bluuebunny/crossref_metadata_2025 huggingface dataset:
269-LB: Modeling Alpha-Cell Dysfunction Using Stem Cell–Derived Alpha Cells
Authors: SHRESTHA SWIKRITI , PETERSON QUINN P.
Published: June 2023

Type 1 Diabetes (T1D) therapies have focused on restoring beta cell function via exogenous insulin or islet transplant. While promising, these approaches fail to account for the role of alpha cells and intra-islet communication in disease etiology. Alpha cells secrete glucagon and maintain effective paracrine signaling with beta cells to maintain glucose homeostasis and metabolic control. Mounting evidences suggest that impaired alpha cell function is a significant contributor to disease progression. Understanding triggers of alpha cell dysfunction and the resulting effects will be crucial for restoring both beta and alpha cell function in T1D. Lack of human alpha cell models have limited progress towards this goal. We recently reported a protocol to generate human alpha cells from stem cell sources (SC-alpha). Using these SC-alpha cells, we have established a T1D disease model to identify the triggers that induce alpha cell dysfunction. Importantly, we have identified defects in proglucagon processing that mimic those observed in diabetes and have identified conditions that modulate proglucagon processing and secretion. Here we demonstrate that exposure of SC-alpha cells to diabetogenic stressors such as hyperglycemia, hyperlipidemia, and ER stress impacts the processing of proglucagon and ultimately results in alpha cell dysfunction. We show that upon exposure to these stressors, SC-alpha cells secrete elevated glucagon compared to the control conditions and show a loss of glucose responsiveness. We also observed changes in the secretion of alternate proglucagon processing products, GLP-1, GLP-2, and glicentin. Interestingly, glicentin levels were affected by ER stress induction, but were unaffected by other stressors, suggesting that ER stress plays a direct role in the disruption of proglucagon processing, leading to alpha cell dysfunction. Identifying triggers of alpha cell dysfunction and assessing impacts in proglucagon processing will be a step towards restoring islet paracrine signaling.

Disclosure

S. Shrestha: None. Q. P. Peterson: None.
269-OR: Empagliflozin on the Risk of Retinopathy in Patients with Type 2 Diabetes—Results from the EMPRISE Study
Authors: TESFAYE HELEN , HTOO PHYO T. , PAIK JULIE M. , ZAKOUL HEIDI , SCHMEDT NIKLAS , DERUAZ-LUYET ANOUK , KOENEMAN LISETTE , WEXLER DEBORAH J. , PATORNO ELISABETTA
Published: June 2023

EMPRISE aims to assess the effectiveness and safety of empagliflozin in patients with type 2 diabetes (T2D) in routine care. Within EMPRISE, we investigated two diabetic retinopathy (DR) outcomes among adults with T2D initiating empagliflozin or DPP4 inhibitors (DPP4i) in 2 separate cohorts. Using data from Medicare-fee-for-service and 2 U.S. commercial claims databases (2014-2019), we compared the risk of non-proliferative DR (NPDR) onset (cohort 1) and the risk of DR progression (cohort 2). To evaluate the onset of NPDR, we identified 34,262 1:1 propensity-score matched (PSM) patient pairs without history of any DR (Table). To evaluate DR progression (see Table for definition), we identified 7,839 1:1 PSM patient pairs with history of NPDR and without diagnosis or treatment for advanced DR prior to cohort entry. We estimated pooled HR and RD/1,000 PY with 95% CI adjusting for 143 baseline covariates. Compared to DPP4i, a similar risk of NPDR onset was observed with empagliflozin initiation [HR: 1.05 (0.95, 1.16); RD: 1.52 (-1.61, 4.65)] and a decreased risk of DR progression [HR: 0.77 (0.62, 0.95); RD: -9.49 (-16.90, -2.08)], over a mean follow-up of ~8 months on treatment. In routine care in a broad population of patients with T2D empagliflozin was associated with a lower risk of DR progression in line with direction and magnitude of a similarly defined DR outcome in the EMPA-REG OUTCOME trial.

Disclosure

H.Tesfaye: None. P.T.Htoo: Employee; Johnson & Johnson. J.M.Paik: None. H.Zakoul: None. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. D.J.Wexler: Other Relationship; Novo Nordisk A/S. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration.
270-LB: Pancreatic Glial Cells Distribution Patterns Are Distinct between Human and Mouse
Authors: NIU JINGJING , HACKNEY DARYL J. , AHMADI PABLO , HARA MANAMI , HULL-MEICHLE REBECCA L. , TONG JENNY
Published: June 2023

Glial cells are components of the central and peripheral nervous systems, which provide physical support for neuron and modulate synaptic transmission. We and others previously showed that in mice, pancreatic glial cells are located in close association with the extensive neuro-endocrine-vascular network that surrounds the islet perimeter. It is well known that differences exist in mouse and human islet architecture, in particular in vascular density and innervation. We therefore sought to determine whether density and/or organization of pancreatic glial cells also differs between mouse and human. Glial fibrillary acidic protein (GFAP) was used to identify pancreatic glial cells and was examined by confocal microscopy. In mouse pancreas, GFAP+ cells were frequently identified around the islet periphery and were less frequently seen in the core of the islet. In human pancreas, however, most of the GFAP+ cells were found in the exocrine tissue, resulting in fewer peri-islet glial cells relative to mice (table). High-fat diet feeding significantly increased %peri-islet GFAP+ area in mice while no difference was seen between obese and lean human donors (table). These findings indicate that pancreatic glial cell distribution patterns differ between mouse and human, raising the possibility that these cells may affect islet-cell function differently between the two species.

Disclosure

J. Niu: None. D. J. Hackney: None. P. Ahmadi: None. M. Hara: None. R. L. Hull-meichle: Employee; Veterans Administration, Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health, Veterans Administration. J. Tong: None.

Funding

University of Washington
273-LB: The Effect of Bispecific GLP-1R/GLP-2R Agonist Compared with Dual GLP-1R/GLP-2R Agonist and Dual GLP-1R/GIPR Agonist in Diet-Induced Obesity Mouse Model
Authors: OH TIMOTHY , YANG SANG-IN , ROH JAEIL , YOON SUNG JEE
Published: June 2023

Obesity is a global health challenge with few pharmacological options associated with type 2 diabetes and cardiovascular (CV) complications. MG12, a bispecific GLP-1R/GLP-2R Fc-fused agonist, was manufactured to show its potential advantage over current comparable dual incretin agonists. In this study, we observed that MG12 was superior in body weight (BW) reduction when compared to dual GLP-1R/GLP-2R agonist as well as combination therapy of GLP-1R and GLP-2R Fc-fused agonist. We predicted this as the result of the optimized state of increasing GLP-1 activity and the bispecific structural nature. Also, MG12 showed BW reduction in a dose-dependent manner. Interestingly, MG12 at a high dose showed similar BW reduction to dual GLP-1R/GIPR agonist despite a lesser decrease in food intake after the first injection. Additionally, we noted a higher reduction in fat/muscle mass ratio after the last injection in the comparable BW reduced group. Furthermore, MG12 showed a decrease in low grade inflammation biomarkers, which may indicate a potential CV outcome benefit. Therefore, MG12 may be a promising new therapeutic approach for obesity-related metabolic disorders.

Disclosure

T. Oh: Employee; Progen. Co., Ltd, SL Metagen. Co., Ltd. S. Yang: None. J. Roh: None. J. Sung: None.
274-LB: Complement Factor D Contributes to Metabolic Dysregulation by Hepatic CD9 Deficiency
Authors: ZHENG YI
Published: June 2023

Diabetes-induced metabolic diseases involve functional integration among inter-organ communication, and the liver is central to this process. Here we show that deficiency of cell-surface protein tetraspanin CD9 in the liver of diabetic mice stimulates hepatocytes to synthesize and secrete complement factor D (CFD), which undermines whole-body metabolic homeostasis. Specifically, silencing liver CD9 exacerbated diet-induced obesity and fatty acid synthesis in white adipose tissue of mice with a markedly elevated CFD expression in both liver and plasma. Consistently, liver CFD-overexpressed mice exhibited severe hepatic steatosis, increased fat adipose deposition and decreased energy expenditure under HFD feeding. Mechanistically, CFD exerted its deleterious metabolic effects by activating its receptor C5aR-AKT dependent axis in the adipose tissues, and blockade of C5aR in adipocytes obviously abolished the CFD-induced lipogenesis and -suppressed thermogenesis in vitro and in vivo. Furthermore, we determined an increased CFD with the decreased CD9 expression in the fatty livers of human subjects, and also a negative correlation between CD9 and CFD was established in NAFLD patient samples. Together, these findings identify CFD inhibition as a potential pharmacological target for the management of diabetes and related metabolic disorders.

Disclosure

Y. Zheng: None.

Funding

National Natural Science Foundation of China (82122013, 82100910)
279-LB: The Role of Body Composition Phenotypes on Insulin Resistance in Nondiabetic Asians—The Korea National Health and Nutrition Examination Survey (KNHANES) 2008–2011
Authors: REUM KHANG AH
Published: June 2023

It is increasingly recognized that obesity as defined by body fat distribution as well as body mass index (BMI) contributes to metabolic disturbances. The relationship between body fat percent (%BF) and insulin resistance in the Asian population remains uncertain. We investigated the association between insulin dynamics and the four body composition phenotypes using BMI and %BF; normal with normal-fat percent (NN), normal with high-fat percent (NH), obese (overweight/obesity) with normal-fat percent (ON), and obese with high-fat percent (OH). We performed a cross-sectional study with 16,578 adult participants aged between 19 and 80 in the fourth and fifth KNHANES with Dual Energy X-ray Absorptiometry (DEXA) data. The subjects with diabetes are excluded. The mean age was 42.72 (standard error (SE) 0.30) years old. The prevalence of impaired fasting glucose, hypertension, and dyslipidemia was higher depending on the body composition phenotypes (p for trend <0.001). Homeostatic model assessment of insulin resistance (HOMA-IR) increased and the quantitative insulin check index (QUICKI) decreased significantly according to the body composition phenotypes (p for trend <0.001). The OH group exhibited significantly the highest HOMA-IR (mean 2.69, SE 0.03) and the lowest QUICKI (mean 0.335, SE 0.001) values. The odds ratio (OR) for high HOMA-IR (men >2.5, women >2.0) and low QUICKI (men <0.347, women <0.343) was increased according to the body composition phenotypes. NH group showed significantly higher OR than ON group, compared to NN group (OR 1.25, 95%CI 1.02-1.53 vs OR 0.91, 95% CI 0.70-1.19, respectively).

In conclusion, using body fat percent with BMI to categorize obesity is useful for estimating HOMA-IR and QUICKI. Although subjects have normal BMI, the amount of their fat mass plays an important role in insulin dynamics. The subjects with high-fat percent need to detect and intervene earlier for future prognosis.

Disclosure

A. Khang: None.
281-OR: Neonatal Outcomes in Early and Incident Gestational Diabetes Mellitus—Are They Normalized with Treatment from 24–28 Weeks’ Gestation?
Authors: SIMMONS DAVID , IMMANUEL JINCY , WAH CHEUNG N. , HAGUE WILLIAM , TEEDE HELENA , NOLAN CHRISTOPHER J. , BACKMAN HELENA E. , HIBBERT EMILY , PEEK MICHAEL J. , MCLEAN MARK , SWEETING ARIANNE , MOHAN VISWANATHAN , HARREITER JÜRGEN ,   TOBOGM CORE INVESTIGATOR GROUP
Published: June 2023

Aim: To compare neonatal outcomes between women with early GDM (eGDM: diagnosed<20 weeks’ gestation), incident GDM (iGDM: diagnosed ≥ 24 weeks’ gestation) and normoglycemia

Methods: Pregnant women with GDM risk factors were enrolled <20 weeks’ gestation into an eGDM treatment trial across 17 sites in Australia, India, Europe. Women undertook a 2-h 75g oral glucose tolerance test on entry & at 24-28 weeks’ gestation. GDM was defined by WHO 2013 criteria. Logistic regression compared outcomes between women with eGDM, iGDM and normoglycemia adjusted for age, body mass index (BMI), site, smoking status, parity and tertiary qualifications. Women randomized to receive eGDM treatment were excluded from this analysis.

Results: Baseline characteristics differed by age, BMI, parity and glycemia across the 3211 women (Table 1). Similar proportions of eGDM and iGDM women received pharmacotherapy. eGDM group gestational weight gain was lower; eGDM and iGDM neonatal outcomes were similar; neonatal intensive care unit admission and respiratory distress were higher in offspring of eGDM than normoglycemic women.

Conclusions: Adverse neonatal outcomes are increased in pregnancies complicated by eGDM with delayed treatment.

Disclosure

D.Simmons: Consultant; Sanofi, Speaker's Bureau; Abbott Diabetes. M.Mclean: None. A.Sweeting: None. V.Mohan: None. J.Harreiter: None. Tobogm core investigator group: n/a. J.Immanuel: None. N.Cheung: None. W.Hague: None. H.Teede: None. C.J.Nolan: None. H.E.Backman: None. E.Hibbert: None. M.J.Peek: None.

Funding

National Health and Medical Research Council (1104231, 2009326); Region Örebro Research Committee (OLL-970566, OLL-942177); Medical Scientific Fund of the Mayor of Vienna (15205); South Western Sydney Local Health District Academic Unit (2016); Western Sydney University Ainsworth Trust (2019)
290-OR: FoxK1-Associated Gene Regulatory Network—A New Transcriptional Regulator of Hepatic Insulin Action
Authors: ALLU PRASANNA , PAN HUI , DREYFUSS JONATHAN , RONALD KAHN C.
Published: June 2023

Insulin acts on the liver to maintain glucose homeostasis, and disruption of insulin action in liver is central in the pathogenesis of diabetes and metabolic syndrome. While most previous studies of insulin action on gene expression in liver have focused on FoxO1, we have found that Forkhead box protein K1 (FoxK1) is another important regulator of hepatic gene expression which acts in a complementary manner. Thus, upon insulin stimulation, FoxK1 translocates from the cytoplasm to nucleus while FoxO1 translocates from nucleus to cytoplasm. Chromatin immunoprecipitation (ChIP) sequencing shows that FoxK1 binds to >1000 gene regulatory elements in the proximal promoters and enhancers in hepatic chromatin, with TGTTTAC being the major FoxK1 DNA binding motif. De novo motif analysis suggested that HNF4A is also one of the major co-regulators for FoxK1 in mediating gene expression. Insulin stimulated binding of FoxK1 to promoters was observed in up-regulation of genes involved in steroid biosynthesis and cell cycle, and down-regulation of genes involved in autophagy. FoxK1 is also a potential transcription factor for insulin receptor (IRβ) mediated gene regulation as evidenced by its binding to LARS1 and TIMM22 promoters. Both FoxK1 and IRβ share regulation of genes involved in rRNA processing, mitotic cell cycle and nonsense-mediated decay. Interestingly, gene promoters of genes in glucose metabolism (PCK1, G6PC and PKM) are bound by FoxK1, but not by IRβ in response to insulin. FoxK1 can also work with FoxO1 in regulation of genes involved in mitochondrial translation, and with both IRβ and FoxO1 in insulin regulation of AHCY, PPRC1, and CDKN1A, i.e., genes involved in cell senescence, amino acid metabolism and mitochondrial biogenesis. Thus, FoxK1 is a potential factor priming the response to insulin and helps with the recruitment of IRβ or FoxO1 in regulation of gene expression in liver in metabolism and other important biological pathways.

Disclosure

P.Allu: None. H.Pan: None. J.Dreyfuss: None. C.Kahn: None.
291-LB: Possible Alpha-Cell Regeneration from Mucin-Producing Ducts in Zinc-Binding Site-Mutated CRY1-Expressing Diabetic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHIRO , SASAKI YU , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU
Published: June 2023

C414A-CRY1 transgenic mice (TG) show the symptoms of diabetes due to cellular senescence-like phenotypes in their β-cells as we have reported at ADA Scientific Sessions in 2015. Due to the cellular phenotypes, structural remodeling in islets of TG progresses with age (S. Okano et al., ADA 2016-2022): the increase of the population ratios of α-cell to β-cell and of δ-cell to β-cell as well as the occurrence of fibrillation, angiogenesis and also the generation of mucin-producing intra-islet ductal cells (IIDCs) were observed. Contrary to normal ductal cells, IIDCs only weakly react with DBA lectin, indicating unique characters different from normal ductal cells (ADA 2019). Also, we have shown the results suggesting that δ-cells may play some role as the source for β-cells to supply new β-cells in TG (ADA 2022). To examine the possible roles of IIDCs to maintain of the amount of pancreatic endocrine cells under hyperglycemia for prolonged period in TG, in this study, we conducted detailed immune-staining experiments which focused on fully developed IIDCs, not small ones that still not fully developed. We distinguished IIDCs from normal ducts, PanINs as well as PDGs as the measure of the reactivity to DBA-lectin. Chromogranin A-positive cells were observed in IIDCs, but not in normal ducts, PanINs and PDGs. Then we examined IIDCs with anti-hormone antibodies. In the region of developed IIDCs, cytokeratin 17/19 and glucagon double-positive cells were predominantly observed. Only small portion of somatostatin-positive cells were clearly located adjacent to IIDCs. Cluster of β-cells were located apart from IIDCs. In addition, scrutinized observations suggested the delamination of glucagon-positive cells from the ductal epithelium of the IIDCs. Taken together, these results strongly suggest the possible neogenesis of endocrine cells in IIDCs, that is, IIDCs and their lining cells play roles as the source for endocrine cells, particularly for α, and also for δ cells.

Disclosure

S. Okano: None. A. Yasui: None. S. Kanno: None. Y. Sasaki: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.

Funding

Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer
292-LB: Cholesterol Accumulation in Islets Exacerbates Insulin Secretory Defects in a Model of Mild ß-Cell Dysfunction
Authors: AKTER REHANA , BARROW BREANNE , HULL-MEICHLE REBECCA L. , ZRAIKA SAKENEH , KAHN STEVEN E.
Published: June 2023

Hypercholesterolemia is common in diabetes. We sought to determine whether cholesterol (Chol) can exacerbate impaired insulin secretion in islets from a mouse model of mild β-cell dysfunction. To induce β-cell dysfunction, C57BL/6J male mice were treated with low-dose (30 mg/kg, i.p.) streptozotocin (STZ) or vehicle (VEH) once daily on 3 consecutive days. Mice were then fed a 9% fat diet for 4 weeks, after which islets were isolated and cultured for 24 h ± Chol prior to endpoint measures. After 4 weeks, body weight (STZ 28.9±1.0 vs VEH 29.1±1.1 g) and fed glucose (STZ 191.2±11.0 vs VEH 177.8±8.2 mg/dl) did not differ. When cultured with 0 mM Chol, isolated islets from STZ-treated mice showed reduced glucose (20 mM)-stimulated insulin secretion (GSIS: 973.9±191.7 vs 1714.8±384.6 pM, n=5, p<0.05) and a trend for lower insulin content (180.6±18.2 vs 230.4±22.9 nM, n=5, p=0.06), compared to islets from VEH-treated mice. Having established STZ-induced β-cell dysfunction, islets from STZ-treated mice were cultured ± 0.5 mM Chol, then Chol content and GSIS measured. Culture in 0.5 mM (vs 0 mM) Chol resulted in increased islet Chol content (58.9 ± 4.3 vs 17.6 ± 3.0 µg/mg protein; n=3, p<0.01). A trend for increased basal insulin secretion (2.8 mM glucose: 185.8±64.7 vs 32.8±3.5 pM, n=5, p=0.09) and reduced GSIS (305.3±60.3 vs 973.9±191.7 pM, n=5, p<0.05) were observed in islets cultured with 0.5 mM Chol. Insulin content was also reduced (125.8±10.8 vs 180.6±18.2 nM, n=5, p<0.01) with 0.5 mM Chol culture. In sum, we have developed a STZ-based, euglycemic mouse model of subclinical β-cell dysfunction. Chol treatment of islets from these mice exacerbates β-cell dysfunction, in keeping with a deleterious effect of Chol. This model now provides the ability to determine whether hypercholesterolemia in vivo results in further impairment of β-cell dysfunction and the development of hyperglycemia, an observation that would be relevant to the progression of prediabetes to diabetes and diabetes per se.

Disclosure

R. Akter: None. B. Barrow: None. R. L. Hull-meichle: Employee; Veterans Administration, Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health, Veterans Administration. S. Zraika: None. S. E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Other Relationship; Novo Nordisk.

Funding

U.S. Department of Veterans Affairs (I01BX001060); National Institutes of Health (P30DK017047); Diabetes Research Connection (46)
293-LB: Dorzagliatin, a Glucokinase Activator, Restores Glucose-Sensing in Type 2 Diabetic Human Islets
Authors: ROMAN JEFFEREY , ZHU QIUSHA , YUAN YUE , LI CHANGHONG , CHEN LI , DOLIBA NICOLAI M.
Published: June 2023

Introduction: Glucokinase (GK) has been considered a drug target for type 2 diabetes (T2D) to restore glucose sensing in beta cells. However, GK activators such as MK-0941 have had limited clinical success, causing hypoglycemia and other serious adverse events in terminated clinical trials. In contrast, the novel GK activator dorzagliatin, an approved therapy for T2D, showed sustained reduction in HbA1c in T2D patients and no serious adverse events. The purpose of the current study is to compare the effects of dorzagliatin with other GK activators, including MK-0941, on GK enzyme kinetics and the function of islets from T2D donors.

Methods: Insulin secretion was assessed in islets from 8 T2D donors and 38 controls obtained through the Integrated Islet Distribution Program. Both glucose step and glucose ramp perifusion protocols were used to assess glucose-stimulated insulin secretion (GSIS). GK-GK activator binding was performed using molecular dynamics analysis. Publicly available data from the Human Pancreas Analysis Program were also used.

Results: Unlike MK-0941 which strongly activates GK enzyme even at very low glucose levels, dorzagliatin activation of GK is glucose dose-dependent. This can be explained by molecular dynamics analysis showing dorzagliatin binds to GK with less affinity than MK-0941. T2D islets showed a right-shifted glucose threshold for GSIS and/or a reduction in the maximal rate of GSIS (Vmax) compared to controls in response to high glucose and IBMX, and dorzagliatin recovers both the threshold and Vmax. In contrast, MK-0941 induces a rapid and transient insulin spike at very low glucose concentrations but has a reduced response to high glucose.

Conclusion: In isolated T2D islets, dorzagliatin recovers both the normal glucose threshold and Vmax and has a wider dose range compared to MK-0941. These findings may explain why MK-0941 causes hypoglycemia whereas dorzagliatin improves blood glucose without any serious adverse events in T2D patients.

Disclosure

J. Roman: None. Q. Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. Y. Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. C. Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology. L. Chen: Employee; Hua Medicine. N. M. Doliba: None.
297-OR: Systematic Review of Immune Interventions Trials in Recent Onset Type 1 and Effect on HbA1c
Authors: POZZILLI PAOLO , FALLUCCA SARA , PIERALICE SILVIA , MARELLI MARTA , MANCINI LORENZO
Published: June 2023

There has been no meta-analysis that addressed the essential issue of efficacy of immunomodulatory agents on HbA1c in patients with recent onset type 1 diabetes (T1D). The aim of this study was to conduct a systematic review and meta-analysis to estimate the treatment effect of different immunotherapeutic strategies vs. placebo on HbA1c in subjects with T1D over the first 2 years of disease. We searched PubMed and Clinicaltrials.gov from 1990 until November 2022 to identify randomized clinical trials (RCTs) and observational investigations that compared the efficacy of immunomodulatory agents in adult and children with recent onset T1D. The study included 35 trials with a total of 2987 participants, 2086 in the treatment groups and 901 in the control groups. We extracted information about year of publication, study and exposure duration, immunotherapy type, no. patients, age, sex, weight, and BMI. HbA1c was evaluated at baseline, and at 3, 6, 9, 12 and 24 months. Funnel plots with confidence regions were used to explore small-study and publication biases. A random-effects model to pool effect sizes Knapp-Hartung adjustments was used to calculate confidence intervals. The evaluation outlined a significantly higher HbA1c in the treatment group at baseline (MD = 0.26 %, 95% confidence interval (CI) 0.0025 to 0.51). Heterogeneity was detected (I2 = 67%; p<0.01; prediction interval -0.71 to 1.23). Small trials with higher HbA1c in the treatment group seem to be underrepresented, however, most of the studies provided non-significant results. In analysis at 12 months (12 trials) results showed a significantly higher HbA1c in the treatment group (MD = 0.13 %, 95% confidence interval (CI) 0.09 to 0.16). This result is almost driven by one study. Results of the metanalysis indicate that overall, in the first 2 years of the disease and irrespective of the immunointervention agent tested, no effect on HbA1c levels could be detected vs. placebo. A few exceptions were observed in the data analysis with some agents.

Disclosure

P.Pozzilli: None. S.Fallucca: Consultant; Dompé. S.Pieralice: None. M.Marelli: Employee; Dompé. L.Mancini: None.
3-OR: Severe Hypoglycemia among Older Adults with Diabetes (iNPHORM, USA)
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , ZOU GUANGYONG , RYAN BRIDGET L. , HARRIS STEWART B.
Published: June 2023

Despite an aging US diabetes population, little is known about the real-world frequency of iatrogenic severe hypoglycemia (SH) among older adults. We analyzed iNPHORM data to address this gap. People ≥60-year-old with T1DM or T2DM on insulin and/or secretagogues were recruited from a probability-based internet panel. Data on SH were obtained via a screener, baseline, and 12 monthly follow-ups. Crude SH incidence rates (IRs) and proportions (IPs) were calculated overall, and by diabetes type, medication type, and mode of SH recovery. N=307 were analyzed (T1DM: 8.5%; age: 67.5 [SD:5.5] years; male: 54.1%; retention rate: 81.8%). Among T2DM respondents, 39.9% used insulin without secretagogues, 50.2% secretagogues without insulin, and 10.0% insulin and secretagogues. The overall IP of SH was 19.9 (95%CI: 15.8-24.7)%, and the IR was 0.89 (95%CI: 0.62-1.27) events per person-year (EPPY). People with T1DM had a higher total IP (42.3 [95%CI: 25.5-61.1]%) and IR (2.07 [95%CI: 0.98-4.38] EPPY) than those with T2DM (IP: 17.8 [95%CI: 13.8-22.7]%; IR: 0.78 [95%CI: 0.52-1.15] EPPY), including insulin without secretagogue users (1.09 [95%CI: 0.66-1.80] vs. 0.61 [95%CI: 0.26 to 1.45] [insulin with secretagogues] and 0.50 [95%CI: 0.23 to 1.05] [secretagogues without insulin] EPPY). Emergency care and hospitalization constituted 3.6% (T1DM: 0%; T2DM: 6.7%) and 1.8% (T1DM: 0%; T2DM: 2.2%) of SH (n=224), respectively. Paramedical/hospital-based SH was more common in T2DM (0.06 [95%CI: 0.02-0.19]) than T1DM (0 EPPY) with IRs highest among insulin without secretagogue users (0.11 [95%CI: 0.03-0.47] EPPY). This is the first US prospective study on SH frequency in older adults with diabetes. Most (96.4%) events occurred at-home, underscoring the need for self-reported SH capture. Overall IPs and IRs were greater in T1DM than T2DM; but those with T2DM had more healthcare-based events. To mitigate undue health and economic costs, it is imperative clinicians remain vigilant to preventing SH in this vulnerable and growing population.

Disclosure

A.Ratzki-leewing: Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Sanofi. J.E.Black: None. G.Zou: None. B.L.Ryan: None. S.B.Harris: Advisory Panel; Bayer Inc., AstraZeneca, Eli Lilly and Company, Dexcom, Inc., Novo Nordisk A/S, Novo Nordisk Canada Inc., Sanofi, Consultant; Abbott Diabetes, Janssen Pharmaceuticals, Inc., Other Relationship; American Diabetes Association, Research Support; Abvance Therapeutics, Canadian Institutes of Health Research.

Funding

Sanofi Global
300-OR: Stage Transitions in Preclinical Type 1 Diabetes—Protective Effect of IA2 Variant Autoantibody Positivity
Authors: BEAM CRAIG , PIETROPAOLO SUSAN , ACEVEDO-CALADO MARIA J. , HERMAN MARK A. , REDONDO MARIA J. , PIETROPAOLO MASSIMO
Published: June 2023

We previously demonstrated that the IA2 variant (IA2var) autoantibody (AA) is associated with enhanced prediction of type 1 diabetes (T1D) in at-risk individuals but its effect on progression through preclinical T1D stages is unknown. We aimed to assess the influence of IA2var AA on rates and risks of transitions from Stage 1 (multiple AA positive, no dysglycemia) to Stage 2 (multiple AA positive, dysglycemia) and to Stage 3 (clinical T1D). Participants in the Diabetes Prevention Trial (DPT-1) with Stage 1 or Stage 2 T1D at baseline and having ≥2 glucose tolerance tests during follow-up were selected (N=175). Standard AA (GAD65, ICA, ICA512 and insulin AA) were considered as biomarkers in addition to IA2var. Data analysis used Markov transition models. The estimated 12-month probability of transition from Stage 1 to 3 (N=89) was 13.8% (95% CI: 9.7%, 18.8%) and from Stage 2 to 3 (N=86) it was 41.3% (30.6%, 52.6%). IA2var AA, sex, age and were statistically significant risk factors for the Stage 2 to 3 transition (Table 1, B). Importantly, IA2var AA (the only significantly influential AA) was associated with a reduction in the risk of transition from Stage 2 to 3. In sum, male sex, older age and positive IA2var AA significantly decreased the risk of transition from Stage 2 to Stage 3 T1D. This information has important implications for the selection of candidates for T1D prevention in clinical and research practices.

Disclosure

C.Beam: None. S.Pietropaolo: None. M.J.Acevedo-calado: None. M.A.Herman: Research Support; Eli Lilly and Company. M.J.Redondo: None. M.Pietropaolo: None.

Funding

National Institutes of Health (2R01DK053456-19A1); Robert and Janice McNair Foundation
305-OR: Short-Term Hyperglycemia Impacts Mouse Skeletal Muscle in a Sex-Specific Manner
Authors: HULETT NICHOLAS A. , KNAUB LESLIE , POTT GREGORY , RAMIREZ DAVID , JOHNSTON ASPEN , SCALZO REBECCA L. , REUSCH JANE E.B.
Published: June 2023

Cardiorespiratory Fitness (CRF) a universal predictor of cardiovascular and all-cause mortality, is lower in people with diabetes. Skeletal muscle is a key determinant of CRF, in particular mitochondrial content, function and oxygen extraction. Hyperglycemia is implicated in the dysfunction of microvascular blood flow. Our previous work demonstrated lower mitochondrial density/fiber and capillary mean flow velocity (MFV) with 4 weeks of hyperglycemia in males and females. Treadmill running resulted in greater capillary MFV and mitochondrial density in only hyperglycemic females. We hypothesize that along with alterations in mitochondrial density and blood flow, there is a disruption in skeletal muscle mitochondrial function with hyperglycemia, and that these parameters will respond to nitrite (NO2-) treatment in a sex-specific manner. We used a model of short-term hyperglycemia with tamoxifen inducible β-cell deletion of glucokinase. Two weeks after induction, blood flow in the gastrocnemius (gastroc) was measured using intravital microscopy, and the gastroc was collected from male (M) and female (F) mice with blood glucose >400mg/dl (HG) and euglycemic controls (EG). A subset of mice received NO2- treatment for 1-2 weeks prior to gastroc measurements. Immunofluorescence imaging of gastroc were analyzed for expression of COX1 (mitochondrial marker), Dystrophin (muscle fiber sarcolemma boundary), and CD31 (capillary marker). Mitochondrial respiration was measured in gastroc fibers using Oroboros O2k. Mitochondrial respiration was lower in HG compared to EG (p<0.0009), but only respiration in M appeared to respond to NO2- treatment (p=0.0252). No difference was observed in mitochondrial density in EG versus HG. Capillary MFV was greater with HG and mitigated by NO2-treatment. NO2- targets mitochondrial function by improving capillary blood flow, but only in males. Our combined data sets suggest HG-associated mitochondrial defects need to be treated in a sex-specific manner.

Disclosure

N.A.Hulett: None. L.Knaub: None. G.Pott: None. D.Ramirez: None. A.Johnston: None. R.L.Scalzo: None. J.E.B.Reusch: Advisory Panel; Medtronic.

Funding

U.S. Department of Veterans Affairs (BX002046, CX001532); National Institutes of Health (P30DK116073, 5T32AG000279-20)
313-OR: The Efficacy and Safety of Glucagon-Like-Peptide-1 Agonists in Patients with Familial Partial Lipodystrophy
Authors: IMAM SALMAN K. , FOSS-FREITAS MARIA C. , MERAL RASIMCAN , ORAL ELIF A. , DILL GOMES ANABELA , GRISSI FATIHA
Published: June 2023

Familial partial lipodystrophy (FPLD) syndromes are a rare group of conditions with abnormal fat distribution and deposition of fat in ectopic tissues such as liver and muscle, leading to challenging metabolic abnormalities. Glucagon-like peptide-1 receptor agonists (GLP1R-A) are used for management of other metabolic dysfunction, but their efficacy in FPLD syndromes is not known. In this retrospective EMR review, we evaluate the effect of GLP1R-A for DM management in patients with FPLD for whom there are no approved treatments in the US. We collected data from 17 patients with FPLD (age 58 ± 12; 76.47 % females) and 17 patients with type 2 DM (age 58 ± 13; 71% females) before and 6 months after starting GLP1R-A. Only cases where the sole change was the addition of GLP1R-A were included in the analyses. Reduction in weight (p=0.002), BMI (p=0.001), HbA1c (p=0.02), and fasting glucose (p=0.04) (Figure 1A-D) were observed in patients with FPLD. Only the change in triglycerides after six months of treatment was greater in patients with FPLD compared to patients with DM (p=0.02, 95%CI: 13.6 to 215.8) (Figure 1E). Overall, there were no differences in changes in other parameters, and no serious events were reported. However, we observed acute pancreatitis in two cases with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP1R-A in patients with FPLD for the first time.

Disclosure

S.K.Imam: None. M.C.Foss-freitas: None. R.Meral: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. A.Dill gomes: None. F.Grissi: None.
314-OR: The Triglyceride–Glucose Index May be a Surrogate for Both Insulin Resistance and Atherogenic Lipid Profile in Africans
Authors: WORTHY CHARLITA , DE DIEU GATETE JEAN , HURSTON JAMAIICA , SCHENK BLAYNE R. , MABUNDO LILIAN , DUBOSE CHRISTOPHER , JAGANNATHAN RAM , SUMNER ANNE E.
Published: June 2023

As the insulin assay is expensive and often unavailable in low income countries, the triglyceride-glucose index (TyG) is undergoing global evaluation as both a surrogate marker of insulin resistance (IR) and predictor of cardiovascular disease (CVD). Yet the value of the TyG in African-born populations is uncertain. Therefore, in 555 African-born Blacks currently living in the Washington, DC area (Age: 39±0.4y (mean±SE), Male: 65% (358/555), BMI: 27.7±0.2 kg/m2) we determined: 1) ability of TyG to predict the presence of IR; and 2) correlations between TyG and four lipid parameters, specifically HDL-C and LDL-C, LDL-particle size and LDL-number. Fasting lipid profiles and OGTT were performed. IR was defined by the lowest quartile of the Matsuda Index (≤2.85). Ability of TyG to predict IR was assessed with AUC-ROC curve. Pearson correlations were performed between the lipids and both TyG and Matsuda Index. Diabetes, prediabetes and normal glucose tolerance occurred in 7% (37/555), 31% (173/555) and 62% (345/555) resp. AUC-ROC for the prediction of IR by TyG was 0.75±0.02. Correlations between the lipids and both TyG and Matsuda Index were highly significant (Table). But correlations with each lipid were stronger with TyG than Matsuda Index. Overall, TyG is marker of IR in Africans and may be better than Matsuda Index in predicting CVD because of stronger correlations with atherogenic lipids.

Disclosure

C.Worthy: None. J.Gatete: None. J.Hurston: None. B.R.Schenk: None. L.Mabundo: None. C.Dubose: None. R.Jagannathan: None. A.E.Sumner: None.
319-OR: Effect of Vertical Sleeve Gastrectomy (VSG) on the Kidney Transcriptome of Youth with Type 2 Diabetes (T2D)
Authors: NAIK ABHIJIT , ALAKWAA FADHL , SCHAUB JENNIFER A. , MCCOWN PHILLIP J. , NAIR VIJI , EDDY SEAN , PYLE LAURA , VIGERS TIMOTHY B. , KELSEY MEGAN M. , FULLER KELLY N.Z. , LADD PATRICIA E. , SANDOVAL DARLEEN A. , GROSS SUSAN , ZEITLER PHILIP , NADEAU KRISTEN J. , RYDER JUSTIN R. , INGE THOMAS , HODGIN JEFFREY B. , BROSIUS FRANK C. , NELSON ROBERT G. , KRETZLER MATTHIAS , BJORNSTAD PETTER
Published: June 2023

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)
32-OR: Reduction of Macrophage-iPLA2ß–Derived Proinflammatory Lipids Inhibit Type 1 Diabetes Development
Authors: ALMUTAIRI ABDULAZIZ , GAI YING , NADLER JERRY , CHALFANT CHARLES E. , RAMANADHAM SASANKA
Published: June 2023

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, but the leading causes for this process remain elusive. Our lab revealed that Ca2+-independent phospholipase A2β (iPLA2β) modulates the polarization of macrophages (MΦ). Recently, we showed that selective iPLA2β-derived lipid signals (iDLs) produced by MΦ from spontaneous-T1D prone mice (NOD) is high during the pre-diabetic phase. Therefore, we examined the impact of bone marrow-derived macrophages (BMD-MΦ)-iDLs on T1D development by generating NOD mice with conditional reduction in MΦ-iPLA2β (NOD. cM Φ iPLA2𝛽;-/- and NOD. cM Φ iPLA2𝛽;+/-). Our data show that BMD-MΦ from NOD. cM Φ iPLA2𝛽;-/- or NOD. cMΦiPLA2𝛽;+/- are skewed towards an M2 anti-inflammatory phenotype, compared with NOD BMD-MΦ. Also, BMD-MΦ from NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/- have significantly less proinflammatory lipids (PGs, DHETs, and TXB2), compared to NOD BMD-MΦ. Moreover, selective inhibition of PGE2 (EP4 antagonist) or DHET (TPPU) signaling inhibits NOD BMD-MΦ polarization towards an M1 proinflammatory phenotype, as reflected by reductions in M1 markers (Arg2, CXCL10, STAT1, and TNFα) and increases in M2 markers (Arg1, RELA, STAT6, and MRC1). Furthermore, pancreata from NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/- have significantly reduced immune cell (CD4, CD8 and, CD19) infiltration and a higher abundance of M2 anti-inflammatory macrophages relative to NOD pancreata. These outcomes were associated with improved glucose tolerance and significant reduction of T1D incidence in the NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/-, as compared with the incidence in the NOD mice. In summary, reduction of select proinflammatory iDLs production by BMD-MΦ favors M2 anti-inflammatory phenotype, reduced T1D pathogenesis, and T1D incidence. We conclude that MΦ-iDLs contribute to T1D onset and that inhibition of selected macrophages-derived iDLs production can be targeted to counter T1D development

Disclosure

A.Almutairi: None. Y.Gai: None. J.Nadler: None. C.E.Chalfant: None. S.Ramanadham: None.
324-OR: VEGF Is a Contributing Factor for the Reduction of Retinal Function in Diabetic Retinopathy and Hypoxic Retinal Disorders
Authors: LE YUN , ZHU MEILI
Published: June 2023

Vascular endothelial growth factor (VEGF or VEGF-A), a major therapeutic target for blood-retina barrier breakdown (BRB) in diabetic retinopathy (DR), neovascular age-related macular degeneration (AMD), and other and hypoxic retinal diseases, has been shown to act as a direct functional regulator for peripheral and central nervous system (CNS) neurons. To investigate the direct effect of VEGF on photoreceptor function in DR and hypoxic retinal diseases, we examined and compared the effect of recombinant (rVEGF) on retinal function with electroretinography (ERG) in Akita spontaneous diabetic mice and wild-type (WT) mice kept under normal environment and hypoxia (8 percent oxygen for 5 days). Retinal function was measured with ERG in dark-adapted mice immediately after rVEGF intravitreally delivery under long-wavelength illumination. While the rVEGF caused a significant reduction of scotopic ERG a-wave and b-wave amplitudes and photopic ERG b-wave amplitudes in a dose-dependent manner in WT mice kept under normal conditions, the effect of rVEGF on the alteration of ERG amplitudes was diminished in age-matched Akita diabetic and hypoxic mice in which retinal VEGF levels are upregulated. Our results suggest that VEGF is a most likely direct functional regulator of photoreceptors. Our data strongly support that VEGF upregulation is a likely cause of the reduced photoreceptor function in DR and hypoxic retinal disorders. As VEGF is a major therapeutic target for BRB breakdown in DR, AMD, and other hypoxic retinal BRB diseases, our work provides the mechanistic insights for the therapeutic effects on visual acuity and for the care of anti-VEGF drug treated patients.

Disclosure

Y.Le: None. M.Zhu: None.

Funding

National Institutes of Health (R01EY26970, P30EY021725, P30GM122744); Oklahoma Center for the Advancement of Science and Technology (HR20-065)
33-OR: Epigenetic Reader BRD4 Directs Fast-Twitch Myofiber Gene Programs Influencing Skeletal Muscle Endurance Capacity and Systemic Glucose Homeostasis
Authors: ZHOU ZHENG , LIU LIN , XU ZHISHENG , FU TINGTING , YANG LIKUN , YAN MAO , GAN ZHENJI
Published: June 2023

Skeletal myofibers exhibit remarkable diversity and plasticity in contractile and metabolic functions and play a key role in controlling systemic metabolism. Previous studies of muscle fiber-type switching have centered on the specification of slow-twitch myofibers. However, mechanisms that drive fast-twitch myofibers formation remain unclear. Here, we showed that BRD4, an epigenetic reader enriched in fast myofibers, plays a critical role in controlling fast-twitch myofiber identity as well as systemic glucose homeostasis. BRD4 levels are associated with fast-twitch myofiber gene expression in human muscle. Skeletal muscle-specific ablation of BRD4 in mice (Brd4f/fHSA-Cre, BRD4 mKO) resulted in downregulation of the fast-twitch myofiber gene program, increased number (~100%) of type I myofibers and mitochondrial oxidative capacity. This led to enhanced muscle endurance capacity. In adult mice, acute and inducible BRD4 deletion using a tamoxifen-inducible Cre elicited a similar fast-to-slow fiber type switch in muscle. Mechanically, genome-wide ChIP-seq and mRNA-seq analyses revealed that BRD4 directly binds to and activates transcriptional of fast-twitch myofiber genes through cooperating with MEF2. Furthermore, mice lacking muscle BRD4 were protected against high-fat-diet (HFD)-induced obesity, glucose intolerance and insulin resistance. HFD-fed BRD4 mKO mice had significantly less fat mass (∼50%) compared with HFD-fed WT controls. Histological and biochemical measurements confirmed a pronounced (~60%) decrease in fat deposition in BRD4 mKO livers. Thus, our results uncover a previously unrecognized mechanism underlying the determination of fast-twitch myofiber and provide new therapeutic opportunities for driving muscle fiber-type switch to combat metabolic diseases.

Disclosure

Z.Zhou: None. L.Liu: None. Z.Xu: None. T.Fu: None. L.Yang: None. M.Yan: None. Z.Gan: None.
346-OR: IL-10–Treated Adipose Stromal Vascular Fractions Reverse Insulin Resistance in a Type 2 Diabetes Mellitus Mouse Model
Authors: CHEN LEE-WEI
Published: June 2023

Low IL-10 production capacity is associated with type 2 diabetes. Targeting IL-10 in diabetes patients has resulted in inconsistent results. To test if IL-10-treated adipose stromal vascular fraction could be used to reverse diabetes-induced gluconeogenesis and insulin resistance, we purified stromal vascular fractions (SVFs) from adipose tissue from diabetic (Lepdb/db ) and nondiabetic (Lep+/+) mice, treated them with IL-10, and injected them into adipose tissue of diabetic mice. Injection of IL-10 into adipose tissue of diabetic mice decreased mRNA expression of IL-6 and IL-1β of adipose SVFs but did not change G6PC and PCK1 expression in liver. Injection of IL-10-treated SVFs into adipose tissue of diabetic mice significantly decreased CCL2 and IL-1β expression and increased IL-10 and Foxp3 expression of SVFs of Lepdb/db mice. Moreover, injection of IL-10-treated SVFs significantly increased IL-10 levels of adipose tissue and decreased G6PC and PCK1 and insulin resistance of liver in diabetic mice. Altogether, our data suggest that IL-10-treated adipose SVFs could be used to reverse diabetes-induced gluconeogenesis gene expression and insulin resistance in diabetes. These data suggest that modified-adipose stromal vascular fractions could be used as a promising cell therapy tool in alleviating insulin resistance in diabetes mellitus.

Disclosure

L. Chen: None.

Funding

National Science and Technology Council, Taiwan (110-2314-B-A49A-540-MY3)