bluuebunny/crossref_metadata_2025 huggingface dataset:
16-OR: Protein Kinase C d Mediates Cytokine-Induced ß-Cell Death via Upregulation of Pro-apoptotic Signaling
Authors: COLLINS JILLIAN , FARNSWORTH NIKKI L. , BENNINGER RICHARD K.
Published: May 2022

In type 1 diabetes (T1D) , autoreactive immune cells secrete cytokines, such as tumor necrosis factor-α (TNF-α) , interleukin-1β (IL-1β) , and interferon-γ (IFN-γ) that can initiate β-cell apoptosis. Protein kinase C delta (PKCδ) plays a role in mediating cytokine-induced β-cell apoptosis; however, the exact mechanisms and role in T1D are unknown. We hypothesize that PKCδ mediates cytokine-induced β-cell apoptosis via nuclear translocation and activation of pro-apoptotic signaling. Islets from WT or mice with a β-cell specific knockout of PKCδ (PKCδβ-KO) were cultured for 24hr with cytokines (10ng/ml TNFα, 5ng/ml IL-1β, 100ng/ml IFN-γ) , a caspase-3 inhibitor (Z-DEVD-FMK, 10µg/ml) , or an adenoviral vector for GFP-tagged PKCδ, GFP only, and a PKCδ mutant that cannot be cleaved by caspase-3 (CM-GFP-PKCδ) . Human islets were treated with 10μM PKCδ inhibitor (δV1-1) for 24hr with or without cytokines. Translocation was determined by GFP colocalization with a nuclear stain. Apoptosis was determined by fluorescent microscopy. PKCδ activity was determined with a FRET-based sensor in MIN6 cells. PKCδ’s role in activating pro-apoptotic signaling was determined via western blot. Decreasing PKCδ activity protected against cytokine-induced apoptosis in mouse (p=0.003) and human (p=0.020) islets. PKCδ translocation and activity increased in nuclei of cytokine treated islets (p<0.001, p=0.039) compared to untreated controls. Islets treated with caspase inhibitor (p<0.001) and CM-GFP-PKCδ islets were protected from cytokine-induced death. Western blot analysis demonstrates that PKCδ regulates pro-apoptotic signaling. Inhibiting PKCδ protected islets from cytokine-induced death. The role we identified for PKCδ in mediating pro-apoptotic proteins will provide novel insight to protect against cytokine-induced β-cell death. Our data suggests targeted inhibition of PKCδ has the potential to prevent cytokine-mediated β-cell death in T1D.

Disclosure

J.Collins: None. N.L.Farnsworth: None. R.K.Benninger: n/a.

Funding

American Diabetes Association (7-21-JDF-020) ; Juvenile Diabetes Research Foundation (1-FAC-2020-891-A-N)
161-OR: Cognitive Impairment in Individuals with Post-Bariatric Hypoglycemia
Authors: SHAMLOO TERMEH , CRAIG COLLEEN M. , SNYDER MICHAEL , MCLAUGHLIN TRACEY
Published: May 2022

Background: Post-bariatric hypoglycemia (PBH) is characterized by repeated episodes of severe hypoglycemia accompanied by neuroglycopenic signs and/or symptoms. Many individuals with PBH report chronic symptoms of cognitive impairment even when blood glucose values are not acutely low. In this study, cognitive function in individuals with PBH compared to age- and BMI-matched healthy controls (HC) was assessed using a quantitative visual paired comparison (VPC) task; a measurement validated to predict cognitive decline and Alzheimer’s disease.

Methods: 20 patients with confirmed PBH (plasma glucose <50 mg/dL with concomitant insulin ≥3 uU/mL, other causes having been ruled out) following Roux-en-Y gastric bypass surgery were compared to 54 age- (46±vs. 50±9 yrs, p=0.05) and BMI- (31±vs. 28±4 kg/m2, p=0.07) matched HCs. Patient-reported frequency of clinically-important hypoglycemic events, defined as fingerstick or plasma glucose <60 mg/dL, was collected by standardized questionnaire. The VPC task, which measures cognitive function by utilizing infrared eye tracking to assess the participant’s novelty preference when presented with a series of novel and familiar images, was conducted under standardized conditions when blood glucose was in the normal range in the clinical research unit.

Results: Compared to HCs, PBH patients scored 12% lower on the VPC task (0.65± 0.vs. 0.57 ±0.15, P= 0.005) . The mean VPC score in PBH patients was in the range that predicts a 22% risk of cognitive decline or Alzheimer’s disease over a 3-year period. Among PBH patients, patient-reported frequency of clinically important hypoglycemic events correlated significantly with VPC score (r=0.44, p=0.047) .

Conclusions: Patients with PBH exhibit cognitive impairment when compared to age- and BMI-matched HCs and the degree of impairment correlates with the frequency of clinically important hypoglycemic events.

Disclosure

T.Shamloo: None. C.M.Craig: Employee; Eiger BioPharmaceuticals, Stock/Shareholder; Eiger BioPharmaceuticals. M.Snyder: Stock/Shareholder; January, Inc. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals.

Funding

American Diabetes Association (1-19-ICTS-073) ; NIH 1U54DE02378901
162-OR: Effect of Automated Insulin Delivery on Glucose Counterregulation in Long-Standing Type 1 Diabetes
Authors: FLATT ANNELIESE , PELECKIS AMY J. , DALTON-BAKES CORNELIA V. , NGUYEN HUONG-LAN T. , ILANY SARAH , MATUS AUSTIN M. , MALONE SUSAN K. , JANG SOOYONG , WEIMER JAMES , LEE INSUP , RICKELS MICHAEL R.
Published: May 2022

Automated insulin delivery (AID) systems are likely of value in individuals with long-standing T1D where recurrent hypoglycemia reduces counterregulatory response. This study assessed the impact of 18M AID on counterregulatory response to insulin-induced hypoglycemia in individuals with long-standing T1D and impaired awareness of hypoglycemia.

participants mean±SD age 49±16 years and diabetes duration 34±16 years were initiated on AID systems. CGM outcomes were paired with actigraphy data to assess daytime and sleep hypoglycemia exposure every 3 months. Hyperinsulinemic stepped-hypoglycemic clamp experiments were performed at baseline, 6 and 18 months. Ten and nine participants have been followed-up to 6M and 18M respectively.

Severe hypoglycemia events were reduced from median (IQR) 3 (3-10) to 0 (0-1) events/person·year over 18M (p=0.005) with improved hypoglycemia severity (HYPO, Pre:1134 (808-1686) to 18M:26 (0-128) , p<0.01) and awareness scores (Clarke, Pre:5 (5-6) to 18M:4 (1-5) , p<0.01) . Hypoglycemia exposure was rapidly reduced with effects sustained (%Time<54 mg/dl, Pre:4 (3-7) , 3M:1 (0-1) , 18M:0 (0-1) , p<0.01) and most marked over periods of sleep (%Time<70mg/dl, Pre:11 (4-17) , 3M:1 (0-3) , 18M:0 (0-1) , p<0.001) . Glucose variability was reduced (p<0.01) with more time in range and less in marked hyperglycemia (p=0.02) . HbA1c and insulin dose were not different.

The autonomic symptom response to hypoglycemia improved (Pre:6±2, 6M:6±2, 18M:10±2, p<0.05) with an increase in pancreatic polypeptide (Pre:62±29, 6M:127±44, 18M:187±64 pmol/l, p<0.01) and epinephrine response (Pre:199±53, 6M:332±91, 18M:386±95 pg/ml, p<0.01) . Glucagon and endogenous glucose production response were unchanged.

AID systems lead to a sustained reduction of hypoglycemia exposure and improvement in symptom and epinephrine response however with persistent impairment in glucose counterregulation and so ongoing compromised physiologic defense against hypoglycemia.

Disclosure

A.Flatt: None. I.Lee: Other Relationship; VitalCore Software. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.J.Peleckis: None. C.V.Dalton-bakes: None. H.T.Nguyen: None. S.Ilany: None. A.M.Matus: None. S.K.Malone: None. S.Jang: None. J.Weimer: Other Relationship; Neuralert Technologies, Vasowatch.

Funding

Public Health Services research grants: RDK091331, UDK070430, UL1 TR001878, and P30 DK19525
165-OR: Norepinephrine Acts on Glutamatergic Neurons in the Ventromedial Hypothalamus to Stimulate the Release of Counterregulatory Hormones
Authors: APPADURAI DANIEL A. , CHAN OWEN
Published: May 2022

Release of glutamate in the ventromedial hypothalamus (VMH) is important for stimulating the counterregulatory hormone responses to hypoglycemia. It is currently not known whether VMH glutamatergic neurotransmission is influenced by adrenergic inputs. To address this question, we examined whether ß2-adrenergic receptors are expressed on VMH glutamatergic neurons using immunohistochemistry. Coronal brain sections collected from Sprague Dawley (SD) rats showed fairly extensive co-localization of Vglut2 (a marker of glutamatergic neurons) and ß2-adrenergic receptors. We then used local microinjection in combination with microdialysis to examine whether norepinephrine administration into the VMH stimulated the release of neurotransmitter glutamate and the counterregulatory hormones in the absence of hypoglycemia. About 7-8 rats were randomly allocated to one of two treatment groups: Controls, which received an infusion of artificial extracellular fluid, or the NE group, which received an infusion of 400 nM of norepinephrine. Our results indicate that NE administration into the VMH caused a marked increase in glutamate that was accompanied by an ∼3-fold increase in both plasma glucagon and epinephrine release (P<0.vs. Control) . Our data suggests that NE enhances the release of neurotransmitter glutamate in the VMH that in turn, may stimulate the release of counterregulatory hormones.

Disclosure

D.A.Appadurai: None. O.Chan: None.

Funding

NIH (DK099315)
166-OR: Brain Responses to Hypoglycemia following Contrasting Hypoglycemia Awareness Restoration Strategies: A Comparison of the HARPdoc and HypoAware Studies
Authors: JACOB PETER , AMIEL STEPHANIE A. , NWOKOLO MUNACHISO , CHOUDHARY PRATIK
Published: May 2022

Background: Restoration of symptoms in response to hypogycemia has been seen in people with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) using an education and diabetes technology approach (HypoAware Study) and a psycho-educational approach addressing cognitions (HARPdoc Trial) . We investigated regional brain responses to hypoglycemia following restoration of IAH between the interventions.

Methods: Twelve people with T1D and IAH from HypoAware and from HARPdoc underwent two-step hyperinsulinemic hypoglycemic clamps before and after their intervention. pCASL fMRI brain blood flow images were acquired. A 2x2 study by timepoint ANOVA interaction design was conducted to compare the effect of each intervention on hypoglycemia-euglycemia difference brain blood flow maps. Within group analysis of the difference maps was conducted using paired t-tests.

Results: HARPdoc participants were older, mean±SD age 54.1±12.3 vs. 34.7±9.0 yrs (p<0.001) with similar HbA1c, 7.8±0.9 vs. 7.8±0.7%, Gold score, 6.0±1.0 vs. 6.0±1.0, BMI 24.6±4.6 vs. 24.4±3.6 and diabetes duration 22.2±7.2 vs. 23.6±7.7 yrs (all p>0.05) . Each intervention was associated with enhanced activation in the anterior cingulate cortex (ACC) in within group studies (HARPdoc FWEp=0.048, HypoAware FWEp=0.011) . In the between group analysis, a superior frontal gyrus (SFG) region was more activated at hypoglycemia following HARPdoc than HypoAware (FWEp=0.044) .

Conclusion: We have shown different brain responses to hypoglycemia in treated IAH depending on the therapeutic approach. Enhanced ACC responses were expected following recovery of symptoms. However, the cognitive approach of HARPdoc enhances the hypoglycemia response in the SFG, known to be involved in self-awareness and appreciation of symptoms, is unique to HARPdoc and is consistent with its psychological and cognitive nature. This may increase the potential for lasting effect.

Disclosure

P.Jacob: None. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. M.Nwokolo: None. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi.

Funding

Juvenile Diabetes Research Foundation (3-SRA-2017-484-S-B)
171-OR: Effect of Interventions on Blood Pressure for Black Persons with Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials
Authors: JIANG CHERRY , OSMAN FAWSIA , DECKARD AMBER , WAN WEN , ALEXANDER JASON , SHETTY RAJ , STAAB ERIN M. , LAITEERAPONG NEDA
Published: May 2022

Background: Uncontrolled blood pressure (BP) is a major cardiovascular disease (CVD) risk factor, and CVD is the leading cause of death among non-Hispanic Black persons with type 2 diabetes (T2D) . While many interventions have been designed to improve BP control in this population, disparities persist. A meta-analysis of randomized controlled trials was conducted to evaluate the effectiveness of T2D interventions at improving BP.

Methods: An electronic search of Medline, PubMed, Scopus, CINAHL, and PsychINFO was conducted from 1985 to 2019. Keywords included those related to diabetes, study design and race/ethnicity. We included non-pharmacologic trials with ≥12.5% Black persons (using the 2020 US Census as a standard) . Interventions were aimed at improving outcomes including HbA1c, BP, weight and lipids. For this analysis, we focused on the outcomes mean systolic (SBP) and diastolic blood pressure (DBP) differences between control and experimental groups. A random effects meta-analysis was performed to calculate the pooled effect size to provide summary estimates.

Results: Sixteen trials (n=2314) reported SBP and DBP outcomes; two additional trials (total n=2919) reported only SBP outcomes. The participants were 59% Black and 71% female with a mean age of 55.9 years. Average baseline BP was similar for the control and intervention groups (134/78 and 134/77, respectively) . Interventions included self-management education, telehealth support, lifestyle programs, and pharmacist-led support. Compared to control, these interventions demonstrated no difference in SBP (0.01, 95% CI -0.to 0.mmHg, p=0.55, I2=0%) or DBP (-0.05, 95% CI -0.15 to 0.mmHg, p=0.20, I2=22%) .

Conclusion: In this meta-analysis of trials aimed to improve outcomes in Black patients with T2D, there was no improvement in BP control. Given the high risk of CVD in this population, more effective interventions are needed to improve BP control in Black persons with T2D.

Disclosure

C.Jiang: None. F.Osman: None. A.Deckard: None. W.Wan: n/a. J.Alexander: None. R.Shetty: None. E.M.Staab: None. N.Laiteerapong: None.
176-OR: The Effect of Low-Dose Empagliflozin on Glucose Control in Suboptimally Controlled Adults with Type 1 Diabetes on a Closed-Loop Insulin Delivery System
Authors: PASQUA MELISSA-ROSINA , JAFAR ADNAN , KOBAYATI ALESSANDRA , TSOUKAS MICHAEL , HAIDAR AHMAD
Published: May 2022

Background: For some with type 1 diabetes (T1D) , hybrid closed-loop insulin therapy is insufficient to achieve glycemic targets. Low doses of SGLT2i may improve glycemia in those not able to achieve their targets.

Methods: A double-blinded, cross-over, randomized controlled trial was performed in sub-optimally controlled (HbA1c 7.0-10.5%) adults with T1D who were not able to achieve a time-in-range (3.9-10.0 mmol/L) of > 70% after 14 days on closed-loop therapy. Three 14-day interventions were performed with placebo, empagliflozin 2.5 mg, or empagliflozin 5 mg, as adjunct to closed-loop therapy, with daily ketone testing.

Results: 24 participants completed the study (50% male, age 33 ± 14 yrs, HbA1c 8.1 ± 0.5%) . The time in range was 59 ± 9% for placebo, 72 ± 10% for empagliflozin 2.5 mg, and 70 ± 8 for empagliflozin 5 mg (p < 0.between placebo and empagliflozin 2.5 mg, and placebo and empagliflozin 5 mg) . Empagliflozin 2.5 mg did not increase time spent below 3.9 mmol/L though empagliflozin 5 mg did (p = 0.01) . Average ketone levels were not different between arms (p=ns) . There were no serious adverse events in any intervention.

Conclusion: Both empagliflozin 2.5 mg and 5 mg increased the time spent in target on hybrid closed-loop therapy by 11-13 % compared to placebo, in those who otherwise were unable to attain glycemic targets.

Disclosure

M.Pasqua: None. A.Jafar: None. A.Kobayati: None. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. A.Haidar: Consultant; Eli Lilly and Company, Research Support; ADOCIA, Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc.

Funding

National Institutes of Health (1DP3DK106930)
179-LB: Characteristic Cluster of Metabolic Disorders in Relation to Risk of Cancer in Chinese Patients with Type 2 Diabetes
Authors: ZHANG LEI , WANG JUN , YANG YUXIU , DONG YANHU
Published: May 2022

Aims: The study aimed to investigate the relationship between components of metabolic syndrome (MS) and risk of cancer in patients with type 2 diabetes (T2DM) .

Methods: We enrolled 6587 patients with T2DM who were hospitalized in Qingdao Endocrine and Diabetes Hospital from Feb 2005 to Jan 2016. According to the number of MS component each patient had, they were divided into isolated T2DM, T2DM plus 1 component,2 components, 3 components and 4 components, respectively. The IDF Worldwide Definition of the Metabolic Syndrome was applied. Information on the diagnosis of cancer was obtained by matching ICD-10 codes recorded in local Healthcare medical records database. Prevalence of cancer was compared using Chi-square test. Logistic regression model was used to evaluate risk of cancer associated with MS.

Results: The prevalence of cancer was 4.2% among 6587 patients with T2DM. Female patients had higher prevalence than did male in total or in the MS subgroup. The prevalence of cancer were 3.8%, 3.9%, 3.8%, 5.1% and 5.0% in isolated DM, T2DM plus 1 component of MS, T2DM plus 2, T2DM plus 3 and T2DM plus 4 components, respectively (P for trend <0.05) . Compared with those with less than 3 components, T2DM plus 3 or 4 components had increased risk of having cancer (OR=1.32, 95% CI: 1.04-1.69) . Among T2DM patients who had more than 3 components of MS, a specific cluster of increased waist, elevated triglycerides (TG) and decreased High-Density Lipoprotein Cholesterol (HDL-C) was associated with the highest prevalence of cancer (10.7%) , followed by 8.3% in T2DM patients plus hypertension, elevated TG and decreased HDL-C and 3.2% in T2DM patients plus hypertension, increased waist and elevated TG (χ2=26.6, P<0.05) .

Conclusions: A cluster of metabolic disorders consisting of increased waist, elevated TG and decreased HDL-C seems to be oncogenic among Chinese patients with T2DM. For patients in combination with 3 or 4 MS components, it is important to conduct early cancer screening and prevention.

Disclosure

L. Zhang: n/a. J. Wang: None. Y. Yang: None. Y. Dong: None.
179-OR: Cardiovascular Effectiveness of Empagliflozin vs. Glucagon-Like Peptide-1 Receptor Agonists or Liraglutide in the EMPRISE Study
Authors: HTOO PHYO T. , TESFAYE HELEN , PAIK JULIE M. , WEXLER DEBORAH J. , NAJAFZADEH MEHDI , GLYNN ROBERT , DERUAZ-LUYET ANOUK , FARSANI SOULMAZ F. FAZELI , KOENEMAN LISETTE , SCHNEEWEISS SEBASTIAN , PATORNO ELISABETTA
Published: May 2022

Within the EMPRISE® monitoring program, we evaluated the cardiovascular effectiveness of empagliflozin (EMPA) vs. glucagon-like peptide-1 receptor agonists (GLP1RA) or liraglutide using data from Medicare and 2 U.S. commercial claims databases [2014- (2018 for Medicare) ]. We identified patients ≥18 years with type 2 diabetes initiating (i) EMPA vs. GLP1-RA or (ii) EMPA vs. liraglutide. Primary outcomes were hospitalization for heart failure (HHF) , myocardial infarction (MI) , stroke, and all-cause mortality (Medicare only) . After 1:1 propensity score matching, we estimated pooled HR (95% CI) overall and in subgroups of patients with and without baseline cardiovascular disease (CVD) . We identified 105,955 pairs of EMPA vs. GLP1RA initiators and 72,498 pairs of EMPA vs. liraglutide initiators (Table) . Relative to GLP1RA, EMPA had a lower risk of HHF [HR:0.62 (95% CI, 0.53, 0.71) ] and a similar risk of MI [0.95 (0.85, 1.07) ], stroke [1. (0.94, 1.27) ], and mortality [0.91 (0.77, 1.08) ]. Results were consistent for patients with and without CVD. When we compared EMPA vs. liraglutide, estimates were similar to those from GLP1 RA, both overall and across subgroups. Among real-world patients, EMPA was associated with a reduced risk of HHF, but with similar risk of MI, stroke, and mortality, across the broad spectrum of CVD, compared with GLP-1RA overall or liraglutide.

Disclosure

P.T.Htoo: Employee; Johnson & Johnson. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
180-LB: Plasma miRNAs May Be Associated with Waist Circumference and Insulin Resistance among Women with Polycystic Ovary Syndrome—Pilot Study
Authors: WANDER PANDORA , ENQUOBAHRIE DANIEL , BAMMLER THEO , MACDONALD JAMES , SRINOUANPRACHANH SENGKEO , KALERU THANMAI , KHAKPOUR DORI , TRIKUDANATHAN SUBBULAXMI
Published: May 2022

Background: Insulin resistance (IR) and central obesity are common in PCOS, but pathomechanisms for IR in PCOS are not established. Circulating microRNAs (miRNAs) are non-invasive biomarkers of tissue gene expression that may contribute to the pathogenesis of IR and central adiposity in PCOS.

Methods: We conducted a pilot study to examine associations of circulating miRNAs with IR and central adiposity among women with PCOS (n=11) using high-throughput miRNA sequencing. We fit generalized linear models examining associations of waist circumference and HOMA-IR with plasma miRNAs. We used false discovery rate (FDR) -adjusted cutoff p<0.1 to adjust for multiple testing. We used the miRDB’s Gene Ontology (GO) tool to identify predicted pathways for top hits.

Results: Participants were 27.9 years old on average with mean BMI 32.5 kg/m2. At an FDR<0.1, lower levels of miR-1294 were associated with higher waist circumference (β = -0.10, FDR=0.095) . While no miRNAs were associated with HOMA-IR at our predetermined cut off, 11 miRNAs were associated with waist circumference and 14 miRNAs with HOMA-IR at p<0.01 (Table 1) . Pathways identified in the GO analysis of miR-1294 include “negative regulation of insulin receptor signaling” (p=0.019) .

Conclusions: Plasma miRNAs may be associated with IR and central obesity among PCOS patients.

Disclosure

P. Wander: None. D. Enquobahrie: None. T. Bammler: None. J. Macdonald: None. S. Srinouanprachanh: None. T. Kaleru: None. D. Khakpour: None. S. Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas, Insulet Corporation, Insulet Corporation.

Funding

NIDDK (K08103945)
181-OR: Sympathetic Activity in Patients with Type 2 Diabetes Mellitus Treated with Empagliflozin or Hydrochlorothiazide
Authors: HEUSSER KARSTEN , TANK JENS , FISCHER ANNELIE , HEISE TIM , JORDAN JENS
Published: May 2022

Changes in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose transporter (SGLT2) inhibition on cardiovascular outcomes. We hypothesized that SGLT inhibition with empagliflozin lowers sympathetic activity compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from non-specific responses to increased natriuresis. In this double-blind, randomized study patients with type 2 diabetes mellitus on metformin monotherapy received either 25 mg/day empagliflozin (n=20) or 25 mg/day HCT (n=21) for 6 weeks. Muscle sympathetic nerve activity (MSNA) , blood pressure, cardiovascular, and metabolic biomarkers were assessed at baseline and end of treatment. Empagliflozin significantly increased urinary glucose excretion (difference in change from baseline 47.4 mmol/l vs. HCT) , reduced fasting plasma glucose (-1.91 mmol/l) , HbA1c (-0.58%) , and body weight (-1.23 kg, all p<0.05) . Office systolic blood pressure decreased with both treatments. MSNA (burst frequency -1.95 [95% confidence interval -8.67; 4.78] bursts/min) , baroreflex heart rate control (0.84 [-1.18; 2.87] ms/mmHg) and plasma catecholamines did not change significantly with either treatment. MSNA increased with higher body weight loss with both treatments, but more pronounced and significant only with HCT (p=0.0015) .

In conclusion, neither empagliflozin nor HCT treatment led to clinically relevant changes in sympathetic activity. Given the important role of the sympathetic nervous system in the progression of cardiovascular disease, mechanisms attenuating sympathetic activity in the face of increased sodium excretion deserve further attention.

Disclosure

K.Heusser: None. J.Tank: None. A.Fischer: None. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.Jordan: Consultant; Novo Nordisk, Other Relationship; Eternygen, Research Support; Boehringer Ingelheim International GmbH.
182-LB: Delayed Onset of Parkinson’s Disease among Type 2 Diabetes Subjects—Data from an Observational Study
Authors: COLOSIMO SANTO , CEREDA EMANUELE , DEL SORBO FRANCESCA , CALANDRELLA DANIELA , BARICHELLA MICHELA , PEZZOLI GIANNI
Published: May 2022

Background and aim: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Treatment aims at symptoms control and prevention of complications. Although type 2 diabetes (T2D) is a well-established risk factor for cerebrovascular diseases, evidence is lacking with regards to the possible association between T2D and PD. With the present study we aimed at investigating the prevalence and relative time of occurrence of T2D in a cohort of PD patients from an Italian tertiary level center and compare it with the Italian general population.

Methods: For this retrospective observational study, the database of the Parkinson Institute ASST Pini-CTO in Milan was queried. We have selected from the database to include and analyze in the study the records of consecutive patients with an established diagnosis of PD based on the UK Parkinson disease Brain Bank criteria followed at our Institute over a 10-year period, from January 2010 to December 2019.

Results: A total of 8380 patients were included in the study. At the last follow-up visit, 673 (8.4%) PD patients had T2D. Standardized prevalence of T2D was lower among PD patients compared to the Italian general population (3.8 % vs. 5.3%, p<.05) . Age at PD onset was approximately 67 years in those who had already diagnosed with T2D, a higher mean onset age of 7 years compared with both PD patients with later occurrence of T2D and PD patients without T2D (p<.001) . A multivariate regression analysis showed that PD onset in patients who had T2D for seven years or less was delayed by an average of 2.7 years, while patients with a T2D duration for over seven years displayed a mean delay of 5.7 years compared with patients without T2D before PD onset (p<.001) .

Discussion: As per our knowledge so far no other conditions or agents are associated with a delay in the onset of PD. Data from this study show that patients with T2D have a significant delay in PD onset. Causes may be further investigated looking at treatments, hormones, metabolic changes and dietary regimen of T2D. Whether this delay has an impact on the prevalence of PD in the T2D population, remains unclear and need to be studied.

Disclosure

S. Colosimo: None. E. Cereda: None. F. Del Sorbo: None. D. Calandrella: None. M. Barichella: None. G. Pezzoli: None.

Funding

Fondazione Grigioni per il Parkinson, Brain and Malnutrition in Chronic Diseases Association
183-LB: High Daily Doses of Insulin in Type 2 Diabetes—Predictors beyond Weight
Authors: DURON TABORA JAVIER , AMBLEE AMBIKA , TAHSIN BETTINA , FOGELFELD LEON
Published: May 2022

In clinical practice, needing ≥ 200 units insulin/day is defined as severe insulin resistance. This study seeks to identify predictive characteristics of those with type 2 diabetes and severe insulin resistance (≥ 200 units insulin/day) vs. those using <100 units insulin/day.

This retrospective cross-sectional study analyzed data for a six-month period gathered from a diabetes clinic electronic database. Compared were 59 patients using >200 units daily (high insulin users - HIU) vs. 59 patients using <100 units (low insulin users - LIU) .

For the entire study group (n=118) , mean age was 57.7 ± 9.5 years, 66% were female and 52% Hispanic. Comparing groups, no differences seen in age, race, ethnicity, and A1c. Compared to LIU, HIU had more men (26 vs. 14, P=0.032) , higher BMI (41.8 ± 9.5 vs. 35.1 ± 6.6 kg/m2, p<0.001) , less physically active (42.5 (0.0, 120.0) vs. 140.0 (80.0, 180.0) min/week, p<0.001) , lower HDL (37.5 (32.0, 46.0) vs. 43.0 (37.0, 52.0) mg/dL, p=0.005) , higher insulin units/kg/day (2.3 ± 0.7 vs. 0.9 ± 0.3, p<0.001) , higher use of GLP1-RA medication (16 vs. 6, p=0.018) , higher incidence diabetic neuropathy (36 vs. 18, P<0.001) and co-morbid metabolic conditions like hypertension (58 vs. 50, p=0.024) , congestive heart failure (13 vs. 4, p=0.018) , metabolic liver disease (12 vs. 4, p=0.031) , and obstructive sleep apnea (18 v 7, p=0.013) . Per stepwise multivariate analysis, significant predictors of needing more insulin were being less active, lower HDL, co-morbid conditions like hypertension, neuropathy, obstructive sleep apnea, use of GLP1-RA and higher insulin/kg/day.

Factors responsible for high insulin requirements go beyond weight alone as evidenced by higher insulin/kg/day in HIU. Insulin resistance may be exaggerated in the HIU by physical inactivity. Beta cell secretory dysfunction in HIU may also play a role as implied by their longer diabetes duration and higher rate of metabolic comorbid conditions.

Disclosure

J. Duron tabora: None. A. Amblee: n/a. B. Tahsin: n/a. L. Fogelfeld: Research Support; Lilly, Sanofi.
184-LB: Patient-Reported Outcomes (PROs) to Treatment in Type 1 Diabetes (T1D) from the International Diabetes Management Practices Study (IDMPS)
Authors: GAGLIARDINO JUAN J. , ASCHNER PABLO , ILKOVA HASAN M. , RAMACHANDRAN AMBADY , CLAUDE MBANYA JEAN , SHESTAKOVA MARINA V. , PILORGET VALERIE , MELAS-MELT LYDIE , CHANTELOT JEAN-MARC , CHAN JULIANA C.
Published: May 2022

Introduction: Achieving optimal HbA1c in people with T1D requires good treatment acceptance and self-management.

Methods: IDMPS is an international, observational study investigating care practices and clinical profiles of people with diabetes in developing countries. The present analysis of Wave 8 evaluated PROs in people with T1D and their associations with glycemic control using 1) the chronic treatment acceptance questionnaire (ACCEPT) to assess acceptance of long-term medication advantages/disadvantages, and 2) the diabetes self-management questionnaire (DSMQ) to assess health-related behaviors.

Results: Of 1103 people with T1D (mean ± SD age 34 ± 12 years, diabetes duration 14 ± 10 years, HbA1c 8.6 ± 2.0 %, 52% were women and 19% had HbA1c <7 %) from 13 countries, 69% reported 0-2 hours of diabetes-related education in total, and 52% had experienced hypoglycemia symptoms within the previous 3 months. Most patients completed ACCEPT (99%) and DSMQ (99%) . Acceptance was high for medication effectiveness and side effects, but low for length of treatment, regimen constraints, and medication inconvenience (Figure A) . Self-management scores were low, particularly for physical activity and health care use (Figure B) .

Conclusions: Further education for people with T1D could improve self-management and consequently could benefit medication effectiveness.

Disclosure

J. J. Gagliardino: None. J. C. Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. P. Aschner: Advisory Panel; Merck & Co., Inc., Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. H. M. Ilkova: Advisory Panel; Novo Nordisk. A. Ramachandran: None. J. Mbanya: Advisory Panel; Novo Nordisk, Sanofi, Servier Laboratories. M. V. Shestakova: None. V. Pilorget: None. L. Melas-melt: None. J. Chantelot: Employee; Sanofi, Stock/Shareholder; Sanofi.

Funding

Sanofi
185-LB: Pulmonary Function and Diabetes Risk in a Cohort of Black and White Current and Former Smokers
Authors: CONWAY REBECCA B. , YOUNG KENDRA , LI YISHA , AUSTIN ERIN , KINNEY GREGORY L.
Published: May 2022

The recent COVID-19 pandemic, which saw an increased risk of subsequent diabetes among persons with COVID-19 as well as greater casualties among persons with diabetes, has brought renewed attention to the role of lung function in diabetes. We tested the relationship of lung function and chronic obstructive pulmonary disease (COPD) with diabetes in a population of current and former smokers.

Using data from the COPD Genetic Epidemiology (COPDGene) cohort, we conducted a diabetes follow-up (2012-2018) of a cohort of Black and White current and former smokers with (n=2442) and w/out (n=2214) COPD, aged 39-85 years and w/out diabetes at cohort entry. Lung function was modeled using Forced Expiratory Volume at 1 second % predicted (FEV1%P) . COPD was defined as the ratio of FEV1% to FVC% <0.7. Logistic regression was used to compute ORs (95% CIs) for risk of incident diabetes.

The incidence of diabetes was 8% over the five years of follow-up, representing a 43% increase in prevalence. After controlling for age, sex, and race, COPD at baseline was a significant risk factor for diabetes (OR=1.51, 1.21-1.88) . Significant interaction existed between baseline COPD and baseline Fev1%p (p-interaction=0.01) , such that Fev1%p only predicted diabetes among those w/out (OR=0.98, 0.96-0.99) but not among those with COPD at baseline (OR=0.99, 0.99-1.00) . Upon stratification by race, Fev1%p was a significant predictor among Blacks but not Whites, but effect modification by race was not observed. Blacks were at twice the risk of diabetes overall (OR=2.04, 1.59-2.60) and were at 3 times the risk among those w/out COPD (OR=2.91, 1.98-4.27) . BMI increased risk in both races regardless of COPD status; however, a higher BMI was a stronger risk factor for diabetes among Whites than Blacks, particularly for those with baseline COPD (race*BMI interaction p=0.06) .

In this large population of current and former smokers, our data suggest that lower lung function prior to the development of COPD is a risk factor for diabetes, particularly among Blacks. BMI is an important risk factor in both races, but appears to play a stronger role among Whites.

Disclosure

R. B. Conway: None. K. Young: None. Y. Li: Employee; Vertex Pharmaceuticals Incorporated. E. Austin: None. G. L. Kinney: None.

Funding

National Institutes of Health (U01HL089897)
189-LB: Plasma Sphingolipids in Healthy Black and White Adults With or Without Parental Type 2 Diabetes
Authors: MANDAL NAWAJES , WAN JIM Y. , STENTZ FRANKIE B. , NYENWE EBENEZER , PATEL AVNISHA A. , DAGOGO-JACK SAMUEL
Published: May 2022

Objective: Ceramides (CER) and sphingolipids (SPL) have been linked to type 2 Diabetes (T2D) . Here we compared plasma SPL profiles in Black and White adults without a family history of T2D (FH−) vs. those with parental T2D (FH+) .

Methods: We studied 240 healthy subjects: 140 FH+ (70 B, 70 W) and 100 FH− (50 B, 50 W) . Assessments included OGTT, insulin sensitivity (Si-clamp) and insulin secretion (AIRg) . Liquid chromatography/mass spectrometry was used to assay fasting plasma levels of 54 SPL species (18 each from 3 major classes: CER, monohexosyl ceramide {MHC}, and sphingomyelins {SM}) . We compared mole percent composition of SPL species within each class in FH+ and FH− groups.

Results: The subjects’ mean (SD) age was 43.1 + 12.0 y, BMI 29.4 + 6.21, fasting glucose 91.4 + 6.90 mg/dl and 2-hr plasma glucose (2hPG) 123 + 26.3 mg/dl. Total levels of SPL, CER, MHC and SM did not differ by race or sex, and correlated with 2hPG and AIRg but not age, BMI, FPG or Si-clamp. FH+ and FH− adults were concordant for 37 of 54 SPL and discordant for 17 species. Compared with FH−, the FH+ subjects had higher molar abundance of 8 CER, 4 MHC and 2 SM, but lower values for C24:0 Cer, C24:0 MHC, and C26:0 MHC (Table 1) .

Conclusion: Plasma SPL species correlate with glucose tolerance, are altered by parental T2D history, and may reflect heritable elements linking SPL and glucose metabolism.

Disclosure

N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. E. Nyenwe: None. A. A. Patel: None. S. Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi.

Funding

National Institutes of Health (5R01DK128129)
197-OR: Glucagon Receptor Agonism Stimulates Time-Dependent Glycemic Regulation
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M.
Published: May 2022

Historically, glucagon is proposed to be a key factor in the development of diabetes. However, we demonstrated that while chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and insulin action. These paradoxical actions suggest the mechanisms regulating GCGR-mediated glucose metabolism have yet to be fully elucidated. Glucose metabolism and glucagon-stimulated glucose production are both regulated in a circadian manner. Thus, we hypothesized that chronic GCGR signaling regulates glycemia in a time-of-day dependent manner. We treated lean mice for 4d with vehicle or the GCGR agonist IUB288 administered either during the early (ZT 3) or late (ZT9) light period. Ad libitum glycemia was assessed every 4h over a 24h period after the last injection. Independent of the time injected, IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls. This suggests that chronic GCGR agonism is not exclusively hyperglycemic and variations in GCGR-stimulated glycemia are dependent on the time after treatment, rather than the time of day. Interestingly, ad libitum insulin levels were no different between IUB288 and vehicle-treated mice, suggesting differences in insulin sensitivity. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a greater duration than chow IUB288-treated mice. We used hyperinsulinemic-euglycemic clamps to further dissect the mechanisms of these benefits. In DIO mice, IUB288 treatment increased glucose infusion rate, suppression of endogenous glucose production, and phosphorylation of AKT (S473 and T308) . Together, these data increase our understanding of GCGR pharmacology and its therapeutic role in diabetes and obesity treatment.

Disclosure

S.Nason: None. T.Kim: None. J.P.Antipenko: None. B.Finan: Employee; Novo Nordisk. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc.

Funding

T32 AI007051
2-OR: Exosomes from Adipose Tissue Macrophages Can Mediate Insulin-Sensitizing Effects of Rosiglitazone
Authors: ROHM THERESA V. , REIS FELIPE C.G. , ISAAC ROI , PASZEK MILES , BANDYOPADHYAY GAUTAM , OLEFSKY JERROLD M.
Published: May 2022

Background: The beneficial metabolic effects of the PPARγ agonist rosiglitazone (Rosi) are associated with anti-inflammatory changes in adipose tissue macrophages (ATMs) . One study aim was to characterize the in vivo Rosi-induced phenotypic switch of ATMs using a variety of macrophage markers, including the lipid-associated macrophage markers CD9 and Trem2. As a second aim, since ATM-derived exosomes can exert insulin-sensitizing or desensitizing effects dependent on ATM cell context, we assessed the effects of ATM exosomes from Rosi-treated obese mice on in vitro insulin actions.

Research Design and Method: ATMs were isolated from 4 months HFD/obese mice treated for the last month with Rosi (60 mg/kg HFD) compared to HFD or chow-fed controls. Among CD11b+F4/80+ or CD64+ macrophages, we identified pro-inflammatory (“M1-like” CD11c+ and/or CD9+) , anti-inflammatory (“M2-like” CD11c-CD206+) and lipid-associated (CD9+ and/or Trem2+) ATMs by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated in vitro with µM Rosi for 24h. 3T3-L1 adipocytes, L6 myotubes, and primary hepatocytes were cultured 24h with exosomes isolated from ATMs of Rosi treated obese mice or in vitro Rosi treated BMDMs and then assessed for insulin sensitivity.

Results: Rosi treatment reduced adipose tissue inflammation, as seen by reduced numbers of pro-inflammatory (“M1-like”) ATMs and increased the Trem2 signature in “M2-like” ATMs. Importantly, Rosi directly induced Trem2 expression in vitro in BMDMs. Additionally, exosomes isolated from Rosi-treated obese mice or M1 BMDMs increased glucose uptake and insulin signalling (pAKT) in adipocytes and myotubes and reduced glucose production in hepatocytes compared to control exosomes.

Conclusion: Our data indicate that Trem2 is a PPARγ target gene. Since exosomes from Rosi treated ATMs or BMDMs enhance cellular insulin action, this could provide a new explanation for the well-known insulin-sensitizing effects of PPARγ agonists.

Disclosure

T.V.Rohm: None. F.C.G.Reis: None. R.Isaac: None. M.Paszek: None. G.Bandyopadhyay: None. J.M.Olefsky: None.

Funding

Swiss National Science Foundation (SNF) Early Postdoc.Mobility grant (to T.R.) .
204-LB: An Unusual Case of Autoantibody-Negative Ketosis-Prone Diabetes (KPD) Secondary to Marked Insulin Resistance
Authors: INFANTE MARCO , DIPERNA PASQUALE , PASSERI MARINA , MONETTA ROSANNA , PAPOLA FRANCO , BRANCATI FRANCESCO , CAPRIO MASSIMILIANO , FABBRI ANDREA
Published: May 2022

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1*01,*04; DQA1*01:01P,*03:01P; DQB1*03:02P,*05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were <0.2 mmol/L and HbA1c remained <48 mmol/mol (<6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia.

Disclosure

M. Infante: None. P. Diperna: None. M. Passeri: None. R. Monetta: None. F. Papola: None. F. Brancati: None. M. Caprio: None. A. Fabbri: None.
205-OR: Nutrient Sensor OGT Regulates Glucose Homeostasis through ß-Cell Autophagy via mTORC1 Pathway
Authors: JO SEOKWON , ALEJANDRO EMILYN
Published: May 2022

A key aspect of type 2 diabetes (T2D) is the failure of β-cells to secrete sufficient insulin to tightly control blood glucose. Nutrient sensor mTORC1 balances cell growth and degradative process (autophagy) to maintain β-cell health and function. Changes to mTORC1 activity and autophagy are linked with T2D and β-cell failure; however, the underlying mechanisms driving these relationships remain unclear. Our work highlights nutrient sensor O-GlcNAc Transferase (OGT) as a critical regulator of β-cell health; β-cell OGT deletion (βOGTKO) causes diabetes due to severe β-cell mass loss and insulin secretion deficits. In response to changes in nutrient levels, OGT glycosylates key target proteins to impact multiple cellular processes. We hypothesize that under nutrient stress, OGT directly modulates the mTORC1 pathway, and thereby, autophagy-dependent β-cell function. βOGTKO islets exhibited decreased mTORC1 activity and increased autophagy. To delineate the untested signaling crosstalk between OGT and mTORC1 pathways, we generated a mouse model of increased mTORC1 activity, by deleting TSC2 (mTORC1 inhibitor) in βOGTKO mice. The βTSC2/OGTKO mice exhibited complete rescue in the diabetic phenotype of the βOGTKO mice. Normalization of blood glucose was associated with full rescue in β-cell mass deficit, but not improvement in secretory function, which suggests non-overlapping biological processes between OGT and mTORC1. Of these downstream processes, we tested whether mTORC1-driven autophagy affects OGT dependent β-cell function. To do this, we deleted ULK1 (autophagy initiator downstream of mTORC1) in the βOGTKO mice. Supporting our hypothesis directly, βULK/OGTKO mice showed improved glucose tolerance with attenuated hyperglycemia compared to the βOGTKO mice by increasing β-cell function but not mass. Altogether our data show a novel and important role of OGT as a master nutrient-sensor affecting downstream mTORC1 and autophagy to drive β-cell function and mass.

Disclosure

S.Jo: None. E.Alejandro: None.

Funding

National Institute of Health (DK115720)