipidemia and AST with no adverse effects on other markers of NAFLD and renal function, suggesting long term broad metabolic health benefit of this care model in the real world.

Disclosure

M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.
30-OR: Effects of Vitamin D Supplementation by Race and Weight Status on Serum Vitamin D Measures and Diabetes Risk in the D2d Study
Authors: MONTGOMERY RANEE CHATTERJEE , DAVENPORT CLEMONTINA A. , JOHNSON KAREN C. , KASHYAP SANGEETA , LEBLANC ERIN S. , NELSON JASON P. , VICKERY ELLEN , DAGOGO-JACK SAMUEL , PITTAS ANASTASSIOS G. , DAWSON-HUGHES BESS ,   D2D RESEARCH GROUP
Published: May 2022

Higher blood 25 (OH) D is associated with lower risk of type 2 diabetes (T2D) in people with prediabetes. Blood 25 (OH) D can vary due to skin color and weight. It is not known if blood 25 (OH) D levels have similar impact on T2D risk for people of color or higher weight.

The vitamin D and type 2 diabetes (D2d) study is a randomized clinical trial of participants with high-risk prediabetes and overweight/obesity who were randomized to vitamin D3 4000 IU daily vs. placebo and followed for 2.5 years for the primary outcome of T2D. We compared baseline and intra-trial (mean achieved) serum 25 (OH) D among race-weight groups. We used Cox models to determine the associations between intra-trial serum 25 (OH) D and T2D risk by race-weight groups; we additionally tested for interactions between intra-trial serum 25 (OH) D and race or weight.

Of 2362 D2d participants with self-reported race, Black (n = 616) and White (n = 1616) participants were included in analyses. Baseline serum 25 (OH) D was lower in Black (24.2 ng/mL ± 10.9) compared to White (29.6 ng/mL ± 9.5) participants (P<0.001) ; and were lower in those with higher vs. lower BMI in both races. Intra-trial serum 25 (OH) D was lower in Black participants (P<0.001) overall and those with higher baseline BMI. Both Black and White participants with intra-trial serum 25 (OH) D ≥ 40 ng/mL had significantly reduced risk of T2D [HR (95% CI) ]; Black: 0.51 (0.29, 0.92) ; White 0.42 (0.30, 0.60) ] with no significant race*BMI interaction. Participants with baseline BMI ≤ 40 kg/m2 who achieved intra-trial serum 25 (OH) D levels ≥ 40 ng/mL had significantly reduced risks of T2D but not those with a BMI > 40 kg/m2 with no significant BMI*race interaction.

Conclusions: An intra-trial mean serum 25 (OH) D level ≥ 40 ng/mL was associated with significantly reduced risk of T2D in Black and White D2d participants, but only among those with BMI < 40 kg/m2. Targeting a serum 25 (OH) D level ≥ 40 ng/mL would optimize T2D prevention efforts among people with high-risk prediabetes.

Disclosure

R.Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. B.Dawson-hughes: None. D2d research group: n/a. C.A.Davenport: None. K.C.Johnson: None. S.Kashyap: Advisory Panel; Fractyl Health, Inc., GI Dynamics, Research Support; Janssen Pharmaceuticals, Inc. E.S.Leblanc: n/a. J.P.Nelson: None. E.Vickery: None. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. A.G.Pittas: None.

Funding

American Diabetes Association (1-14-D2d-01) ; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases and Office of Dietary Supplements (U01DK098245)
302-OR: Hypoimmune Human Primary Pancreatic Islets Survive and Function in Humanized Diabetic Mice
Authors: HU XIAOMENG , GATTIS CORIE , YOUNG CHI , OLROYD ARI G. , CHU ELAINE Y.L. , WHITE KATHY , FRIERA ANNABELLE , SCHREPFER SONJA
Published: May 2022

Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We set out to engineer human primary pancreatic islets (PI) using our hypoimmune strategy that could engraft and evade host immune detection in the absence of IS. Human cadaveric PIs were engineered to knock-out function of HLA class I and II and overexpress CD47 (HIP PI) . Unedited PIs were cultured identically (Wt PI) as controls. NSG-SGM3 mice were reconstituted with human CD34+ cells and had >45% engraftment of human CD45+ cells. Mice were rendered diabetic (streptozotocin) . A total of 300 HIP PI or Wt PI were transplanted IM. After 6 days, splenocytes and serum were obtained for immune analyses. HIP PI showed no T cell recognition (ELISpot) , no graft-specific antibodies (Abs) , and were protected from NK cell and macrophage killing. Wt PI had a strong adaptive immune response with high ELISpot frequencies and an increase in graft-directed Abs. Serial BLI showed survival of all HIP PI grafts but rapid rejection of Wt PI, confirmed by histopathology at 4 weeks. Glucose levels gradually decreased after HIP PI transplantation and remained stable around 200 mg/dl after 14 days. These data suggest that hypoimmune engineering may generate HIP PI capable of persisting and functioning in diabetic patients without IS.

Disclosure

X.Hu: None. C.Gattis: None. C.Young: Employee; Sana Biotechnology Inc. A.G.Olroyd: None. E.Y.L.Chu: None. K.White: None. A.Friera: None. S.Schrepfer: Other Relationship; Sana Biotechnology Inc.
308-OR: The Circadian Clock Exerts Coordinated Control of Beige Adipocyte Development via Cytoskeleton-MRTF/SRF Signaling Cascade
Authors: XIONG XUEKAI , LI WEINI , LIU RUYA , YECHOOR VIJAY , MA KE
Published: May 2022

The circadian clock confers temporal regulation in metabolism, and its disruption leads to obesity and insulin resistance. In the current study, we identify that the opposing circadian clock regulators, transcription activator Bmal1 and its repressor Rev-erbα, exert concerted control of the actin cytoskeleton-MRTF/SRF pathway to drive beige adipocyte development, and that this clock regulatory axis is required for beige fat thermogenic capacity. Key components of the MRTF/SRF signaling display circadian oscillations in beige fat, and cistromic analyses revealed Bmal1 and Rev-erbα chromatin occupancy of genes involved in MRTF/SRF regulation. Genetic loss- or gain-of-functions of Bmal1 and Rev-erbα in adipogenic precursors markedly altered actin cytoskeleton organization. Bmal1 silencing inhibits F-actin formation and MRTF/SRF activity whereas its forced expression augments actin cytoskeleton. Notably, Bmal1 and Rev-erbα transcriptional control of the MRTF/SRF signaling modulates beige fat thermogenic capacity in vivo. Prrx1-Cre-mediated subcutaneous beige fat-selective Bmal1 ablation induced browning with augmented mitochondrial metabolism, resulting in resistance to obesity that improved insulin sensitivity. Conversely, overexpression of Bmal1 in beige depot suppressed the thermogenic program with adipose expansion and impaired glucose tolerance. In contrast, Rev-erbα gain-of-function phenocopied that of Bmal1 ablation, leading to browning of beige fat, resistance to obesity and insulin sensitivity. Mechanistically, we show that genetic loss of Bmal1 enhanced beige precursor differentiation and thermogenic induction, whereas Rev-erbα overexpression similarly promoted beige adipogenesis. Collectively, these findings uncover a novel concerted circadian clock control in beige adipocyte development that determines thermogenic capacity via the cytoskeleton-MRTF/SRF signaling cascade.

Disclosure

X.Xiong: None. W.Li: None. R.Liu: None. V.Yechoor: n/a. K.Ma: None.

Funding

NIH 1R01DK112794 to KM and DK097160 to VY
31-OR: Almond Milk Has No Additional Benefits over 2% Milk on Postprandial Glycemia, Lipidemia, and Gastrointestinal Hormones in Patients with Type 2 Diabetes
Authors: MITRI JOANNA , TOMAH SHAHEEN , DREYFUSS JONATHAN , AL-BADRI MARWA , DHAVER SHILTON E. , GARDNER HANNAH , TASABEHJI MHD WAEL , HAMDY OSAMA
Published: May 2022

Almond milk is often used in lieu of dairy milk with the perception of being a healthier substitute, however, its effect on postprandial glycemia compared to 2% milk is not understood. In this study, we compared the 4-hour postprandial effects of almond milk versus carbohydrate- or caloric-matched 2% milk, each served with a similar amount of oatmeal in patients with T2D. In this cross-over, three-way, open-label study, 22 overweight or obese patients with T2D consumed ½ cup (40 g) of oatmeal served with 360 mL almond milk (ALM) or carbohydrate-matched (246 ml) 2% milk (CarbM) or calorie-matched (182 ml) 2% milk, on separate days, in random order. The primary outcome was glucose incremental area under the curve (iAUC 0-240) while changes in other analytes were secondary outcomes. Blood samples for glucose, free fatty acids (FFA) , gastrointestinal (GI) satiety and hunger hormones were drawn at baseline, 15, 30, 60, 90, 120, 180 and 240 minutes. Incremental AUCs were compared between groups using Wilcoxon signed rank test. P-values for analytes other than glucose were adjusted with the false discovery rate (FDR) . P<5% for glucose or FDR<5% were considered significant. There were no differences in iAUC 0-240 for glucose, triglycerides, PYY, active GLP-1 or amylin, leptin, GIP, cholecystokinin, ghrelin or FFA in any pair-wise comparison. However, iAUC 0-240 for insulin and glucagon were significantly higher in CarbM vs. ALM (FDR 0.002 and 0.02 respectively) .

In conclusion, compared to almond milk used with oatmeal, carbohydrate- or caloric-matched 2% milk has similar effects on postprandial glucose, FFA, triglycerides and GI hormones for up to 4 hrs, indicating no additional benefits of almond milk over 2% milk. On the contrary, carbohydrate-matched 2% milk increased insulin and glucagon secretion compared to almond milk. The long-term significance of this increase in insulin release needs to be further elaborated in a long-term study.

Disclosure

J.Mitri: Consultant; dairy management, Lnutra. S.Tomah: None. J.Dreyfuss: None. M.Al-badri: None. S.E.Dhaver: None. H.Gardner: None. M.Tasabehji: None. O.Hamdy: Advisory Panel; L-Nutra Inc., Nestlé, Consultant; Abbott, Sanofi, Research Support; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Healthimation.
316-OR: Genetic Deletion of Beta-Cell Pkm1, Pkm2, and Pck2 Identifies PEP as an Essential Signal for Compartmentalized KATP Closure and Cycling of the Insulin Secretory Pathway
Authors: FOSTER HANNAH R. , HO THUONG , POTAPENKO EVGENIY , CARDONE REBECCA L. , KIBBEY RICHARD , MERRINS MATTHEW J.
Published: May 2022

β-cells use pyruvate kinase to sense nutrients and respond with appropriate insulin secretion. Here, we used β-cell deletion to identify the functions of constitutively active PKm1 and allosterically recruitable PKm2, and assess their regulation by mitochondrial PEP from PCK2. We demonstrate that both PKm isoforms are present in the KATP channel microcompartment. Compartmentation nullifies the disparities in PK isoform expression and activity, allowing the minor but recruitable PKm2 isoform to fully participate in KATP regulation. However, this shared control does not extend to β-cell response to amino acids, which requires PKm1 for the initiation of Ca2+ influx and insulin secretion and PKm2 for their termination. Mitochondrial PEP is required for this cycling between “on” and “off” states, as demonstrated by β-cell-specific deletion of PCK2. PCK2 was revealed to be an essential mechanism of β-cell cataplerosis, possessing metabolic control over cytosolic ATP/ADP generation in response to anaplerotic fuels. Further, PCK2 is required for amino acid-stimulated Ca2+ influx (via PKm1) and efflux (via PKm2) . These data provide strong genetic evidence for a revised oscillatory model of β-cell metabolism in which PKM1- and PKM2-driven PEP cycles play unique roles in the initiation and termination of nutrient-stimulated insulin secretion.

Disclosure

H.R.Foster: None. T.Ho: None. E.Potapenko: None. R.L.Cardone: n/a. R.Kibbey: Consultant; Agios, Inc. M.J.Merrins: None.

Funding

NIH/NIDDK (R01DK113103) HRSA (T32HP10010) NIH/NIA (T32AG000213)
323-OR: Associations of Leukocyte Telomere Length and Related Allelic Variations with the Risk of Coronary Events in People with Long-Standing Type 1 Diabetes
Authors: SANCHEZ MANUEL , POTIER LOUIS , VENTECLEF NICOLAS , FUMERON FRÉDÉRIC , SCHEEN ANDRÉ , GAUTIER JEAN-FRANÇOIS , MARRE MICHEL , ROUSSEL RONAN , MOHAMMEDI KAMEL , VELHO GILBERTO
Published: May 2022

Backgrounds and Aims: Leukocyte telomere length (LTL) is associated with cardiovascular risk. We evaluated associations between LTL, allelic variations (SNPs) in LTL-related genes (associated with LTL in the literature) and the incidence of coronary artery disease (CAD) in adults with long-standing type 1 diabetes.

Participants and Methods: LTL was measured by real-time PCR in 260 participants of the GENEDIAB cohort (males 60%, age 45±12 years, duration of diabetes 29±years at baseline, mean±SD) . Thirty-three SNPs in LTL-associated genes were genotyped in 826 participants from GENEDIAB and GENESIS cohorts (males 55%, age 43±12 years, duration of diabetes 27±9 years at baseline) . The risk for CAD (myocardial infarction or coronary artery revascularization) during follow-up was analyzed using Cox models according to LTL (expressed in tertiles of distribution) and SNPs.

Results: The cumulative incidence of CAD in GENEDIAB (11±7-year follow-up) was 21.2%. The incidence of CAD by LTL tertiles was 27.6% (shorter LTL) , 23.3% (intermediate LTL) and 12.6% (longer LTL) . Hazard ratio (HR) for shorter vs. longer LTL was 1.63 (95%CI 1.15-2.37) , p=0.005, unadjusted model, and 1.58 (95%CI 1.08-2.39) , p=0.02, after adjustment on sex, age, duration of diabetes, blood pressure, kidney function and history of CAD at baseline. The cumulative incidence of CAD in GENEDIAB and GENESIS pooled data (followed by 11±6 years) was 15.1%. Six SNPs located in three genes (TERC, NAF1 and TNKS) were significantly associated with the incidence of CAD.

Discussion: Shorter LTL at baseline was associated with an increased risk of CAD during the follow-up in adults with long-standing type 1 diabetes. Allelic variations in LTL-related genes were also associated with coronary risk in these subjects.

Disclosure

M.Sanchez: None. G.Velho: None. L.Potier: Board Member; Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Consultant; AstraZeneca, Sanofi. N.Venteclef: None. F.Fumeron: None. A.Scheen: Advisory Panel; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Gautier: Other Relationship; Novo Nordisk, Sanofi, Speaker's Bureau; Eli Lilly and Company. M.Marre: Board Member; AstraZeneca, Consultant; Novo Nordisk. R.Roussel: None. K.Mohammedi: Board Member; Lilly, Novo Nordisk, Sanofi, Research Support; Cyclerion Therapeutics, Inc., Speaker's Bureau; Abbott, AstraZeneca.
324-OR: Pathway-Specific Role of Insulin in an In Vivo Model of Restenosis
Authors: LIU ZHIWEI , GONZALEZ MAREL , OU SONGXIAN , QIU LANHUI , GIACCA ADRIA
Published: May 2022

Percutaneous transluminal coronary angioplasty is an effective treatment for stenotic lesions, but restenosis remains as a common adverse effect and contributes to post-angioplasty failure. Patients with type 2 diabetes have higher risk of post-angioplasty restenosis due to insulin resistance. In vitro studies showed that insulin has a vasculoprotective effect on endothelial cells (ECs) which is likely mediated by phosphoinositide 3-kinase (PI3K) /Akt pathway, while its mitogenic effects are mainly manifested on vascular smooth muscle cells (VSMCs) and likely mediated via mitogen-activated protein kinase (MAPK) pathway. Currently, there is not much information about pathway-specificity of insulin’s vascular effects in in vivo models. This study aims to determine the Akt2- and MEK1 (MAPK kinase activator) -mediated effects on neointimal growth in a murine model of restenosis. Akt2/MEK1 floxed mice were crossed with tamoxifen-inducible Cre recombinase under the control of vascular endothelial cadherin (Cdh5) or smooth muscle myosin heavy chain (SMMHC) promoters. Mice were implanted subcutaneously with either insulin pellets (0.U/day) or blank pellets three days prior to femoral artery wire injury surgery. Femoral arteries were collected 28 days after surgery for histology analysis. We found that both neointimal area (NA) and intima-to-media ratio (I/M) were lowered in Akt2 floxed Cre- and and wild type Cre+ control mice following insulin treatment, however, insulin failed to have the same effect in both EC and SMC Akt2 deficient mice. Preliminary data suggest that the effect of insulin on decreasing NA and I/M may be greater in EC MEK1 deficient mice but not in SMC MEK1 deficient mice than controls. These data suggest that both EC and VSMC Akt2 contribute to the beneficial effects of insulin, while EC-specific MEK1 knockdown may accentuate the beneficial effects of insulin.

Disclosure

Z.Liu: None. M.Gonzalez: None. S.Ou: None. L.Qiu: None. A.Giacca: None.