bluuebunny/crossref_metadata_2025 huggingface dataset:
1254-P: ß-Cell Cdk1 Deletion Reveals a- and ß-Cell Compensatory Mechanisms for Hypoplasia
Authors: SDAO SOPHIA , ADAMS MELISSA , FOSTER HANNAH R. , BLUM BARAK , MERRINS MATTHEW J.
Published: June 2021

Diabetes is characterized by a loss of functional β-cell mass. With current rodent models of chemically-induced diabetes such as streptozotocin, it is difficult to distinguish the consequence of β-cell loss from the decline in individual β-cell function. Here, we generated a mouse model of severe β-cell mass loss by deleting β-cell CDK1 within the first week of life (Cdk1Ucn3Cre, Cdk1-floxed:Ucn3-Cre). At 4 weeks of age, islet mass in Cdk1Ucn3Cre islets is comparable to controls, although islet architecture is disrupted with α-cells having formed more heterotypic contacts with β-cells. By 12 weeks of age, Cdk1Ucn3Cre mice exhibit significantly reduced β-cell mass as well as α-cell mass, but maintain glucose tolerance and ex vivo insulin secretion in response to glucose, amino acids, and the gut incretin GIP. We therefore hypothesized that functional compensations in Cdk1Ucn3Cre islets arise from both β- and α-cells, which are insulinotropic in the fed state. Interestingly, α-cell glucagon secretion from Cdk1Ucn3Cre islets exhibits hypersensitivity to suppression by glucose, including when glucagonotropic amino acids are present. In parallel, we observed a reduction in amino acid-stimulated cAMP in β‑cells from Cdk1Ucn3Cre islets. We also found a left-shift in the glucose dependence of β-cell calcium oscillations in Cdk1Ucn3Cre islets, identifying β-cell recruitment as one mechanism offsetting the loss of α-cell paracrine signaling. Importantly, GIP elicited a much larger glucagon response from glucose- and amino-acid stimulated Cdk1Ucn3Cre islets, implying that α-cell compensation contributes significantly to the maintained insulin secretory output in vivo. In sum, the Cdk1Ucn3Cre model reveals the interdependence of α- and β-cell mass, and function, and will be useful to define the temporal sequence of islet compensation for chronic loss of β-cell mass under stressed conditions.

Disclosure

S. Sdao: None. M. Adams: None. H. R. Foster: None. B. Blum: None. M. J. Merrins: None.
1257-P: LncRNA Kcnq1ot1 Affects Islet ß-Cell Proliferation and Insulin Secretion
Authors: CHEN YALAN , LI YANLI , LIU ZIYU , XU WEN , LIN BEISI , SU YANNA , YAN JINHUA , LI WANGEN
Published: June 2021

Background: Accumulating evidences indicated that long noncoding RNA (LncRNA) were involved in the regulation of diverse biological functions, including the islet function. In our previous study, relatively high expression of LncRNA Kcnq1ot1 was found in the pancreas of normal mice. This study was designed to clarify the role of LncRNA Kcnq1ot1 in pancreatic β cells.

Methods: The expressions of LncRNA Kcnq1ot1 in different tissues of normal adult male C57BL/6J mice were detected by qRT-PCR. siRNA was used to downregulate Kcnq1ot1 in MIN6 β cells. The proliferation and apoptosis of β cells were measured by cell counting kit-8 (CCK-8) assay and flow cytometry. Glucose stimulated insulin secretion (GSIS) assay was used to determine the effect of Kcnq1ot1 on insulin secretion of β cells. Moreover, the expressions of cell cycle and insulin related genes (including Ccnd1, Ccnd2, Ins1 and Ins2) were assessed by qRT-PCR. The LncRNA Kcnq1ot1 siRNA and scrambled siRNA were injected into the tail vein of male C57BL/6J, then, the blood glucose and serum insulin levels were measured at 72h after injection.

Results: The expression of Kcnq1ot1 was much more abundant in islets of normal male C57BL/6J mice than other tissues. The CCK8 and mRNA expression of Ccnd1 and Ccnd2 showed that the proliferation of Min6 cells was significantly decreased with the downregulation of kcnq1ot1 at 48h and 72h. However, flow cytometry indicated that inhibition of Kcnq1ot1 had no effects on β cells apoptosis. Impaired β-cell function measured by GSIS was found in kcnq1ot1 silenced Min6 cells, along with decreased mRNA levels of INS1 and INS2. Higher glucose and lower serum insulin were detected in the LncRNA Kcnq1ot1 siRNA-treated mice when compared to control group.

Conclusions: LncRNA Kcnq1ot1 has multiple effects on β-cell function, including enhanced proliferation and insulin secretion, which suggest Kcnq1ot1 as a new biomarker of islet function.

Disclosure

Y. Chen: None. Y. Li: None. Z. Liu: None. W. Xu: None. B. Lin: None. Y. Su: None. J. Yan: None. W. Li: None.

Funding

National Natural Science Foundation of China (81800682)
126-LB: Evaluation of the Efficacy of the Therapeutic Agent Cytoreg in Patients with Diabetic Foot: A Clinical Humanitarian Protocol
Authors: CARRILLO DARIO A. , VILLASANA KATIUSCA , TORRES GEIZON , POZO LEWIS J. , JIMENEZ WILLIAM J. , BAUTA WILLIAM E. , DUGARTE LEONARDO
Published: June 2021

Diabetic foot wound complications, including bacterial infections, ulcerations, and gangrene, are a major cause of hospitalizations and account for 85% of diabetic amputations. The investigational therapeutic agent Cytoreg®, an aqueous mixture of hydrofluoric, hydrochloric, sulfuric, phosphoric, phosphoric, citric, and oxalic acids, was recently shown to increase arterial oxygen levels in an orally administered Wistar rat model. It previously demonstrated bactericidal effect. Under a compassionate use protocol, we tested oral and topical treatment with diluted Cytoreg in patients with diabetic foot ulcers in a 30-day study in Venezuela. The total study population was ten patients under informed consent. On average, all patients received oral Cytoreg daily for 30 days. Five patients received oral Cytoreg plus topical wound cleansing with Cytoreg in isotonic saline. In addition to standard clinical observations, wound healing was monitored using the St. Elian’s checklist system. Four of five patients in the oral plus topical group had complete closure of their wounds after thirty days. Two of the patients in the oral group had complete wound closure. There was no significant change in oxygen saturation in the affected tissues, nor in insulin and glycemia levels. However, there were significant increases in arterial hemoglobin and arterial oxygen-pO2- were observed. Significant decreases HbA1c, aspartate aminotransferase, glutamic-pyruvic transaminase, creatinine, and urea levels were also observed. The overall results are encouraging and justify an expanded study in the treatment of diabetic foot wounds.

Disclosure

D. A. Carrillo: Research Support; Self; Cytorex Biosciences Inc. K. Villasana: None. G. Torres: Research Support; Self; Cytorex Bioscience Inc. L. J. Pozo: None. W. J. Jimenez: Board Member; Self; Cytorex Biosciences Inc. W. E. Bauta: Advisory Panel; Self; Cytorex Biosciences, Vascular Perfusion Solutions, Employee; Self; bioAffinity Technologies. L. Dugarte: None.
1265-PUB: Basic Carbohydrate Counting in Patients with Type 2 Diabetes: Improvement in Glycemic Control and Effects on Body Compositions
Authors: TANIGUCHI MARIKO , MORITA RYUHEI , HARADA REIKO , YOSHINO FUYUMI , MUKAI YUMI , IKEDA MIWA , HARADA KAZUE , YOSHIYAMA MAO , NAKANO HIROMI , MAEDA KANAKO
Published: June 2021

Objective: This study aims to show the usefulness of basic carbohydrate counting (BCC) in the glycemic control of patients with type 2 diabetes (T2DM) and to investigate the effects of BCC on body compositions.

Subjects and Methods: We included T2DM 20 patients in no insulin therapy with stable dosage of antidiabetic medication 8 weeks before and during the study period. We provided the meal planning according to the indicated sugar mass, which was set to 50% of their energy amount per day. HbA1c levels, daily carbohydrate intake, and body compositions (measured with InBody 770) were collected before and 12 ± 4 weeks after BCC.

Results: Before/after BCC of their daily carbohydrate intake and HbA1c levels were 210.7 ± 42.1/171.5 ± 34.9 g (p = 0.0018), and 8.1 ± 1.1/7.4 ± 0.9 % (p = 0.0002), respectively. To examine the effects of BCC on their body compositions, 16 patients with improved HbA1c levels were selected for further analysis. BCC improved their body weight (before/after BCC, 64.4 ± 17.6/63.0 ± 16.6 kg, p = 0.005), BMI (25.7 ± 5.3/25.2 ± 5.0 kg/m2, p = 0.004), body fat mass (21.8 ± 9.5/20.1 ± 8.7 kg, p = 0.014), and abdominal circumference (95.0 ± 13.6/92.9 ± 13.2 cm, p = 0.0004). There was no significant difference in overall SMI, but the muscle mass of right arm, left arm, and trunk significantly decreased while the muscle mass of legs was not affected by BCC.

Discussion and Conclusion: Our findings demonstrate that BCC is an effective strategy for improving the glycemic control of T2DM patients. The patients with improved HbA1c levels also showed significant reduction in their body weight, BMI, body fat mass, and abdominal circumference. While preserving the muscle mass of their legs, the muscle mass reduction in their arms and trunks was observed. Combining with resistant training of arms and trunk, BCC may make more positive effects on T2DM patients.

Disclosure

M. Taniguchi: None. K. Maeda: None. R. Morita: None. R. Harada: None. F. Yoshino: None. Y. Mukai: None. M. Ikeda: None. K. Harada: None. M. Yoshiyama: None. H. Nakano: None.
1267-PUB: Sustained Reduction of A1C through Use of AI Digital Coach and Consumer-Friendly Glucose Measurement
Authors: BALDER TIM
Published: June 2021

Management of diabetes has always depended upon sustained self-management by the person with diabetes. Data continues to show that people do a poor job of diabetes management. Many telehealth solutions achieve short-term, but not sustained results. This investigated platform implements two unique elements to improve the ability to achieve sustained self-management. One element is an Artificial Intelligence (AI) digital coach that exists in the mobile app--keeping the right behaviors in front of people with diabetes and encouraging continual engagement. The second element is an integrated glucose meter with a dramatically more friendly user experience--defined by smaller size, discreet (no visible assembly), and less painful. The platform has been commercialized for more than 12 months. A clinical registry has been established and currently includes 50 commercial users of the platform and more than 25,000 glucose tests are included. Demographics include both type 1 and type 2, 42% male, 58% female, with ages ranging from 24 to 69 years old. With use of the platform, Figure 1 shows a significant decrease in A1C, as calculated from glucose measurements, of 1.4 points (p = 0.0001) in early use to a sustained reduction of 0.9 points (p=0.0001). These results may indicate that easier visibility of results causes immediate reduction of glucose and that this easier visibility combined with the AI coach may sustain results. These results potentially demonstrate that a simpler experience for self-management will improve sustained diabetes management results. Future studies of the registry data will include improved compliance toward ADA guidelines and glucose time in range.

Disclosure

T. Balder: Advisory Panel; Self; POPS Diabetes Care.
1279-PUB: Postpartum Screening for Diabetes in Women with a History of Gestational Diabetes
Authors: RAKHRA VARUNDEEP , RILEY MARCELLA , JORDAN SYMONE , BULCHANDANI SHEETAL , ALLSWORTH JENIFER , DREES BETTY
Published: June 2021

Background: Gestational diabetes (GDM) is glucose intolerance detected for the first time during pregnancy. Women with a history of GDM have a 7-fold higher lifetime risk of developing type 2 diabetes (DMII) compared to women without a history of GDM. Women with a history of GDM should be screened for DMII 6 to 12 weeks postpartum with a 2-hour 75-g oral glucose tolerance test (OGTT) and then again one year after delivery. The long-term goal of this project is to improve screening for DMII in women with a history of GDM. This report establishes the prevalence of GDM, determines the postpartum screening rate, and assesses for barriers to screening at an urban safety-net hospital. This information will be used to design interventions to improve postpartum screening.

Methods: We conducted a retrospective chart review of women who had a delivery at Truman Medical Center between January 1, 2017 to December 31, 2019 and had a diagnosis of GDM. Charts were reviewed for demographic data, management of GDM, postpartum appointments, and screening for DMII.

Results: There were 9569 deliveries during the three-year period. Of the total deliveries, 537 (5.6%) had a diagnosis of GDM. Of the patients with GDM, 426 (79%) had a postpartum visit scheduled, 354 (66%) attended a 6-week postpartum appointment, 219 (41%) had the recommended test ordered, and 49 (9%) completed the test. The data revealed a significant association with ethnicity, language, insurance type, and site of prenatal care with attending the postpartum appointment (p<0.05) as well as with insurance status on completing the screening test (p<0.05).

Conclusion: There is gap in the number of women with GDM and those who are screened for DMII in the postpartum period. There appears to be a disconnect in the ordering of the recommended 2-hour OGTT and the completion of the test. The baseline data supports a multi-prong approach including patient education, system changes, and advocacy for extended insurance benefits to cover screening.

Disclosure

V. Rakhra: None. M. Riley: None. S. Jordan: None. S. Bulchandani: None. J. Allsworth: None. B. Drees: None.
144-LB: Collaborative Telehealth Approach Where Traditional Care Fails Diabetes Care Network
Authors: CLARK KRISTY , LARSON MEG J. , LUTZ-MCCAIN STACEY J. , BANDI ARCHANA
Published: June 2021

Clinical inertia is the failure to initiate or intensify treatment in a timely manner in people with type-2 diabetes mellitus (T2DM) in primary care (PC) where collaborative care can be an approach to overcome inertia. Diabetes care network (DCN) is a telehealth based collaborative care model to address clinical inertia in the PC environment. In DCN, initial care was delivered via E-Consult by hub diabetes team for Veterans with A1c of 9% or higher and the longitudinal collaborative care delivered by PC liaison with weekly team huddle. To study the difference in the clinical outcomes with DCN vs. PC practices, we compared the DCN cohort (97.7% male, 90.8% white, with a mean age 67.2 (8.9), with a PC cohort (100% male, 94.9% white, mean age: 68 year (10.5), with A1C >9%).

Methods: Means (SD), frequencies and percentages were presented. The DCN cohort had a significant decline in the baseline A1C of 10.2% (1.4), to 8.1% (0.99), 7.6% (0.96), 7.5 % (0.86) at 3, 6, and 12 months while A1c in PC cohort stayed poor with baseline A1C of 10.1% (0.89), to 10.2% (1.69), 9.7% (1.74) and, 9.5% (1.83) at 3, 6, and 12 months. Patients who achieved A1c less than 8% in DCN cohort were 38 (43.6%), 56 (64%), and 56 (64%) at 3, 6, and 12 months and were 1(1.7%), 5(8.5%), and 6(10.2%) at 3, 6, and 12 months in PC cohort. An A1c of less than 7% was achieved in DCN cohort in 10 (11.4%), 21 (24.1%), and 23 (26.4%) patients at 3, 6, and 12 months and only 1(1.7%), 0(0%), and 0(0%) patients achieved A1c less than 7% at 3, 6, and 12 months in PC cohort. Our study shows participation in the DCN telehealth program for 1 year was associated with significant improvement in A1c. This improvement was not seen within the PC with traditional care practices. Thus, addressing clinical inertia in PC will need a paradigm shift in current practices. The proposed collaborative approach of DCN can overcome clinical inertia in PC and improve care for people with T2D by supporting PC access to specialty care expertise, decreasing the burden of diabetes care for patients and PC providers.

Disclosure

K. Clark: None. M. J. Larson: None. S. J. Lutz-McCain: None. A. Bandi: None.
146-OR: A New Type 2 Diabetes Microsimulation Model to Estimate Long-Term Health Outcomes, Costs, and Cost-Effectiveness
Authors: HOERGER THOMAS J. , HILSCHER RAINER , NEUWAHL SIMON , CHENG YILING J. , BENOIT STEPHEN R. , SHAO HUI , LAXY MICHAEL , YANG WENYA , CINTINA INNA , KAUFMANN MATTHEW , CHEN HAIYING , ANDERSON ANDREA M. , STAIMEZ LISA R. , NARAYAN K.M. VENKAT , ZHANG PING
Published: June 2021

We developed a new microsimulation model to estimate health effects, costs, and cost-effectiveness of public health interventions for type 2 diabetes. The model combined risk equations for complications and mortality, risk factor progression equations, and patient utility equations based on the U.S. ACCORD and Look AHEAD studies with a cost equation estimated from a large panel dataset of privately insured U.S. adults. The model features a web-based interface that allows users to change model parameters. The model includes interventions for glycemic, blood pressure, and cholesterol control; smoking cessation; and a generic intervention that users can modify to represent control of multiple risk factors.

To demonstrate how the model estimates cost-effectiveness, we analyzed an intervention to reduce HbA1c from 9% to 7%. We estimated the long-run health effects, costs, and quality-adjusted life-years (QALYs) for a simulated cohort of 10,000 U.S. adults with type 2 diabetes. On average, the simulated cohort of U.S. patients was projected to have 20.16 remaining life-years (from a mean age of 61), incur $187,435 in discounted medical costs, and experience 8.89 discounted QALYs. Results were most sensitive to age and duration of diabetes at baseline and the discount factor. The intervention to reduce HbA1c produced $3,151 in incremental costs and gained 0.4 QALYs, yielding an incremental cost-effectiveness ratio of $7,838 per QALY.

The model performed well in internal validation exercises. External validation results were more mixed, with the model better at predicting clinical trial results than at predicting observational study results.

As the model’s risk progression, patient utility, and costs are all derived using recent U.S. studies, our new model can more accurately project the long-run health impact, costs, and cost-effectiveness of interventions for type 2 diabetes in the United States than existing models.

Disclosure

T. J. Hoerger: None. M. Kaufmann: None. H. Chen: None. A. M. Anderson: None. L. R. Staimez: None. K. Narayan: None. P. Zhang: None. R. Hilscher: None. S. Neuwahl: None. Y. J. Cheng: None. S. R. Benoit: None. H. Shao: Research Support; Self; Sanofi. M. Laxy: None. W. Yang: None. I. Cintina: None.

Funding

Centers for Disease Control and Prevention (200-2016-92270)
154-OR: People Who Get More Hours of Sleep Have Lower Mean Glucose: Analysis of Continuous Glucose Monitoring and Fitbit Data in a Free-Living Population without Diabetes
Authors: CRAWFORD MARGARET A. , PICKUS SARAH K. , HAMES KAZANNA C. , JOHNSON MATTHEW , KLEIN ILENE J. , NORMAN GREGORY J.
Published: June 2021

Background: Sleep disorders are associated with having or developing type 2 diabetes, increased insulin resistance, and higher BMI. The relationship between sleep duration and continuous glucose monitoring (CGM) metrics has not been well studied. We examined the relationship between CGM-based metrics and sleep duration in a population without diabetes.

Methods: Glucose metrics from a 10-day blinded CGM (Dexcom G6) wear and sleep metrics from a concurrent unblinded Fitbit wear were collected. Participants (mean (SD) age= 49.1 (10) years, BMI= 29.5 (8) kg/m2, 90% female, 14% African American) were recruited from an employee health plan in the Southeastern US. Forty-nine individuals without diabetes or prediabetes were included in this analysis. A linear regression model adjusting for age and BMI was used to evaluate the relationship between mean daytime glucose and nightly hours of sleep.

Results: Participants recorded a median (IQR) 6.4 (6.1, 7.1) nightly hours of sleep, 6416 (5112, 8071) daily steps, and 12.7 (12.1, 13.5) daily sedentary hours. Mean (SD) mean daytime glucose was 112.7 (11.5) mg/dL and coefficient of variation was 15.4 (3) %. Mean daytime glucose was significantly and inversely associated with nightly hours of sleep (Beta= -3.1, p <0.05).

Conclusion: In this population without diabetes, each additional one hour of sleep was associated with 3.1 mg/dL lower mean daytime glucose. This finding aligns with existing research on the protective effects of sleep on glycemic health and suggests it may be beneficial for people at risk for developing diabetes to improve their sleep habits. Longitudinal research where behavioral data is collected along with CGM can provide further insights into correlates of developing prediabetes and type 2 diabetes.

Disclosure

M. A. Crawford: Employee; Self; Dexcom, Inc. S. K. Pickus: Employee; Self; Dexcom, Inc. K. C. Hames: Employee; Self; Dexcom, Inc. M. Johnson: Employee; Self; Dexcom, Inc. I. J. Klein: None. G. J. Norman: Employee; Self; Dexcom, Inc.
163-OR: Evidence for Circadian Control of Glucose-Stimulated Insulin Secretion in Transplanted Human Stem-Cell-Derived Pancreatic ß-Cells
Authors: SEN SATISH K. , HASSOUN SHAIMAA , PETERSON QUINN P. , MATVEYENKO ALEKSEY
Published: June 2021

Cell replacement strategies utilizing stem cell-derived β-cells (SC-β cells) hold therapeutic potential for patients with diabetes. In order for cell therapy to be effective, transplanted SC-β cells must recapitulate physiological features of insulin secretion in humans. In this regard, circadian regulation of insulin release is critical for normal β cell physiology, where intrinsic β cell circadian clocks function to optimize glucose-stimulated insulin secretion (GSIS) during the active/feeding phase of the circadian cycle. Thus, to elucidate whether transplanted SC-β cells retain capacity for circadian control of insulin secretion, SC-β cells were generated using a six-step directed differentiation protocol and transplanted (n=13 independent transplants) under the kidney capsule into immunocompromised (SCID-beige) mice. Prior to transplantation, differentiated SC-β cells were confirmed to express core circadian clock genes (e.g.,BMAL1, CLOCK, PER1 and REV-ERBα). Provided this information, we next assessed in vivo glucose tolerance and corresponding insulin secretory response (using human insulin ELISA) in SCID-beige mice during the inactive/sleep and active/feeding circadian cycles. Both parameters demonstrated robust diurnal rhythmicity (p<.05, inactive vs. active) with markedly enhanced glucose tolerance and in vivo SC-β cell secretory function evident during active/feeding circadian phase in mice. Notably, among 13 independent transplantations, ~90% of mice demonstrated statistically significant GSIS in response to intraperitoneal glucose injection during active/feeding compared to ~30% during inactive/sleep circadian phase. Our results provide evidence that transplanted SC-β cells retain circadian control of insulin secretion which should be taken into consideration for assessment and design of future β cell replacement strategies.

Disclosure

S. K. Sen: None. S. Hassoun: None. Q. P. Peterson: Other Relationship; Self; Semma Therapeutics, Inc. A. Matveyenko: None.

Funding

National Institutes of Health (R01DK098468 to A.M.)
164-OR: Brown Adipose Tissue as a Novel Site for Islet Transplantation
Authors: KEPPLE JESSICA , BARRA JESSIE , HUNTER CHAD S. , TSE HUBERT M.
Published: June 2021

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells. While islet transplantation is a promising alternative to insulin therapy for T1D treatment, finding ideal transplant sites that are readily accessible, exhibit glucose regulation, are immune-privileged, and promote vascularization for islet survival has remained a challenge. A novel site which exhibits these traits is the brown adipose tissue (BAT). BAT functions as a thermogenic adipose tissue that maintains body temperature and regulates metabolism. We hypothesize that murine islets transplanted into BAT will display normal islet graft and BAT function while providing immunological protection. Syngeneic transplant of 250 NOD.scid islets into the BAT of streptozotocin-treated diabetic NOD.scid mice restored euglycemia for over ten weeks, which was comparable to kidney capsule transplant controls. BAT histology and mRNA analysis assessed ten weeks after transplantation showed engrafted islets maintain expression of hallmark hormones, like insulin and glucagon, and critical transcription factors. Evaluation of BAT function after transplantation revealed no impairments in glucose and insulin tolerance, cold tolerance, or whole-body energy expenditure. Flow cytometry analysis displayed an enrichment of immunomodulatory T regulatory cells and anti-inflammatory M2 macrophages in BAT compared to kidney, possibly allowing greater immunoprotection for engrafted islets. Strikingly, adoptive transfer and allogeneic transplant studies revealed that islets transplanted into BAT showed significant delays in autoimmune and allograft rejection compared to islets transplanted under the kidney capsule. Overall, our data suggest BAT as a novel and efficacious site for islet transplantation to potentially combat T1D.

Disclosure

J. Kepple: None. J. Barra: None. C. S. Hunter: None. H. M. Tse: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK099550 to H.M.T.), (DK111483 to C.S.H.), (DK126456 to H.M.T., C.S.H.), (F31DK121414 to J.K.); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B to H.M.T.); National Institute of General Medical
166-OR: Coinfusion of Mesenchymal Stem Cells Improves Human Islet Survival in the Hepatic Islet Transplantation Mouse Model
Authors: GOU WENYU , STRANGE CHARLIE , WANG HONGJUN
Published: June 2021

Islet survival is improved when islets are co-transplanted with mesenchymal stromal cells (MSCs) under the kidney capsule. We assessed whether co-infusion of MSCs with human islets into the liver, as performed in patients, would protect those islets from death post-transplantation (PT) in streptozotocin-induced diabetic NOD-SCID mice (blood glucose, BG >350mg/dl). Blood glucose levels were measured as surrogate markers for islet survival and function. Transplantation of a suboptimal islet number led to normoglycemia (BG<200mg/dl) at 60 days PT in 33% of 6 mice. In contrast, 91% (n=12) of mice receiving islets co-infused with MSCs (Islet+MSC) reached and remained normoglycemic. Mice receiving islet+MSC showed lower non-fasting glucose levels, higher baseline and stimulated c-peptide levels and better function when challenged with high glucose during an intravenous glucose tolerance test. Immunohistochemistry staining of beta cells identified that significantly more islets and islet positive area were observed in the livers of islet+MSC compared to islets alone mice (even in mice with normoglycemia). We show that MSCs led to better islet survival in MSC-co-infused mice after transplantation. By using firefly luciferase-expressing MSCs, we found that co-transplanted luciferase+ (Luc+) MSC was detected up to 7 days in the liver PT. Insulin expressing MSCs were detected at 60 days PT, suggesting MSCs can stay in the liver long-term and may convert into insulin+ cells. Inflammatory-related chemokines, including IL-6, KC, and MCP-1, were also significantly reduced in islet+MSC mice serum at day 1-3 PT. The protective effects of MSC on beta cell survival was confirmed in vitro when human islets were co-cultured with MSCs in a Transwell system. These data suggest that the mechanisms of MSC protection were mediated through suppression of the innate immune response and inflammation-induced β cell death when MSC and islets were co-transplanted into the liver.

Disclosure

W. Gou: None. C. Strange: None. H. Wang: None.

Funding

National Institutes of Health (1R01DK105183, DK120394, DK118529); U.S. Department of Veterans Affairs (I01BX004536)
177-LB: The Association between the Baseline Glycemic Control and Antihyperglycemic Therapy with the Severity of SAR-CoV2 Infection in Ethnic Minority Patients with Diabetes
Authors: BERARDO JERONIMO , MIHAILESCU DAN , TAHSIN BETTINA , FOGELFELD LEON
Published: June 2021

Objective: To analyze the relationship between the baseline glycemic control and antihyperglycemic therapy with the severity of the SARS-COV-2 infection (COVID-19) in ethnic minority patients with diabetes.

Methods: We conducted a retrospective chart review of 179 consecutive patients at an academic hospital in Chicago, Illinois. A sample of patients who tested positive for COVID-19 between March 21st, 2020 and January 12th, 2021were divided in 3 groups according to the clinical severity of COVID: 1) Mild (outpatient treatment only); 2) Moderate (hospital admission); 3) Severe (ventilatory support and/or death).

Results: Mean hemoglobin A1c (HbA1c) before COVID-19 was 8.43 (±2.0) %. Mean age was 59.6 (±11.9) years, 57.54% were male, 51.9% Hispanic and 41.9% African Americans. Sixty-four patients (35.8%) had mild disease (outpatient treatment, group 1), 93 (52%) moderate (hospital admission without the need for ventilatory support, group 2), and 22 (12.3%) severe disease (intubation and/or death, group 3). Baseline glycemic control was not associated with the clinical outcomes of COVID. Among various therapeutic agents, only metformin use was significantly associated with mild disease versus moderate and severe forms of COVID, controlling for GFR. Fifty-four patients (84.4%) in group 1 were taking metformin, compared with 63 (35%) and 11 (50%) in the moderate and severe groups, respectively.

Conclusion: Here we report that use of metformin was associated with a lower chance of developing moderate (hospitalization) or severe forms (ventilatory support and/or death) of COVID-19 in ethnic minority patients with diabetes. Prospective investigation is required to make precise estimates of the impact of metformin in COVID-19 outcomes.

Disclosure

J. Berardo: None. D. Mihailescu: None. B. Tahsin: None. L. Fogelfeld: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi.
178-OR: Lipotoxicity Stimulates ß-Cell Extracellular Vesicle Secretion Which Induces ß-Cell Dysfunction and Perturbs ß-Cell Transcriptional Identity
Authors: HER TRACY K. , BROWN MATTHEW , MATVEYENKO ALEKSEY , JAVEED NAUREEN
Published: June 2021

Chronically elevated circulating free fatty acids (FFA) contribute to β-cell dysfunction and thus to the onset of obesity-driven type 2 diabetes (T2DM). Prolonged β-cell exposure to FFA is associated with reduced glucose-stimulated insulin secretion (GSIS), alterations in β-cell transcriptional identity, and apoptosis. However, the mechanisms that contribute to the demise of β-cells under lipotoxic conditions have yet to be fully elucidated. Increasing evidence suggests that aberrant release of extracellular vesicles (EV) contribute to the pathogenesis of β-cell failure in T2DM. However, what remains to be deciphered is the role of β-cell-derived EV in lipotoxicity-mediated β-cell failure. We set out to test the hypothesis that lipotoxicity-mediated β-cell dysfunction is mediated in part by paracrine release of ‘toxic’ β-cell-derived EV. To address this, MIN6 β-cells were exposed to palmitate (0.5 mM, 24h) and EV were isolated using differential ultracentrifugation to yield palmitate (PAL) EV (vs. control (CTL) EV). Nanoparticle Tracking Analysis (NTA) revealed a significant increase in PAL EV concentration (~1.5 fold vs. CTL EV) with a reduction in average particle size (CTL EV = 121 nm vs. PAL EV = 75 nm). β-cell functional assessment of mouse islets exposed to PAL EV (48h) resulted in significant suppression of GSIS (~3.4 fold decrease in stimulation index). Global transcriptomic analysis was assessed using RNA-Seq on islets exposed to PAL EV. Over 900 genes were differentially upregulated and ~450 genes downregulated upon PAL EV exposure (p<.05, FC>1.5). Genes upregulated with PAL EV encoded for KEGG pathways regulating protein digestion/absorption, ECM-receptor interaction, and PI3K/Akt signaling, while downregulated genes encode for pathways regulating glycolysis and protein processing in ER (FDR<.05). These data suggest the novel relevance of β-cell-derived EV in free fatty acid-induced β-cell failure in T2DM.

Disclosure

T. K. Her: None. M. Brown: None. A. Matveyenko: None. N. Javeed: None.

Funding

National Institutes of Health (R01DK098468, T32HL105355)
181-LB: Hyperglycemia at Hospital Presentation Associated with Severity and Mortality in COVID-19 Patients without Type 2 Diabetes
Authors: CHAROENNGAM NIPITH , HOLICK MICHAEL F. , APOVIAN CAROLINE
Published: June 2021

There is a bidirectional association between hyperglycemia (HG) and COVID-19 severity. We conducted a retrospective cohort study in COVID-19 patients aged ≥18 years hospitalized at the Boston Medical Center during March 1 - August 4, 2020 with the aim to determine the relationships among HG, presence of type 2 diabetes (T2D) and outcomes of COVID-19. Blood glucose levels (BG) measured on admission were extracted from the hospital database. HG was defined as BG >200 mg/dL. Patients with type 1 diabetes or BG <70 mg/dL were excluded. Outcomes were in-hospital death and intensive care unit (ICU) admission. Multivariate analysis was used to determine the associations between exposures and outcomes. A total of 1,434 patients were included in the analysis. The mean ± SD age was 56 ± 17 years, 642 (45%) were female and 458 (32%) had a history of T2D. HG occurred in 193 patients with T2D (42%) and 42 patients without T2D (4%). The rates of death and ICU admission were 9% and 19%, respectively. Among patients without T2D, after adjusting for age, sex, body mass index, race and comorbidities, patients with HG had a significantly higher odds of death (aOR 4.5, 95%CI 1.8 - 11.2) and ICU admission (aOR 3.7, 95%CI 1.8 - 7.5) than patients without HG. Among patients with T2D, patients with HG had a significantly higher odds of ICU admission (aOR 1.7, 95%CI 1.0 - 2.8) and tended to have a higher odds of death (aOR 1.6, 95%CI 0.8-3.0) than patients without HG after adjusting for potential confounders. Among the 235 patients with HG, the odds of death and ICU admission were higher in the 42 HG patients without T2D than the 193 patients with T2D (death: aOR 5.1, 95%CI 1.3 - 19.0; ICU admission: aOR 2.7, 95%CI 1.1 - 6.7) after adjusting for potential confounders including BG. HG in the subset of patients without T2D could be a marker of high inflammatory burden leading to higher mortality or undiagnosed diabetes leading to increased severity of COVID-19 due to metabolic dysfunction.

Disclosure

N. Charoenngam: None. M. F. Holick: Consultant; Self; Biogena Inc, Ontometrics Inc, Other Relationship; Self; Quest Diagnostics, Speaker’s Bureau; Self; Abbott. C. Apovian: Board Member; Self; Abbott, Allergan plc, Gelesis, Novo Nordisk, Nutrisystem, Tivity Health, Xeno Bioscience, Zafgen, Inc.

Funding

National Institutes of Health (2T32DK7201-42 to N.C.), (P30DK046200 to C.A.)
181-OR: Amino Acid-Stimulated Alpha Cell Proliferation Requires Glutaminase Activity
Authors: SIV WALTER , SELLICK KATELYN , REUTER AUSTIN , SHOU MATTHEW , STANLEY JADE , SPEARS ERICK , CHEN WENBIAO , DEAN DANIELLE
Published: June 2021

Interrupted glucagon signaling reduces hyperglycemia. However, interrupted glucagon signaling increases serum amino acid and glucagon levels and stimulates amino acid-dependent alpha cell proliferation as part of an endocrine feedback loop, the liver-alpha cell axis. Our previous studies showed that glutamine and SLC38A5, a transporter of glutamine and other amino acids, are required for amino acid-stimulated alpha cell proliferation. To understand the mechanism of glutamine-stimulated proliferation, we analyzed published transcriptomics data for enzymes involved in the glutamine metabolism pathway and found 3-fold greater gene expression of glutaminase (Gls/GLS) in mouse and human alpha cells than in other pancreatic endocrine cells, while Gls2/GLS2 expression was extremely low in islet cells. Immunohistochemical analyses of mouse and human pancreata showed greater protein expression of GLS in islets versus the surrounding exocrine tissue. Within islets, both human and mouse alpha cells had higher expression than beta cells, suggesting that alpha cells may have increased capacity for glutamine metabolism. This expression pattern was also observed in individuals with either type 1 or type 2 diabetes. To examine the role of GLS activity in alpha cell proliferation, we treated the αTC1-6 mouse glucagonoma cell line with a competitive GLS inhibitor CB-839. GLS inhibition resulted in a 1.6-fold decrease in cell count over an 8-day cell growth assay (DMSO: (9.7 ± 1.3)x105, 10 μM CB-839: (6.2 ± 1.4)x105; n=2-4). In isolated mouse islets cultured in high glutamine and amino acid containing media, GLS inhibition inhibited alpha cell proliferation (DMSO: 7.6 ± 2.2%, 0.1 μM CB-839: 0.11 ± 0.05%**, 1.0 μM: 0.04 ± 0.02**, 10 μM: 0.02 ± 0.01%**, n=3-4, p<0.01). These data indicate that glutamine metabolism through GLS is critical for amino acid-dependent alpha cell proliferation in mice and support that alpha cells are unique amino acid sensors playing a critical role in amino acid homeostasis.

Disclosure

W. Siv: None. K. Sellick: None. A. Reuter: None. M. Shou: None. J. Stanley: None. E. Spears: None. W. Chen: None. D. Dean: None.

Funding

National Institutes of Health (DK117969, DK117147, DK020593); JDRF (2-SRA-2016-149-Q-R)
185-LB: Effect of the COVID-19 Lockdown on Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus
Authors: MALIK IS-HAQ O. , NAHER KAMRUN , THRUPTHI KOMANDUR , ZAIDI BUSHRA , LEUNG VIVIEN
Published: June 2021

Objective: The rapid emergence of the SARS-COV2 virus that caused COVID-19 pandemic in early 2020 led to authorities instituting lockdown protocols to curb spread of the virus. Prior studies in patients with T1DM have demonstrated a short-term favorable or neutral effect of the lockdown on glycemic parameters; however, data is limited in T2DM patients. We sought to identify how the lockdown affected the glycemic control of adult patients with T2DM within a specific region of New York Design & Methods: In this retrospective cohort study, we analyzed data from patients with regular outpatient visits within an integrated-delivery health system in South Bronx, New York who had A1C levels measured within 6 months prior to the initiation of lockdown (Mar ’20) and a repeat A1C within 3 months after the first phase of reopening in New York (June ’20). Analysis of comparison between pre- and post-lockdown HbA1c values was performed using paired samples T-test.

Results: A total of 2489 adult patients with an established diagnosis of T2DM and A1C levels available during the study period were identified. 632 patients were excluded due to pregnancy, prediabetes, new-onset diabetes, residency in long-term care facility or hospital admission during the study period. Age range was 18 to 95 years with a mean age of 61. 58% of the patients were female and 41% male. Mean pre-lockdown A1C was 7.64% and mean post-lockdown A1C was 7.76%, indicating an increase of 0.122% (95% CI, 0.0613-0.1827)

Conclusions: The COVID-19 lockdown was associated with a small but statistically significant increase in HbA1C levels (0.122%) in a large cohort of community-dwelling adult patients with type 2 diabetes in South Bronx. Interruptions to regular outpatient care, difficulty in obtaining medications from pharmacies, changes in physical activity or diet and psychological stress related to the pandemic may have been potential contributing factors and need to be addressed to avoid further worsening of diabetes control in the longer term.

Disclosure

I. O. Malik: None. K. Naher: None. K. Thrupthi: None. B. Zaidi: None. V. Leung: None.
199-OR: Insulin Infusion Decreases Extracellular Vesicles in Adults with Metabolic Syndrome
Authors: HEISTON EMILY , BALLANTYNE ANNA , STEWART NATHAN , MUSANTE LUCA , ERDBRUEGGER UTA , MALIN STEVEN K.
Published: June 2021

Elevated extracellular vesicles (EVs) are associated with glucose dysmetabolism. However, the direct effects of insulin on EVs and subsequent relationship with insulin sensitivity and substrate oxidation is unknown in adults with metabolic syndrome (MetS). Fifty sedentary adults (54.5 ± 1.0 yr; VO2peak: 22.3 ± 0.6 ml/kg/min) with MetS (36.3 ± 0.7 kg/m2; ATP III Criteria: 3.46 ± 1.0) underwent a 2-hr euglycemic-hyperinsulinemic clamp (90 mg/dl; 40 mU/m2/min) to determine EV responses to insulin and metabolic insulin sensitivity (M-Value). Endothelial (CD105+, CD41-/CD31+), leukocyte (CD45+), platelet (CD41+, CD41+/CD31+), and tetraspanin-derived EVs (TX+), as well as platelet endothelial cell adhesion molecule (CD31+) were detected in platelet poor plasma samples at 0 and 2-hr of the clamp using spectral flow cytometry. Fat (Fox) and carbohydrate oxidation (CHOox) were also measured (indirect calorimetry) to determine metabolic flexibility. Despite low metabolic insulin sensitivity (2.55 ± 0.2 mg/kg/min), insulin (82.9 ± 3.7 uU/ml) reduced Fox (delta, P=0.001) compared to fasting. Insulin also decreased CD105+ (P<0.01), CD41-/CD31+ (P=0.03), CD41+ (trend: P=0.06), TX+ (P<0.01), and CD31+ (P=0.03). Surprisingly, there were no correlations between EVs and metabolic insulin sensitivity. However, higher fasting insulin levels were related to lower insulin-stimulated changes in CD105+ (r=0.32, P=0.03), CD41-/CD31+ (r=0.33, P=0.05), and CD45+ (r=0.33, P=0.04). Further, fasting TX+ and CD41+ (r=0.33, P=0.05 and r=0.42, P<0.01) were related to fasting CHOox while CD105+ was inversely associated with fasting Fox (r=-0.33, P=0.03). Fasting TX+ (r=-0.42, P=0.01), CD31+ (r=-0.33, P=0.04), and CD41+ (r=-0.32, P=0.04) also correlated with CHOox metabolic flexibility. Insulin infusion decreases EVs in adults with MetS. Additional work investigating the role of EVs on substrate metabolism is warranted to elucidate mechanisms for type 2 diabetes risk.

Disclosure

E. Heiston: None. A. Ballantyne: None. N. Stewart: None. L. Musante: None. U. Erdbruegger: None. S. K. Malin: None.

Funding

National Institutes of Health (R01HL130296)
2-LB: Flash Glucose Monitoring in the Reduction of Hypoglycemia in Diabetic Kidney Disease: A Randomised Controlled Trial
Authors: LING JAMES , NG JACK K. , MA RONALD C. , KONG ALICE P. , LUK ANDREA , SZETO CHEUK CHUN , CHAN JULIANA C. , CHOW ELAINE
Published: June 2021

Patients with moderate-to-advanced diabetic kidney disease (DKD) are at high risk of hypoglycemia. There are few studies evaluating personal continuous glucose monitoring (CGM) use in this group. We investigated whether flash glucose monitoring (FGM) was effective in reducing hypoglycemia compared with standard self-monitoring of blood glucose (SMBG) in individuals with chronic kidney disease (CKD) stages 3b-5 (non-dialysis). This was a single-centre, parallel-group randomised clinical trial of 94 adults with diabetes and CKD [G3b (n=36), G4 (n=44) and G5 (n=14)] and a history of hypoglycemia. Patients were randomly assigned 1:1 to FGM or SMBG for 16 weeks. Both groups received structured education on hypoglycemia and monthly reviews by healthcare professionals. Blinded CGM was performed at baseline and end of study in both groups. Patients were aged (mean±SD) 65.4±9.0 years with estimated glomerular filtration rate (eGFR) 26.1±9.6 ml/min/1.73m2, HbA1c 7.4±0.8% and median duration of diabetes for 20 years. 93 patients had type 2 diabetes and 99% were on insulin. After 16 weeks, percentage time <70mg/dL (3.9 mmol/L) decreased significantly from 4.0% to 2.5% in FGM group (- 1.7%; 95% CI -3.4 to -0.01%) but not in SMBG group (-1.1%; 95% CI -2.6 to 0.4%; between-group difference, p=0.73). Mean HbA1c improved significantly in both FGM (-0.33%, 95% CI -0.52 to -0.1) and SMBG groups (-0.36%, 95% CI -0.52 to -0.21; between-group difference p=0.08). One severe hypoglycemic event occurred in the FGM and none in SMBG group. The acceptability of FGM was high with overall 87% mean sensor use and average 8 scans per day. FGM was effective in reducing hypoglycemia and improving HbA1c in moderate-to-advanced DKD, but not significantly different from SMBG. Future studies are needed to assess whether real-time CGM with alerts would further reduce hypoglycemic episodes in this high-risk group.

Disclosure

J. Ling: None. J. K. Ng: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. C. Szeto: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis.

Funding

Hong Kong College of Physicians; University Grants Committee Research Matching Grant Scheme
203-OR: Measurement of Intact Insulin by Mass Spectrometry Identifies Nonalcoholic Fatty Liver Disease (NAFLD)
Authors: BRIL FERNANDO , MCPHAUL MICHAEL J. , KALAVALAPALLI SRILAXMI , LOMONACO ROMINA , BARB DIANA , GODINEZ EDDISON , CUSI KENNETH
Published: June 2021

Patients with NAFLD are characterized by insulin resistance (IR) and hyperinsulinism. However, prior studies have been unable to predict NAFLD based on IR measurements. The aim of this study was to explore the application of a newly validated measurement of intact insulin by mass spectrometry to predict NAFLD in patients without diabetes. Ninety-eight patients were recruited and underwent: a 2-hour OGTT with measurements of insulin every 30 min, and a liver magnetic resonance spectroscopy (1H-MRS) to measure liver fat and diagnose NAFLD. A mass spectrometry method was used to measure intact molecules of insulin. A total of 62 patients had NAFLD (48±11 yr, 66% male, BMI: 34.4±4.6kg/m2, A1c: 5.8±0.4%); and 36 did not have NAFLD (52±12 yr, 56% male, BMI: 30.5±6.8kg/m2, A1c: 5.5±0.4%). Fasting insulin levels were higher in NAFLD patients (17±10 vs. 7±3 μU/ml, p<0.001), but showed similar excursions during the OGTT (120 min incremental AUC: 7.4 [4.4-14.5] vs. 5.7 [4.2-8.9], p=0.22). Fasting intact insulin measurements had an AUROC of 0.90 (0.84-0.96) to predict NAFLD. This was significantly better than measuring insulin by radioimmunoassay (RIA) (AUC 0.80 [0.71-0.89], p=0.007). Using a cut-off of 10.5 μU/ml, we observed a sensitivity, specificity, PPV, and NPV of 92% (87-98%), 71% (62-80%), 79% (71-87%), and 89% (83-95%), respectively. Intact fasting insulin was better than other clinical variables (e.g., ALT, AST, triglycerides, HDL, glucose, A1c, and BMI) to predict NAFLD. When combined with ALT (intact insulin x ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and PPV and NPV of 93 and 88%, respectively. This newly described approach was significantly better than previously validated non-invasive scores such as NAFLD-LFS (p=0.009), HIS (p<0.001) and TyG index (p=0.039).

Conclusions: In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and non-invasive strategy to predict presence of NAFLD.

Disclosure

F. Bril: None. M. J. Mcphaul: Employee; Self; Quest Diagnostics. S. Kalavalapalli: None. R. Lomonaco: None. D. Barb: None. E. Godinez: None. K. Cusi: None.

Funding

The Obesity Society; University of Florida