Loss Of Glycemic Control Research Articles

Circulating Metabolite Biomarkers of Glycemic Control in Youth-Onset Type 2 Diabetes.

We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. We measured 480 metabolites in fasting plasma samples from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Participants (N = 393; age 10-17 years) were randomly assigned to metformin, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Additional metabolomic measurements after 36 months were obtained in 304 participants. Cox models were used to assess baseline metabolites, interaction of metabolites and treatment group, and change in metabolites (0-36 months), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared with clinical risk factors. Loss of glycemic control (HbA1c ≥8% or insulin therapy) occurred in 179 of 393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q < 0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youths with higher baseline levels of these two compounds had a lower risk of treatment failure with metformin alone. For three metabolites, changes from 0 to 36 months were associated with loss of glycemic control (q < 0.05). Changes in d-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c or measures of β-cell function. Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes.

The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Youth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk. To identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D. This post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023. Plasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1). Main outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index). This analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P < .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P < .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], -0.02 [0.006]; P < .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007). This study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk. ClinicalTrials.gov Identifier: NCT00081328.

165-LB: Circulating Metabolomic Biomarkers of Glycemic Control in Youth with Type 2 Diabetes (T2D)

There are few biomarkers of glycemic response among youth with T2D, despite increasing disease prevalence and suboptimal response to approved therapies. We hypothesized that plasma metabolites may predict glycemic outcomes in youth-onset T2D. We measured 480 metabolites in fasting plasma samples in the Treatment options for T2D in Adolescents and Youth (TODAY) study (n=391), in which youth with T2D aged 10-17 years were randomized to metformin alone, metformin + rosiglitazone, or metformin + intensive lifestyle intervention. Metabolite associations with loss of glycemic control (defined as HbA1c ≥8% for 6 months or need for insulin therapy) were modeled using Cox proportional hazards regression adjusted for baseline age, sex, race/ethnicity, BMI, treatment group, and fasting glucose. Loss of glycemic control was observed in 150 of 391 youth (mean 2.6 years). Baseline levels of 11 metabolites were associated with loss of glycemic control (FDR&amp;lt;0.05, Fig. 1A). Treatment group modified the association of hexose and xanthurenic acid levels with glycemic control. For both compounds, youth with higher baseline levels had a lower risk of treatment failure when randomized to metformin therapy alone (Fig. 1B). Thus, metabolomics provides insight into circulating analytes associated with loss of glycemic control, and may highlight different effects of specific treatments in youth with T2D. Disclosure Z. Chen: None. C. Lu: None. X. Shi: None. S. Zheng: None. D. Wolfs: 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. R. E. Gerszten: None. E. M. Isganaitis: None. Funding National Institutes of Health (K23DK127073)

134-OR: Associations of Growth Hormone (GH) Mediators with Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

T2D in youth has a more severe phenotype than in adults, with puberty as a potential contributor to this difference. Pubertal changes in GH mediators (e.g., insulin-like growth factor 1 (IGF-1), growth hormone receptor (GHR), insulin-like growth factor binding protein 1 (IGFBP-1)) may impact insulin sensitivity and beta cell function. We examined associations of GH mediators with loss of glycemic control in youth with T2D using the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort (N= 310). We performed paired comparison of plasma concentrations of IGF-1, GHR, and IGFBP-1 (ELISA), between 0mo and 36mo based on TODAY primary outcome of loss of glycemic control vs. maintained glycemic control (LGC vs MGC), with LGC defined as HbA1c ≥ 8% for 6 months and/or insulin dependence. We studied associations of GH mediators with HbA1c, insulinogenic index, oral disposition index, and 1/fasting insulin. Models were adjusted for age, sex, race, treatment arm, and baseline HbA1c (linear regression). Mean plasma IGF-1 (ng/mL) was lower in LGC group at 0mo (LGC: 451 ± 141, MGC: 485 ± 155, p = 0.04), and at 36mo (LGC: 340 ± 117, MGC: 400 ± 136, p&amp;lt; 0.0001). Increase in IGF-1 between 0-36mo predicted lower HbA1c at 36mo (B = -3.2E-3, SE = 9.0E-4, p &amp;lt; 0.001). Higher GHR was associated with higher HbA1c (B = 1.2E-2, SE = 3.0E-3, p &amp;lt; 0.001) and lower 1/fasting insulin (B = -6.6E-4, SE = 2.1E-4, P &amp;lt; 0.01) at 0mo. Increase in GHR between 0-36mo predicted higher 36mo HbA1c (B = 3.0E-2, SE = 9.4E-3, p &amp;lt; 0.01). IGFBP-1 was positively associated with 1/fasting insulin at 0m (B = 1.1E-3, SE = 4.9E-4, p = 0.03). In exploratory analyses stratified by Tanner stage (TS) at study entry, GH mediators changed differentially between TS 1-3 (n = 31) vs TS 4-5 (n = 274). In conclusion, GH mediators differed based on primary outcome in TODAY, and were associated with HbA1c and insulin sensitivity. Whether changes in GH mediators contribute to, or are the result of, changes in glucose metabolism is a key area for future studies. Disclosure C.Lu: None. D.Wolfs: None. L.El ghormli: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. E.M.Isganaitis: None. Funding National Institutes of Health (2T32DK007260-46); National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK061230-16)

1094-P: Longitudinal Trajectories of Fasting C-Peptide in Youth-Onset Type 2 Diabetes—The SEARCH for Diabetes in Youth Study

In youth-onset type 2 diabetes (YO-T2D; diabetes diagnosed &amp;lt;20 years-old) loss of glycemic control is more rapid than in adults, partly attributed to accelerated beta cell decline. However, no studies have investigated the potential heterogeneity in the longitudinal trajectories of beta cell function and whether genetic factors might contribute to heterogeneity. We derived longitudinal trajectories of fasting C-peptide (FCP) levels, a surrogate measure of beta cell function, via discrete mixture modeling of repeated measures collected over 15 years of follow-up in youth with YO-T2D (antibody negative and insulin resistant; n=266) from the SEARCH for Diabetes in Youth cohort study. We tested the association between the derived trajectories and T2D genetic risk score (GRS) using a multinomial logistic regression model with adjustment for relevant covariates. A four-trajectory model best fit the data, classifying youth with YO-T2D as having either “initial low FCP and stable over time” (32%), “initial high FCP and slow incline” (8%), “initial high FCP and slow decline” (53%), or “initial very high FCP and rapid decline” (7%) (Figure). T2D GRS was not associated with FCP trajectory membership. These data demonstrate substantial heterogeneity in trajectories of FCP in YO-T2D and suggest that genetic predisposition to T2D is not a significant determinant of this heterogeneity. Disclosure A.Shapiro: None. A.Bellatorre: None. J.M.Stafford: None. A.S.Shah: None. C.Pihoker: None. F.Malik: None. A.D.Liese: None. D.J.Pettitt: None. D.Dabelea: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK127208-01, 1UC4DK108173); Centers for Disease Control and Prevention (U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139)

830-P: Preclinical Development of ALN-KHK, an Investigational RNAi Therapeutic for Type 2 Diabetes Mellitus

Fructose consumption is implicated in increased rates of metabolic syndrome and type 2 diabetes worldwide. In the liver, ketohexokinase (KHK) is required for fructose metabolism, phosphorylating fructose to fructose-1-phosphate (F1P), a substrate for synthesis of fatty acids, contributing to nonalcoholic fatty liver. Excess liver fat is associated with insulin resistance and loss of glycemic control. Lowering KHK expression should reduce fatty acid synthesis and thus reduce insulin resistance and improve glycemic control in obese individuals with T2DM. We developed a robust RNAi therapeutics platform for delivery of siRNAs to liver using GalNAc conjugates to specifically silence hepatocyte-expressed genes. Liver-directed silencing of KHK improved insulin sensitivity in pre-clinical models of T2DM. ALN-KHK was selected based on in vitro assessment of a large set of GalNAc-siRNAs targeting human and primate KHK. ALN-KHK demonstrated suppression of liver KHK mRNA and protein in cynomolgus macaques after a single subcutaneous (SC) injection with potent and durable reduction in KHK protein (94.1% lowering through day 85 at the 10 mg/kg dose) supporting evaluation of infrequent dosing in the clinic. To evaluate impact of KHK silencing on fructose metabolism and establish circulating biomarkers of pharmacology, cynomolgus macaques were administered an oral fructose bolus on Day 30 following SC injection of ALN-KHK of 0.3, 3 or 10 mg/kg. ALN-KHK treatment resulted in a dose-dependent increase in circulating fructose with a 4.6-fold increase and a 10.7-fold decrease in FGF21 (which is regulated by liver F1P), at 2 hr post fructose bolus, associated with 90.7% KHK liver protein reduction. These data suggest monitoring of circulating fructose and FGF21 to assess KHK silencing in the clinic. In IND-enabling rat and non-human primate toxicology studies ALN-KHK was safe and well tolerated, supporting the planned initiation of first-in-human studies in obese healthy volunteers. Disclosure L. Noetzli: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. A. Borodovsky: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. X. Chua: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. R. Tymon: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. J. Darcy: None. S. Belozerova: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. M. Keibler: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. H. Tu: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. E. Maratos-Flier: Employee; Novartis, Alnylam Pharmaceuticals, Inc.

Ectopic adrenocorticotrophic hormone syndrome secondary to treatment-related neuroendocrine differentiation of metastatic castrate-resistant prostate cancer.

A 64-year-old man with progressive metastatic castrate-resistant prostate adenocarcinoma presented with recurrent fluid overload, severe hypokalaemia with metabolic alkalosis and loss of glycaemic control. Clinical features were facial plethora, skin bruising and proximal myopathy. Plasma adrenocorticotrophic hormone (ACTH), serum cortisol and 24-h urinary cortisol levels were elevated. Low-dose dexamethasone failed to suppress cortisol. Pituitary MRI was normal and 68Gallium-DOTATATE PET-CT scan showed only features of metastatic prostate cancer. He was diagnosed with ectopic ACTH syndrome secondary to treatment-related neuroendocrine prostate cancer differentiation. Medical management was limited by clinical deterioration, accessibility of medications and cancer progression. Ketoconazole and cabergoline were utilised, but cortisol remained uncontrolled. He succumbed 5 months following diagnosis. Treatment-related neuroendocrine differentiation of prostate adenocarcinoma is a rare cause of ectopic ACTH syndrome. Neuroendocrine differentiation following prostate adenocarcinoma treatment with androgen deprivation has been described. Ectopic adrenocorticotrophic hormone (ACTH) syndrome should be considered where patients with metastatic prostate cancer develop acute electrolyte disturbance or fluid overload. Ketoconazole interferes with adrenal and gonadal steroidogenesis and can be used in ectopic ACTH syndrome, but the impact may be insufficient. Inhibition of gonadal steroidogenesis is favourable in prostate cancer. More data are required to evaluate the use of cabergoline in ectopic ACTH syndrome. Ectopic ACTH syndrome requires prompt management and is challenging in the face of metastatic cancer.

Maternal Diabetes in Youth-Onset Type 2 Diabetes Is Associated With Progressive Dysglycemia and Risk of Complications.

Prenatal exposures, including undernutrition, overnutrition, and parental diabetes, are recognized risk factors for future cardiometabolic disease. There are currently no data on effects of parental diabetes on disease progression or complications in youth-onset type 2 diabetes (T2D). We analyzed effects of parental diabetes history on glycemic outcomes, β-cell function, and complications in a US cohort of youth-onset T2D. Participants (N = 699) aged 10 to 17 years with T2D were enrolled at 15 US centers and followed for up to 12 years as part of the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 follow-up studies. Information about diabetes diagnosis in biological mothers was available for 621 participants (never = 301; before or during pregnancy = 218; after pregnancy = 102) and in biological fathers for 519 (no diabetes = 352; paternal diabetes = 167). Maternal, but not paternal, diabetes was associated with loss of glycemic control over time, defined as glycated hemoglobin A1c greater than or equal to 8% for more than 6 months (P = .001). Similarly, maternal, but not paternal, diabetes was associated with increased risk of glomerular hyperfiltration (P = .01) and low heart rate variability (P = .006) after 12 years of follow-up. Effects were largely independent of age, sex, race/ethnicity, and household income. Maternal diabetes during vs after pregnancy had similar effects on outcomes. Maternal diabetes, regardless of whether diagnosed during vs after pregnancy, is associated with worse glycemic control, glomerular hyperfiltration, and reduced heart rate variability in youth with T2D in TODAY. The strong associations of diabetes outcomes with maternal diabetes suggest a possible role for in utero programming.

749-P: Clinically Relevant Predictors of Cardiovascular Events: Exploratory Analysis from the VERIFY Study of Initial Treatment of Type 2 Diabetes Mellitus

The VERIFY study of primary treatment in type 2 diabetes mellitus (T2DM) , showed delayed glycemic failure (HbA1c ≥7.0% at two consecutive scheduled visits post randomization) with early combination of vildagliptin and metformin (EC) versus initial metformin monotherapy in patients with newly diagnosed T2DM (HbA1c 6.5%-7.5%) . Throughout the 5-year study, 57 adjudicated cardiovascular (CV) events were collected but the study was not powered to test the hypothesis that EC was also able to decrease CV events. Here we explore whether simple clinical data at T2DM onset (Framingham risk equation, CV disease history [CVD-Hx]) could identify patients at risk of subsequent CV events. At baseline, Framingham risk score (FRS) was 14.9±9.2% and 220 (12.3%) patients had CVD-Hx. A significant higher risk in patients with CVD-Hx and FRS ≥20% was visually apparent on KM curves and log rank-test (p=0.001; Figure) . Baseline HbA1c, age and gender were not significantly associated with the CV outcome, whereas treatment failure within the first 3 years was significantly associated with a higher risk of CV events (HR [95% CI]: 3.1 [1.7, 5.6]; p=0.0001) . These analyses suggests that both CV risk stratification at onset of T2DM and early loss of glycemic control may identify patients at higher risk of subsequent CV events. Disclosure D.R.Matthews: Advisory Panel; Novo Nordisk A/S, Other Relationship; Novartis AG, Speaker's Bureau; Servier Laboratories. 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 &amp; Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. P.M.Paldanius: Consultant; Glyconics Ltd, UPM Biomedicals, Speaker's Bureau; Novartis AG, UPM Biomedicals. G.Bader: Employee; Novartis AG. Funding Novartis

Dietary fat quality impacts metabolic impairments of type 2 diabetes risk differently in male and female CD-1® mice.

Metabolic impairments associated with type 2 diabetes, including insulin resistance and loss of glycaemic control, disproportionately impact the elderly. Lifestyle interventions, such as manipulation of dietary fat quality (i.e. fatty acid (FA) composition), have been shown to favourably modulate metabolic health. Yet, whether or not chronic consumption of beneficial FAs can protect against metabolic derangements and disease risk during ageing is not well defined. We sought to evaluate whether long-term dietary supplementation of fish-, dairy- or echium-derived FAs to the average FA profile in a U.S. American diet may offset metabolic impairments in males and females during ageing. One-month-old CD-1® mice were fed isoenergetic, high-fat (40 %) diets with the fat content composed of either 100 % control fat blend (CO) or 70 % CO with 30 % fish oil, dairy fat or echium oil for 13 months. Every 3 months, parameters of glucose homoeostasis were evaluated via glucose and insulin tolerance tests. Glucose tolerance improved in males consuming a diet supplemented with fish oil or echium oil as ageing progressed, but not in females. Yet, females were more metabolically protected than males regardless of age. Additionally, Spearman correlations were performed between indices of glucose homoeostasis and previously reported measurements of diet-derived FA content in tissues and colonic bacterial composition, which also revealed sex-specific associations. This study provides evidence that long-term dietary fat quality influences risk factors of metabolic diseases during ageing in a sex-dependent manner; thus, sex is a critical factor to be considered in future dietary strategies to mitigate type 2 diabetes risk.

Secondary metformin monotherapy failure in individuals with type 2 diabetes mellitus

IntroductionTo assess secondary metformin monotherapy (MM) failure in a real-world type 2 diabetes mellitus (T2DM) cohort.Research design and methodsUsing the IQVIA Electronic Medical Record (formerly GE Centricity) database, adults with...

19-OR: Maternal Diabetes Is Associated with Adverse Diabetes Characteristics and Accelerated Onset of Complications in Youth with Type 2 Diabetes (T2D) in TODAY

Background: Prenatal exposures, including parental nutrition and diabetes (DM) status, are increasingly viewed as risk factors for future cardiometabolic health. There are currently no data on effects of parental DM on disease progression or complications in youth-onset T2D. Aims: To analyze effects of parental history of DM on glycemic outcomes and complications in the TODAY study. Methods: Participants (n=699) aged 10-14 yr with newly diagnosed T2D were enrolled at 14 U.S. centers and followed for up to 15 yr. Subjects had negative islet autoantibodies and BMI &amp;gt;= 85th %. Information about DM diagnosis in mothers of participants was available for 621 participants [Never (MN) =301; During pregnancy (MD) =218; After pregnancy (MA)=102)] and in biological fathers in 519 (No DM=352; Paternal DM=167). Results: Maternal, but not paternal, DM was associated with accelerated loss of glycemic control, defined as HbA1c &amp;gt;8% for over 6 months (p &amp;lt; 0.0001). Participants whose mothers had diabetes had 60% higher risk of loss of glycemic control [MD vs. MN hazard ratio (HR): 1.58 (1.28, 1.95), p &amp;lt; 0.0001; MA vs. MN HR: 1.57 (1.20, 2.04), p = 0.0009]. Similarly, maternal, but not paternal, diabetes was associated with glomerular hyperfiltration [MD vs. MN HR: 1.58 (1.18-2.1), p = 0.0021; MA vs. MN HR: 1.56 (1.08, 2.24), p = 0.0170;], diabetic retinopathy (MD: 50.0%; MA: 59.7%; MN: 41.8%, p=0.0439), and pulse wave velocity indices reflecting heart rate variability, including SD of normal R-R interval [(SDNN), MD: 42 ± 26 ms; MA: 41 ± 26 ms; MN: 54 ± 31 ms; p = 0.0005] and proportion of successive NN intervals greater than 50 ms [(pNN50%), MD: 14.1 ± 19.4; MA: 16.2 ± 21.5; MN: 21.9 ± 23.5; p = 0.0069], after 10 to 15 yr of follow-up. Associations were maintained after adjusting for multiple confounders. Conclusions: Maternal, but not paternal, diabetes is associated with adverse diabetes outcomes and accelerated onset of complications in their offspring with T2D in TODAY. Disclosure E. M. Isganaitis: None. M. A. Van name: None. R. Shah: None. S. Chernausek: None. R. M. Farrell: Stock/Shareholder; Self; Tandem Diabetes Care. M. Geffner: Advisory Panel; Self; Daiichi Sankyo, Novo Nordisk, Pfizer Inc., Consultant; Self; Gilead Sciences, Inc., Other Relationship; Self; Ascendis Pharma A/S, McGraw-Hill, UpToDate, Research Support; Self; Novo Nordisk. J. Keady: None. M. M. Kelsey: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp. B. Tesfaldet: None. J. B. Tryggestad: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254)

165-OR: Antioxidant-Based Encapsulation Strategies to Enhance Islet Allotransplantation

The destruction of insulin-producing cells is a hallmark of type 1 diabetes (T1D) and results in a loss of glycemic control. Islet transplantation can restore glucose homeostasis and prevent hypoglycemic events; however, long-term graft survival is low. Oxidative stress mediates islet transplant rejection. Therefore, suppressing oxidative stress with nanothin encapsulation materials comprised of alternating layers of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), a scaffold polymer, may allow for improved graft survival. We hypothesize that (PVPON/TA)-encapsulation of islets will prolong graft function and delay allotransplantation rejection in the absence of systemic immunosuppression. We recently published that allogeneic transplantation of encapsulated C57BL/6 islets into NOD mice significantly delayed graft failure, decreased free radical-adduct formation, and reduced infiltrating immune cell effector responses. These data suggest local immunosuppression with (PVPON/TA)-encapsulation may be a promising technique to prolong islet graft function in islet allotransplants. To enhance immunosuppression, we conjugated CTLA-4-Ig to the outer surface of (PVPON/TA) layers. (PVPON/TA/CTLA-4)-encapsulated islets display significantly delayed allograft rejection compared to (PVPON/TA) controls. Flow cytometry analysis demonstrated reduced CD80/CD86 costimulatory receptor and MHC-II expression on innate immune populations, enhanced FOXP3+ regulatory T cells, and enhanced PD1+ CD8 T cells within (PVPON/TA/CTLA-4)-encapsulated grafts. To monitor graft integrity in vivo, we conjugated (PVPON/TA) layers with the fluorophore Cy5.5. Transplantation of (PVPON/TA/Cy5.5)-encapsulated islets restored glucose tolerance and was detected in vivo for up to eight weeks post-transplant. The ability to modify our (PVPON/TA) coatings opens the door for endless possibilities to improve clinical islet transplantation. Disclosure J. Barra: None. V. Kozlovskaya: None. E. Kharlampieva: None. H. M. Tse: None. Funding National Science Foundation (1608728); National Institute of Diabetes and Digestive and Kidney Diseases (DK-099550); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B)

Biomedical applications of electrospun nanofibers in the management of diabetic wounds.

Diabetes mellitus (DM) is a complex disease that affects almost all the body's vital organs. Around 415 million people have been diagnosed with DM worldwide, and most of them are due to type 2 DM. The incidence of DM is estimated to increase by 642 million individuals by 2040. DM is considered to have many complications among which diabetic wound (DW) is one of the most distressing complication. DW affects 15% of people with diabetes and is triggered by the loss of glycaemic control, peripheral neuropathy, vascular diseases, and immunosuppression. For timely treatment, early detection, debridement, offloading, and controlling infection are crucial. Even though several treatments are available, the understanding of overlying diabetes-related wound healing mechanisms as therapeutic options has increased dramatically over the past decades. Conventional dressings are cost-effective; however, they are not productive enough to promote the overall process of DW healing. Thanks to tissue engineering developments, one of the promising current trends in innovative wound dressings such as hydrocolloids, hydrogels, scaffolds, films, and nanofibers which merges traditional healing agents and modern products/practices. Nanofibers prepared by electrospinning with enormous porosity, excellent absorption of moisture, the better exchange rate of oxygen, and antibacterial activities have increased interest. The application of these nanofibers can be extended by starting with a careful selection of polymers, loading with active therapeutic moieties such as peptides, proteins, active pharmaceutical ingredients (API), and stem cells, etc. to make them as potential dosage forms in the management of DWs. This review explains the potential applications of electrospun nanofibers in DW healing. A schematic view of role of nanofibers in diabetic wounds.

High dimensional single cell characterization of autoreactive CD8 T-cells reveals heterogeneous phenotypes that play a role in disease progression in Type 1 Diabetes

Abstract Type 1 Diabetes (T1D) is caused by beta cell destruction, eventually resulting in loss of glycemic control. Following onset, subjects with T1D exhibit diverse amounts of residual c-peptide, indicating varying levels of beta cell function. Persistence of c-peptide is correlated with reduced risk of complications and its preservation has been used as an endpoint in clinical trials. However, the immunologic factors that differentiate subjects who retain measurable c-peptide from those who do not are not well characterized. We investigated the number and phenotype of beta cell specific CD8+ T-cells in peripheral blood samples from a cohort of T1D subjects, stratified into slow progressors (c-peptide &amp;gt; 0.1ng/ml) and rapid progressors (undetectable c-peptide), including longitudinal samples. Using tetramers corresponding to HLA-A2 epitopes, we enumerated epitope specific T-cells and sorted single cells for RNA-Seq. Differential gene expression between slow and rapid progressors indicated differences in effector, exhaustion, and regulatory pathways which were consistent with a recently published high dimensional CyTOF data set. Assembly of autoantigen specific TCRs revealed differences in clonal expansion for specific cell clusters. Pseudotime trajectory analysis of the scRNAseq data revealed that CD8+ T cells expressing the same TCR resided in different phenotypic end states. Furthermore, flow cytometric analyses demonstrated differential expression of lineage-specific cell surface markers, which correlated well with the transcriptional profiles within each cluster. Cumulatively, we discovered specific aspects of T cell function and repertoire that differ between slow- and rapid-progressing T1D subjects.

Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis.

In type 1 diabetes (T1D), autoimmune destruction of pancreatic β cells leads to insulin deficiency and loss of glycemic control. However, knowledge about human pancreas pathophysiology in T1D remains incomplete. To address this limitation, we established a pancreas tissue slice platform of donor organs with and without diabetes, facilitating the first live cell studies of human pancreas in T1D pathogenesis to our knowledge. We show that pancreas tissue slices from organ donors allow thorough assessment of processes critical for disease development, including insulin secretion, β cell physiology, endocrine cell morphology, and immune infiltration within the same donor organ. Using this approach, we compared detailed pathophysiological profiles for 4 pancreata from donors with T1D with 19 nondiabetic control donors. We demonstrate that β cell loss, β cell dysfunction, alterations of β cell physiology, and islet infiltration contributed differently to individual cases of T1D, allowing insight into pathophysiology and heterogeneity of T1D pathogenesis. Thus, our study demonstrates that organ donor pancreas tissue slices represent a promising and potentially novel approach in the search for successful prevention and reversal strategies of T1D.

123-OR: Effect of Surgical vs. Medical Therapy on Diabetic Kidney Disease (DKD) in Severely Obese Adolescents with Type 2 Diabetes (T2D)

To compare DKD rates over 5-years of follow-up in two cohorts of severely obese adolescents with T2D undergoing medical vs. surgical interventions. A secondary analysis of data collected by the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of type 2 diabetes in Adolescents and Youth (TODAY) studies was performed. Teen-LABS participants underwent bariatric surgery; TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, and insulin therapy was given when there was loss of glycemic control. TODAY participants (irrespective of treatment group assignment) were frequency matched to the 30 Teen-LABS participants with T2D by baseline age (13-18 years), ethnicity, sex, and baseline BMI (&amp;gt;35 kg/m2). Urinary albumin excretion (UAE), estimated glomerular filtration rate (eGFR) by creatinine and cystatin C equation, and prevalence of elevated UAE (≥ 30mg/g) and hyperfiltration (eGFR ≥ 135ml/min/1.73m2) were assessed. Thirty Teen-LABS participants with T2D (mean±SD age, 16.9±1.3 years; 70% female; 66% white; BMI 54.4 kg/m2) and 63 TODAY participants (15.3±1.3 years; 44% female; 71% white; BMI 40.5 kg/m2) were compared. During 5-years of follow-up, hyperfiltration decreased from 20% to 13% in Teen-LABS and increased from 5% to 37% in TODAY. Elevated UAE decreased from 27% to 5% in Teen-LABS and increased from 21% to 43% in TODAY. Adjusting for baseline age, sex, BMI and HbA1c, Teen-LABS participants had 15-fold lower odds of hyperfiltration (OR: 0.06, 95% CI 0.01-0.38) and 27-fold lower odds of elevated UAE (OR: 0.04, 95% 0.01-0.20) at 5-years of follow-up. Decreases in HbA1c and BMI showed the strongest associations with attenuation of hyperfiltration and elevated UAE, respectively. Compared with medical treatment, bariatric surgery of severely obese youth with T2D was associated with significantly lower odds of DKD over 5-years of follow-up. Disclosure P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. K.S. Hughan: None. M.M. Kelsey: None. A. Shah: None. J.L. Lynch: Board Member; Self; American Academy of Pediatrics. Consultant; Self; Novo Nordisk Inc. Research Support; Self; Daiichi Sankyo Company, Limited, National Institutes of Health, Novo Nordisk Inc., Pediatric Diabetes Consortium. E. Nehus: Other Relationship; Self; Certara. M. Mitsnefes: None. T.M. Jenkins: None. P. Xu: None. C. Xie: None. T.H. Inge: Other Relationship; Self; Independent Medical Expert Consulting Services, Standard Bariatrics, UpToDate. K.J. Nadeau: None. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases

Rationale for and Design of the Study of Early Enteral Dextrose in Sepsis: A Pilot Placebo‐Controlled Randomized Clinical Trial

Sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection and affects over 1 million Americans annually. Loss of glycemic control in sepsis is associated with increased morbidity and mortality, and novel approaches are needed to promote euglycemia and improve outcomes in sepsis. Recent studies from our laboratory demonstrate that early low-level enteral dextrose infusion in septic mice attenuates the systemic inflammatory response and improves glycemic control by inducing intestine-derived incretin hormone secretion. The aim of the Study of Early Enteral Dextrose in Sepsis (SEEDS) is to test the effect of a 24-hour enteral dextrose infusion in critically ill septic patients as a therapeutic agent to decrease systemic inflammation and promote euglycemia. SEEDS is a single-center, double-blind, randomized, controlled trial that will enroll 60 septic patients admitted to the intensive care units at the University of Pittsburgh Medical Center Health System in Pittsburgh. Participants will be randomized 1:1 to receive enteral dextrose (n=30) or water (placebo, n=30) infusion for 24 hours. The primary outcome is the circulating interleukin-6 level measured after the 24-hour infusion compared between dextrose and placebo groups. Secondary outcomes include postinfusion circulating insulin, incretin, and other proinflammatory cytokine levels, as well as incidence of hyperglycemia and hypoglycemia during the infusion period. This trial will characterize the effects of early enteral dextrose on endogenous endocrine pathways and the systemic inflammatory response in sepsis. The results of this trial will inform future larger interventional studies of early enteral nutrients in critically ill patients with sepsis.

Radiation-induced loss of glycemic control in a patient with refractory lymphoma

Radiation-induced loss of glycemic control in a patient with refractory lymphoma