bluuebunny/crossref_metadata_2025 huggingface dataset:
190-LB: Using Genetics to Uncouple Higher Adiposity from Its Adverse Metabolic Effects
Authors: MARTIN SUSAN , TYRRELL JESSICA , THOMAS ELIZABETH L. , BOWN MATTHEW , ELDER JAMES T. , KABRHEL CHRISTOPHER , PAPADIMITRIOU NIKOS , GUNTER MARC , VINCENT EMMA E. , BELL JIMMY D. , FRAYLING TIMOTHY M. , YAGHOOTKAR HANIEH
Published: June 2021

Type 2 diabetes is linked to higher risk of many non-metabolic conditions (e.g. cancers, neuropsychiatric and musculoskeletal disease) which all share a common risk factor: obesity. The causal pathways from excess weight to disease are unknown. We aimed to use specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects. Using metabolic biomarkers from 442,278 UK Biobank individuals, we identified two clusters of body fat % increasing alleles: a) 36 “favourable adiposity” (FA) alleles associated with a favourable metabolic profile (higher HDL and SHBG and lower triglyceride and liver enzymes); b) 38 “unfavourable adiposity” (UFA) alleles associated with an unfavourable profile (lower HDL and SHBG and higher triglyceride and liver enzymes). We used two-sample Mendelian randomization with 43 diseases from non-UK Biobank GWASs. We identified two sets of diseases. 1) Those where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here the FA and UFA clusters had an opposing effect on the risk of disease: type 2 diabetes (FA: 0.11 OR per 1 standard deviation higher body fat % [95%CI: 0.08, 0.16] vs. UFA: 5.50 [4.29, 7.05]), stroke (0.65 [0.52, 0.83] vs. 1.43 [1.23, 1.67]), gout (0.44 [0.29, 0.68] vs. 2.49 [1.88, 3.29]), breast cancer (1.12 [0.64, 1.94] vs. 0.52 [0.39, 0.68]) and colorectal cancer (0.67 [0.52, 0.85] vs. 1.20 [1, 1.50]). 2) Those where the mechanical excess weight (or other non-metabolic effects) is likely a cause of the disease. Here the FA cluster, despite having lower metabolic risk, and the UFA cluster were both associated with higher disease risk: venous thromboembolism (2.52 [1.82, 3.47] vs. 1.63 [1.25, 2.13]), osteoarthritis (1.45 [1.19, 1.76] vs. 2.20 [1.64, 2.95]), depression (2.85 [1.38, 5.89] vs. 2.59 [1.60, 4.21]). Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects in non-metabolic diseases pathophysiological mechanisms.

Disclosure

S. Martin: None. J. D. Bell: None. T. M. Frayling: None. H. Yaghootkar: None. J. Tyrrell: None. E. L. Thomas: None. M. Bown: None. J. T. Elder: None. C. Kabrhel: Research Support; Self; Diagnostica Stago, Grifols. N. Papadimitriou: None. M. Gunter: None. E. E. Vincent: None.

Funding

Diabetes UK (17/0005594)
200-LB: Circadian Regulation of the MRTF-SRF Signaling Promotes Beige Adipocyte Development
Authors: XIONG XUEKAI , LIU RUYA , YECHOOR VIJAY , SAHA PRADIP , MA KE
Published: June 2021

The adipogenic progenitor transformation into mature adipocytes requires dissolution of intracellular actin cytoskeleton, and the cytoskeleton-MRTF/SRF signaling blocks adipogenesis. The circadian clock confers temporal control in metabolism, with tissue-intrinsic clock circuits contributing to metabolic homeostasis. In the current study, we identify a novel clock-MRTF/SRF regulatory axis that suppresses beige adipogenesis that is required for whole-body glucose metabolism. Key components of the cytoskeleton-MRTF/SRF signaling cascade display circadian oscillations in beige fat depot mediated by Bmal1 transcriptional activity. Genetic loss- or gain-of-functions of Bmal1 in adipogenic precursors markedly altered actin cytoskeleton organization, with silencing of Bmal1 inhibiting F-actin formation and MRTF/SRF activity whereas its forced expression augmenting actin architecture. Furthermore, we show that Bmal1 circadian control of the MRTF/SRF pathway drives beige thermogenic capacity in vivo. Prrx1-Cre-mediated beige fat-selective Bmal1 ablation induced beige depot browning with augmented mitochondrial metabolism, resulting in improved whole-body insulin sensitivity and resistance to obesity. Conversely, beige fat-specific overexpression of Bmal1 suppressed beige thermogenic program leading to impaired glucose tolerance and adipose expansion. Mechanistically, we show that Bmal1 deficiency enhanced beige precursor differentiation and thermogenic induction. Collectively, our findings uncover a temporal regulation of the cytoskeleton-MRTF/SRF signaling that modulates beige thermogenic capacity to maintain metabolic homeostasis.

Disclosure

X. Xiong: None. R. Liu: None. V. Yechoor: None. P. Saha: None. K. Ma: None.

Funding

National Institutes of Health (DK112794, DK097160-01); American Heart Association (17GRNT33370012)
204-OR: ADA Presidents’ Select Abstract: Cardiovascular Autonomic Neuropathy Is Associated with Rapid Kidney Function Decline in Type 2 Diabetes: Findings from the ACCORD Trial
Authors: TANG YALING , JUNIOR CARLOS BUENO , SHAH HETAL , ANG LYNN , POP-BUSUI RODICA , DORIA ALESSANDRO
Published: June 2021

Cardiovascular autonomic neuropathy (CAN) has been shown to predict progressive kidney function decline among persons with type 1 diabetes. We aimed to determine whether CAN has a similar effect on kidney function decline in type 2 diabetes (T2D). To this end, we investigated the association between measures of CAN obtained at baseline and GFR decline during a 5-year follow-up among T2D participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. CAN was defined as ECG-derived heart rate variability indices being below the 5th percentile of the normal distribution (standard deviation of all normal-to-normal R-R intervals [SDNN] <8.2 ms and root mean square of successive differences between normal-to-normal R-R intervals [rMSSD] <8.0 ms). eGFR slopes were estimated by linear regression among participants with ≥3 eGFR measurements during follow up. Of the 6,805 ACCORD participants who had valid measures of CAN and eGFR slope, 1,327 (19.5%) had evidence of CAN at baseline. CAN independently predicted a steeper eGFR decline during follow-up (beta=-0.44 ml/min/1.73m2/year, P=0.0007); 24.6% of participants with CAN at baseline experienced subsequent eGFR loss ≥5 ml/min/1.73m2 per year as compared to 18.6% of participants without CAN (OR=1.39 [1.18 - 1.64], P<0.0001, after adjustment for age, sex, duration of diabetes, BMI, HbA1c, eGFR, urinary albumin-creatinine ratio, and positive CVD history at baseline). Consistent with these findings, in a time-to-event analysis, baseline CAN was associated with a 40% increase in the risk of experiencing a ≥40% eGFR loss during follow-up (adjusted HR=1.40 [1.20-1.63], P<0.0001).

In summary, CAN was an independent predictor of kidney function loss in T2D participants. Further studies are needed to understand whether this association reflects a shared etiology of CAN and diabetic kidney disease or a direct deleterious effect of autonomic nervous system alterations on kidney function.

Disclosure

Y. Tang: None. C. Bueno junior: None. H. Shah: None. L. Ang: None. R. Pop-busui: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Averitas Pharma, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Nevro Corp., Regenacy. A. Doria: None.

Funding

National Heart, Lung, and Blood Institute N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010)
210-LB: Exploring Mechanisms of Insulin Resistance in Mental Illness: Antipsychotic Drugs Alter Metabolic, Inflammatory, and Nonalcoholic Fatty Liver Disease (NAFLD)–Associated Human and Mouse Proteomes in the Absence of Weight Gain
Authors: MAY MEGHAN , BEAUCHEMIN MEGAN , VARY CALVIN , BOUCHARD CELESTE , HOUSEKNECHT KAREN L.
Published: June 2021

Atypical antipsychotic drugs (AA) can cause rapid onset weight gain, insulin resistance, dyslipidemia and NAFLD. Although AA metabolic effects are often associated with obesity, acute AA treatment can cause whole body and hepatic insulin resistance in the absence of weight gain pre-clinically, indicating mechanisms distinct from chronic obesogenic effects of AA. Our aim was to identify pathways involved in AA-associated side effects by correlating differentially expressed traits common to acute AA-exposed mice and drug-exposed human cells using a multi-omic approach. C57BL/6J mice fed chow were treated daily with low, clinically relevant doses of risperidone (RIS; 1 mg/kg BW), olanzapine (OLAN; 5 mg/kg BW) or drug vehicle (VEH; 0.1% acetic acid) for 28 days. Drug treatment had no effect on body weight gain vs. VEH (P>0.05); however, hepatic steatosis was readily observed. Proteomic signatures were generated from hearts and livers of each treatment group, and differentially expressed (DE) proteins (P<0.05; RIS or OLAN vs. VEH) were catalogued. Drug-associated expression signatures consistent with immune disruption, insulin resistance, NAFLD, type 1 and type 2 diabetes occurred with both drugs. Significant (P<0.05) transcriptomic changes between human neuroblastoma cells exposed to 100 nM RIS or VEH were accessed from the Gene Expression Omnibus Database (GSE149611), and overlaid onto proteomic changes of RIS- and OLAN-treated mice. Over 65 pathways associated with metabolic and immune function, insulin resistance, and diabetes were disrupted in both the human and murine systems in the absence of weight gain. These data indicate that AA medications contribute directly to drug-induced immune dysregulation, NAFLD, and metabolic syndrome in patients, potentially via universal mechanisms of systemic dysregulation conserved across species.

Disclosure

M. May: None. M. Beauchemin: None. C. Vary: None. C. Bouchard: None. K. L. Houseknecht: None.

Funding

National Institutes of Health (DK095143)
215-LB: The Role of GLP-1 in Glycemic Response to Protein Ingestion after Gastric Bypass Surgery or Sleeve Gastrectomy
Authors: RAYAS MARIA S. , HONKA HENRI , DEFRONZO RALPH A. , GASTALDELLI AMALIA , SALEHI MARZIEH
Published: June 2021

Protein ingestion increases the plasma insulin and glucagon responses, but the enteral factors involved are entirely unknown. We hypothesized that glucagon-like peptide 1 (GLP-1) signaling regulates glucose metabolism after protein ingestion, and that this effect may be amplified after Roux-en Y gastric bypass (GB) and sleeve gastrectomy (SG). We examined the glucose and islet-cell secretory responses to 50 g protein ingestion with and without GLP-1 receptor antagonist, exendin-(9-39) [Ex-9], in 4 GB-treated subjects, 4 SG-treated, and 4 non-operated controls (CN). The groups were matched for age, BMI, fat-free mass, fasting glucose and insulin, and HbA1c. The surgical groups also were matched for weight loss and time post-surgery; none had diabetes. Protein ingestion resulted in an early rise in glycemia (AUCGlucose 1hr) in GB and SG compared to CN (p<0.05), whose glucose values remained at basal concentrations. Both β- and α-cell hormonal responses were enhanced by protein ingestion in all 3 groups. GLP-1 receptor blockade increased fasting and prandial glycemia in all 3 groups, but to a greater extent in GB (p<0.05, interaction). This glycemic effect of Ex-9 was associated with a ~25% reduction in prandial insulin secretion in GB and SG and ~25% increase in prandial insulin response in CN (p<0.05, interaction). The prandial glucagon responses were larger during studies with Ex-9 compared to those without (p<0.05). Blocking the GLP-1R increased prandial insulin clearance (p<0.05) in all groups, but to a much larger extent in surgical subjects (p=0.1, interaction). Our findings indicate that glucose metabolism after protein ingestion is altered after GB and SG. To our knowledge, this is the first report demonstrating that endogenous GLP-1 contributes to glucose and islet-cell secretory response to protein ingestion, and that GB and SG exaggerate GLP-1 contribution to insulin secretion and clearance after protein ingestion.

Disclosure

M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. H. Honka: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None.

Funding

National Institutes of Health (DK105379)
216-OR: A Random-Order, Double-Blinded, Placebo-Controlled Study of the Bionic Pancreas in the Bihormonal vs. Insulin-Only Configurations Using Two Different Glucose Targets in Adults with Type 1 Diabetes in the Home-Use Setting
Authors: CASTELLANOS LUZ E. , BALLIRO COURTNEY A. , SHERWOOD JORDAN , TUFFAHA MARWA , HILLARD MALLORY , SELAGAMSETTY RAJENDRANATH , EL-KHATIB FIRAS , DAMIANO EDWARD , RUSSELL STEVEN J.
Published: June 2021

Objective: We evaluated the glycemic outcomes with 2 glucose targets in both configurations (bihormonal and insulin-only) of the bionic pancreas (BP) in a home-use study of adults with type 1 diabetes.

Research Design and Methods: 20 participants completed a double-blinded, placebo-controlled (glucagon vs. placebo), random-order, four-arm cross-over trial comparing the bihormonal (BH) and insulin-only (IO) configurations of the BP, each using 2 glucose targets (110 and 130 mg/dl); each arm lasted 3 days. Co-primary outcomes were continuous glucose monitor (CGM) mean glucose level and time <54 mg/dl.

Results: For the BH vs. IO configurations using the 130 mg/dl glucose target, the mean CGM glucose was 156±12 vs. 161±17 mg/dl (p=0.11) and the median percentage of time with CGM glucose <54 mg/dl was 0.0% [IQR 0-0.52%] vs. 0.0% [0-0.35%] (p=0.45). For the BH vs. IO configurations using the 110 mg/dl glucose target, the mean CGM glucose was 148±17 vs. 153±15 mg/dl (p=0.21) and the median percentage of time with CGM glucose <54 mg/dl was 0.0% [0-0%] vs. 0.52% [0.0-1.0%] (p=0.002). The nominal differences in mean CGM glucose between the 110 mg/dl and the 130 mg/dl glucose targets (8 mg/dl in each case) were not statistically significant in either the IO or BH configuration (p>0.05). There was less hypoglycemia in the IO configuration, but not the BH configuration, when using the 130 mg/dl target vs. the 110 mg/dl target (p=0.03).

Conclusions: Both configurations of the BP provided safe and effective glycemic control using both glucose targets during home use. Hypoglycemia was lower with the BH configuration vs. the IO configuration using the 110 mg/dl target. Hypoglycemia was lower in the IO configuration when using the 130 mg/dl target vs. the 110 mg/dl target. Larger and longer studies will be needed to quantify differences in outcomes between the IO and BH configurations of the BP.

Disclosure

L. E. Castellanos: None. C. A. Balliro: Consultant; Self; Beta Bionics, Inc., Novo Nordisk. J. Sherwood: None. M. Tuffaha: None. M. Hillard: None. R. Selagamsetty: Employee; Self; Beta Bionics, Inc. F. El-khatib: Employee; Self; Beta Bionics, Inc., Stock/Shareholder; Self; Beta Bionics, Inc. E. Damiano: Other Relationship; Self; Beta Bionics, Inc., Stock/Shareholder; Spouse/Partner; Beta Bionics, Inc. S. J. Russell: Advisory Panel; Self; Companion Medical, ConvaTec Inc., Consultant; Self; Beta Bionics, Inc., Novo Nordisk, Other Relationship; Self; Beta Bionics, Inc., Research Support; Self; Beta Bionics, Inc., Novo Nordisk, Zealand Pharma A/S.
219-OR: Impact Of Inpen Smart Insulin Pen Use on Real-World Glycemic and Insulin Dosing Outcomes in Individuals with Poorly Controlled Diabetes
Authors: VIGERSKY ROBERT , SMITH MADISON , THANASEKARAN SNEHA , GAETANO ANGELA , IM GLEN HEUNGYONG , CORDERO TONI L. , MACLEOD JANICE
Published: June 2021

Background: Smart insulin pens that track the timing and amount of insulin administration, communicate with phone apps that provide bolus calculators and integrate CGM data are emerging as important technology for users of multiple daily injections (MDI) therapy, as they can improve glycemic outcomes and be more cost-effective compared to some standards of care.1,2 Early real-world outcomes of InPen™ smart insulin pen users were assessed in the present study.

Methods: Deidentified CGM-derived data from N=1736 individuals before and up to 90 days after starting InPen use between Jan. 2018 to Oct. 2020 were evaluated. Glycemic outcomes including mean sensor glucose (SG), glucose management indicator (GMI), and percentage of time spent between 70-180mg/dL (TIR), >180mg/dL (TAR) and <70mg/dL (TBR) ranges were determined and analyzed (Wilcoxon signed-rank test).

Results: Compared to pre-InPen use, individuals (N=423) with suboptimal baseline glycemic control (GMI >8.0%) had increased TIR (+2.3%, 0.6h/day); and reduced GMI (-0.1%), SG (-4.3mg/dL) and TAR (-2.4%); with no change in TBR. Those with poorest glycemic control at baseline (GMI >9.5, N=106) had TIR that improved by +5.0% (1.2h/day), GMI by -0.4%, SG by -14.9mg/dL, and TAR by -5.1% (-1.2h/day), with no change in TBR. From the first month to 90-days post-InPen use, average daily insulin bolus frequency decreased (from 3.7 to 3.6/day and 3.3 to 3.2/day, respectively, for each group) and total rapid acting daily dose of insulin increased (from 26.29 to 27.19 u/day and 27.57 to 29.24 u/day, respectively, for each group). All results were significant at p<0.05.

Discussion: These data show that InPen use is associated with improved glycemic control and increased doses of bolus insulin in users with poor glycemic control.

1. Jendle J, Ericsson Å, Gundgaard J, et al. Diabetes Ther. 2020; doi: 10.1007/s13300-020-00980-1. 2. Adolfsson P, Hartvig NV, Kaas A, rt al. Diabetes Technol Ther;2020;22:709-718.

Disclosure

R. Vigersky: Employee; Self; Medtronic. M. Smith: Employee; Self; Companion Medical, Medtronic. S. Thanasekaran: Employee; Self; Companion Medical, Medtronic. A. Gaetano: Employee; Self; Companion Medical, Medtronic. G. Im: Employee; Self; Companion Medical, Medtronic. T. L. Cordero: Employee; Self; Medtronic. J. Macleod: Employee; Self; Companion Medical, Medtronic.
221-OR: A Machine Learning Approach Identifies Modulators of Congestive Heart Failure Hospitalization Prevention among Patients with Type 2 Diabetes: A Revisit to the ACCORD Trial
Authors: KIANMEHR HAMED , GUO JINGCHUAN , SHI LIZHENG , FONSECA VIVIAN , SHAO HUI
Published: June 2021

Objective: To examine patient characteristics that modulate the efficacy of risk factor reduction in preventing hospitalization for congestive heart failure (CHF) in diabetes management.

Methods: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial tested the cardioprotective effect of achieving A1c< 6.0%, systolic blood pressure (SBP) <120 mmHg, and intensified lipid control by adding fenofibrate among individuals with type 2 diabetes, using a 2x2 factorial design. We analyzed 8,992 participants from the ACCORD glucose trial, 4,178 from the SBP sub-trial, and 4,178 from the lipids sub-trial separately. We applied the casual tree (CT) with cross-validation to each trial to identify baseline characteristics that clustered participants into subgroups with different levels of CHF risk reduction by the corresponding intervention.

Results: Individuals with baseline Alanine transaminase (ALT) at the lowest quartile (<18 mg/dl) benefited the most from SBP control (absolute risk reduction (ARR) in CHF: -1.7%, 95% CI: -3.1% to -0.4%). Individuals with ALT >18 mg/dl and low-density lipoprotein > 110 mg/dl who were receiving ACE inhibitor at baseline also benefited substantially from SBP control (ARR: -1.6%, 95% CI: -2.8% to -0.3%). Optimizing lipid therapy with fenofibrate lowered CHF risk by -1.3% ~ -2.4% in individuals with normal baseline creatine phosphokinase (CPK) (< 200 mg/dl) and A1c < 8%. However, individuals with abnormal CPK at baseline were not associated with changes in CHF risk from fenofibrate. For glucose control, individuals with diastolic blood pressure (DBP) above 69 mmHg and very lower density lipoprotein below 25 mg/dl had an ARR of -0.8% (95% CI -1.6% to 0.0%), and individuals with DBP below 69 mm/Hg had no benefit.

Conclusion: This novel approach demonstrates that ML can identify patients with characteristics that are more or less likely to reduce CHF risk from intensive therapy.

Disclosure

H. Kianmehr: None. J. Guo: None. L. Shi: Research Support; Self; AstraZeneca, Sanofi. V. Fonseca: Consultant; Self; Abbott Diabetes, Asahi Kasei Corporation, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health. H. Shao: Research Support; Self; Sanofi.
224-LB: A Study to Evaluate the Glucagon and Incretin Responses and Identify the Role of Extrapancreatic Glucagon in Patients with Fibrocalcific Pancreatic Diabetes
Authors: SHANKAR ANAND
Published: June 2021

Aim: The aim of this study is to evaluate glucagon and incretin responses in patients with FCPD.

Methods: Nine FCPD patients and six age- and body mass index-matched healthy controls were subjected to 75 g oral glucose tolerance test (OGTT) followed by isoglycemic intravenous glucose infusion (IIGI). Blood samples were analyzed for incretins and glucagon at nine pre-specified time-points over 3 h and the area under curve was calculated.

Results: Glucagon was significantly higher during OGTT compared to IIGI in FCPD patients (98.8 ± 13 pg/ml vs. 63.4 ± 7 pg/ml, P = 0.03) and was also higher when compared to controls (98.8 ± 13 pg/ ml vs. 65.8 ± 18 pg/ml, P = ns). FCPD patients showed very low basal and stimulated c-peptide (0.43 ± 0.14 ng/ml and 1.09 ± 0.3 ng/ ml, respectively) and pancreatic polypeptide (12.3 ± 0.0pg/ml and 12.0 ± 0.6 pg/ml, respectively) levels. Glucagon-like peptide-1 (GLP-1) was significantly higher in cases on OGTT when compared to controls (44.5 ± 9.2 pM vs. 12.8 ± 7.5 pM, P = 0.02). Oxyntomodulin was also insignificantly higher in cases on OGTT when compared to controls (1252 ± 350 pg/ml vs. 859.8 ± 165 pg/ml, P = 0.43). GIP was lower in cases on IIGI when compared to controls (52.9 ± 23.9 pg/ml vs. 144.5 ± 36.1 pg/ml, P = 0.045) and there was blunted response on OGTT as well (106.8 ± 40.3 pg/ml vs. 557.8 ± 96.4 pg/ml, P = 0.003).

Discussion: We found hyperglucagonemia in FCPD on OGTT, which was suppressed on IIGI. Increase in L-cell products: GLP-1 and oxyntomodulin and a good correlation between glucagon and GLP-1 during OGTT were suggestive of extrapancreatic glucagon production probably from L-cell. The blunted GIP could probably be due to: inadequate pancreatic enzyme supplements, a selective PC-2 enzyme up-regulation or a negative feedback regulation from extrapancreatic glucagon.

Conclusion: Extrapancreatic glucagon does exist in FCPD and may contribute to postprandial hyperglycemia and lower GIP levels.

Disclosure

A. Shankar: None.
227-OR: Physical Activity and Glucose Control among Youth with T1D
Authors: GAL JORDAN , LI ZHAOMIAN , WILLI STEVEN M. , RIDDELL MICHAEL
Published: June 2021

Background: Challenges with exercise related glucose control in type 1 diabetes (T1D) may impact adherence to guidelines which recommend 60 minutes daily of moderate to vigorous intensity aerobic activity for youth ages 6-17 years. We examined the association between physical activity and glucose control in youth with T1D.

Methods: Interstitial glucose data from flash continuous glucose monitors (CGM, Abbott Diabetes Care’s Freestyle Libre Pro Flash Glucose Monitor) and physical activity data (Metria IH1 activity patch) were objectively measured. Data from 52 youth 9-17 years old with a median diabetes duration of 6 years (IQR: 3 to 8) and mean (±SD) HbA1c of 9.1 ± 1.5% were analyzed. Partial Pearson’s correlation coefficients adjusting for age, gender, and baseline HbA1c were used to assess the association between daily physical activity and glucose control; the primary analysis used a linear regression model adjusted for age, gender, and baseline HbA1c.

Results: Participants with higher average energy expenditure, as measured by metabolic equivalent minutes (MET-min), on their active days had higher average % time in range (TIR: 70-180 mg/dL) in the 24 hours after exercise than participants with lower average MET-min on active days (p<0.001). For individuals with <200 average daily MET-min, TIR was 26% ± 21%, while TIR was 34% ± 14% for those with 200 to <600 average MET-min, and 49% ± 14% for those with ≥600 average MET-min. Percent time >180 mg/dL decreased with increased activity (p=0.002). Activity was significantly associated with lower mean glucose (p=0.02) without an increase in % time <70 mg/dL or % time <54 mg/dL.

Conclusions: Among youth with T1D, objectively measured physical activity levels are associated with improved glucose control and decreased hyperglycemia. Use of biometric technology, such as activity trackers, may motivate youth to be more physically active, but integration with other diabetes-specific technologies, such as CGM and insulin pumps, may offer solutions for improved blood sugar management.

Disclosure

J. Gal: None. Z. Li: None. S. M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases. M. Riddell: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Lilly Diabetes, Research Support; Self; Dexcom, Inc., Insulet Corporation, Speaker’s Bureau; Self; Novo Nordisk Inc., Sanofi, Stock/Shareholder; Self; Zucara Therapeutics Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
24-LB: Using Q-Methodology to Inform Personalized Diabetes Education for Koreans with Type 2 Diabetes on Insulin Therapy
Authors: CHA EUNSEOK , SHIN MYOUNGHWAN , SMART MICHAEL J. , JANG HYESUN , LEE JOOSEON , JOUNG KYONG HYE , KIM HYUN JIN , FAULKNER MELISSA S.
Published: June 2021

Background: This study classified the profiles of Koreans with type 2 diabetes (T2D) on insulin therapy regarding their perceptions and self-management behaviors in order to inform personalized diabetes education.

Methods: Q-methodology, a semi-qualitative methodology and semi-quantitative technique, was used. Six steps of Q-methodology included: (1) development of Q-population, representative viewpoint statements on diabetes, (2) Q-sample, final statements selected from Q-population, (3) P-sample (Q-sorter) selection, (4) Q sorting, (5) factor analysis, (6) factor extraction. The Summary of Diabetes Self-Care Activity measure and A1C in the past 6 months were used to examine self-care behaviors in each Q-sorter. Of 160 statements, 33 Q-samples were selected. Then, 37-P-samples (24 men; 13 women; 30 to 80 years old) were recruited from a university-affiliated diabetes clinic in South Korea. Q-sorts were analyzed using the PQ method. Varimax rotation revealed five factors while 8 P-samples fell into the confounding factor (loaded on more than one factor); 2 P-samples were non-significant.

Findings: A total of 40.0% variance was explained with 5 factors: Factor 1(n=6): those showing education need with inadequate health literacy (age=59.1±18.9; A1C=7.89±0.53), Factor 2 (n=4): those trying to control diabetes with lifestyle (age= 62.8±8.4; A1C=7.94±2.12 ), Factor 3 (n=5): those controlling diabetes with medical treatment (age=58.0±12.6; A1C=7.74±1.27), Factor 4 (n=6): those not afraid of uncontrolled diabetes due to insufficient diabetes knowledge (age= 65.7±9.9; A1C= 8.06 ±1.27) and Factor 5(n=6): those who overestimated their knowledge and capability to control diabetes (age= 57.0±10.2; A1C=8.20±1.47).

Conclusions: Educational intervention for Koreans with T2D on insulin therapy should be designed depending on patients’ characteristics (knowledge, health literacy, behaviors, emotions) to improve clinical outcomes and quality of life.

Disclosure

E. Cha: None. M. Shin: None. M. J. Smart: None. H. Jang: None. J. Lee: None. K. Joung: None. H. Kim: None. M. S. Faulkner: None.

Funding

National Research Foundation of Korea (2019R1A2C108719912 to E.S.)
241-OR: Effects of Antidiabetes Therapies on Irisin Levels in Type 2 Diabetes Patients
Authors: NATALICCHIO ANNALISA , MARRANO NICOLA , BIONDI GIUSEPPINA , MONTEDORO ANNA , GRAZIE GIULIA LE , GIOIA LUDOVICO DI , GUARINI FRANCESCA , BORRELLI ANNA , CIGNARELLI ANGELO , PERRINI SEBASTIO , LAVIOLA LUIGI , GIORGINO FRANCESCO
Published: June 2021

Irisin is a hormone secreted by skeletal muscle following physical activity or excess of saturated fatty acids, able to promote energy expenditure and improve metabolic homeostasis. Serum irisin levels are reduced in type 2 diabetes (T2D), while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin promotes beta-cell viability and insulin secretory function. This study investigated serum irisin levels in T2D patients according to their antidiabetes treatment. 127 T2D patients were enrolled and stratified by antidiabetes therapy: diet only (17); metformin only (met, 37); met plus sulfonylureas (5); met plus pioglitazone (7); met plus GLP-1 receptor agonists (GLP-1RAs, 31); met plus DPP-4 inhibitors (DPP-4i, 15); and met plus SGLT2 inhibitors (SGLT2i, 15). The control group included 36 sex-, and BMI-matched subjects without diabetes. T2D patients showed lower irisin levels than controls (21.5 [10.1-50.8] vs. 29.1 [14.1-43.5] ng/mL, P<0.01). Serum irisin levels were positively associated with diabetes duration (r=0.214, P<0.05) and negatively associated with total (r=-0.196, P<0.05) and LDL cholesterol (r=-0.214, P<0.05). Patients treated with met plus GLP-1RAs or DPP-4i showed increased serum irisin levels (28.1 [12.4-50.8] and 25.8 [13.2-37.8] ng/mL, respectively) compared to patients treated with diet or met (19.8 [13.5-40.5] and 16.9 [10.7-28.8] ng/ml, respectively; P<0.05), or with other diabetes therapies. Interestingly, in vitro treatment of human skeletal muscle cells with 10 nM exendin-4 resulted in enhanced irisin release in the culture medium compared to control.

In conclusion, in T2D GLP-1-based therapies significantly increase serum irisin to levels comparable to those of nondiabetic subjects, possibly through GLP-1 receptor-mediated stimulation of irisin release by skeletal muscle cells. Irisin may thus represent a new factor in the mechanism of action of GLP-1-based therapies.

Disclosure

A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. S. Perrini: None. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. N. Marrano: None. G. Biondi: None. A. Montedoro: None. G. Le grazie: None. L. Di gioia: None. F. Guarini: None. A. Borrelli: None. A. Cignarelli: None.

Funding

European Union–European Social Fund; PON R&I (2014-2020); AIM (1810057)
254-OR: Bariatric Surgery Influences Insulin Sensitivity through Changes in Subcutaneous Adipose Tissue (SAT) Characteristics
Authors: LENZ ANNIKA , MCLAUGHLIN TRACEY , ZANLEY ELIZABETH J.
Published: June 2021

Although literature describes the influence of bariatric surgery on insulin sensitivity (IS) showing improvement in metabolic parameters, including sustained remission of type 2 diabetes and reduction in cardiovascular disease, the underlying mechanisms remain unclear. Changes in SAT following bariatric surgery make it a key site for investigating mechanisms of glucose control. To test whether changes in SAT are related to improved IS following bariatric surgery, we quantified adipose cell size distribution in SAT harvests, in addition to quantifying insulin resistance (IR) using the steady-state plasma glucose (SSPG) test in 57 obese subjects undergoing bariatric surgery at baseline and one year post surgery. We compared IR and SAT size variables in the post-surgical subjects to those of BMI-matched non-surgical controls. Surgery subjects (n=57) were healthy, morbidly obese men and women without diabetes, ages 23-70, with BMI > 35 kg/m^2, who underwent bariatric surgery, while controls (n=43) were healthy, men and women without diabetes ages 23-70 years with BMIs 22-38.3kg/m^2. Of the surgery subjects, 14 were available at 1 year post-surgery for comparison with controls. Compared to pre-surgery, post-surgery results demonstrated a decrease in average BMI, weight, SSPG, peak diameter, nadir, and percent small cells (p<.05). Compared to the controls (BMI 30.9 +- 4.0 kg/m^2), the post-surgical subjects (BMI 30.5 +/- 3.8 kg/m^2) demonstrated reduced IR, percent small cells, and adipose cell peak diameters, p<0.001. After surgery, SAT exhibits features of healthier fat cells compared to controls, which may account for their lower IR. Independent of weight loss, adipocyte cell qualities may play a role in the improvement in IS due to bariatric surgery. These observations have implications in treatments targeting type 2 diabetes and cardiovascular disease because manipulating fat cell size and percent of small cells may provide a path to improving IS.

Disclosure

A. Lenz: None. T. Mclaughlin: Board Member; Self; January, Inc. E. J. Zanley: None.

Funding

American Heart Association; National Institutes of Health
257-OR: Short-Term Hyperglucagonemia Induces Adipose Tissue Insulin Resistance and Inflammation In Vivo
Authors: CHEN XI , FOURCAUDOT MARCEL , NORTON LUKE , DEFRONZO RALPH A. , TRIPATHY DEVJIT
Published: June 2021

Although the effect of glucagon on glucose metabolism has been well characterized, its effect on adipose tissue and lipid metabolism in humans in vivo has been poorly studied with controversial results. We examined the effect of short-term hyperglucagonemia on adipocyte metabolism in 8 healthy normal glucose tolerant subjects (5M/3F, age=35±5, BMI = 24±1) who received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) with 14C-glycerol infusion; subcutaneous abdominal adipose tissue biopsy was obtained at 6AM. 8 weeks later subjects returned for a repeat study with 12-hour infusion of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml within one hour and remained elevated throughout the study. Glycerol turnover rate (5.1±0.6 vs. 3.8±0.6 µmol/kg•min, p<0.05) increased by 34%, and the adipose tissue insulin resistance index (fasting plasma FFA x Insulin) more than doubled (5.8±0.8 vs. 2.8±0.7 mM•mU/L, p<0.05) after 12-hour glucagon infusion compared to saline. mRNA expression of genes involved in lipolysis in adipose tissue were upregulated after glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p<0.05). Plasma concentration of proinflammatory markers (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p<0.05) and lipidomes involved in inflammatory pathways (lysophosphatidylcholine, 126±11 vs. 51±7 nmol/ml, p<0.005; phosphatidylcholine, 385±24 vs. 306±25 nmol/ml, p<0.01; ceramide, 1.7±0.2 vs. 1.2±0.2 nmol/ml, p<0.01) also increased after 12-hour glucagon infusion. H&E and CD68 immunofluorescence staining in adipose tissue displayed the crown-like structures (CLS) and increased infiltration of macrophages following glucagon infusion.

Conclusion: Short-term (12-hour) physiologic hyperglucagonemia stimulates adipose tissue lipolysis, induces adipocyte insulin resistance, and promotes adipose tissue and systemic inflammation.

Disclosure

X. Chen: None. M. Fourcaudot: None. L. Norton: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. D. Tripathy: None.

Funding

Foundation for Advancing Veterans’ Health Research
283-OR: Inadequate Hepatic Mitochondrial Adaptation in Patients with NASH Is Related to the Severity of Steatohepatitis and Fibrosis Stage
Authors: KALAVALAPALLI SRILAXMI , BARB DIANA , GODINEZ EDDISON , LOMONACO ROMINA , FRIEDMAN JEFFREY , WOHLGEMUTH STEPHANIE , FANOUS NADA , DILLARD RACHEL E. , COWAN TYLER M. , POULTON DANIELLE , MANSOUR LYDIA , SHRESTHA SULAV , BRIL FERNANDO , SUBBARAYAN SREEVIDYA K. , KADIYALA SUSHMA , CUSI KENNETH
Published: June 2021

Dysfunctional mitochondrial function plays an important role in the progression of nonalcoholic steatohepatitis (NASH). Mitochondrial (mt) respiratory function assessed by oxidative phosphorylation/ OXPHOS (activated respiration with mt complex I [OXPHOS CI] and mt complex I + II [OXPHOS CI+II] substrates) and electron transport system capacity [ETC] were measured using high-resolution respirometry (Oroboros Oxygraph 2k). The aim of this study was to assess mitochondrial function in patients a) with vs. without NASH, and b) NASH with vs. without fibrosis. Liver tissue was obtained from 40 patients (age: 52 ± 12 yrs; BMI: 39.4 ± 8.4 kg/m2; HbA1c: 6.9 ± 1.5%) with NAFLD and obesity or T2DM either by percutaneous liver biopsy (n=28) or during bariatric surgery (n=12). Patients with vs. without NASH (n=20 in each group) were more insulin resistant/ IR (HOMA-IR: 8.1 ± 4.2 vs. 4.5 ± 2.7 mg/dl x μU/ml; Adipo-IR: 10.4 ± 7.2 vs. 6.2 ± 3.8 mmol/L x µU/mL) and had higher OXPHOS CI+II (all p<0.05), likely an adaptation to IR and higher FFA flux to the liver. We then compared those with worse steatohepatitis (necroinflammation score/ NIS), divided as mild (n=16), moderate (n=15) or severe (n=9). Patients with moderate vs. mild NIS had increased mitochondrial respiration, expressed as pmol/(s x mg wet weight) (OXPHOS CI: 20.8 ± 4.8 vs. 16.4 ± 4.6; OXPHOS CI+II: 46.0 ± 11.4 vs. 31.3 ± 9.8; ETC: 60.5 ± 17.1 vs. 46.4 ± 15.2; all p<0.05). There was a trend for these parameters to decline with the most severe disease activity, that was significant when patients with NASH also had significant fibrosis vs. mild or no fibrosis (OXPHOS CI+II: 38.6 ± 7.8 vs. 49.8 ± 12.5, p=0.04; ETC: 50.3 ± 12.9 vs. 67.5 ± 16.1; p=0.02).

Conclusion: In patients with NASH vs. simple steatosis, there is an early hepatic mitochondrial adaptation to severe insulin resistance. This adaptation is impaired when disease activity worsens, being most evident once patients develop steatohepatitis with significant fibrosis.

Disclosure

S. Kalavalapalli: None. D. Poulton: None. L. Mansour: None. S. Shrestha: None. F. Bril: None. S. K. Subbarayan: None. S. Kadiyala: None. K. Cusi: None. D. Barb: None. E. Godinez: None. R. Lomonaco: None. J. Friedman: Consultant; Self; Ethicon, Inc. S. Wohlgemuth: None. N. Fanous: None. R. E. Dillard: None. T. M. Cowan: None.
286-OR: FGF21 Decreases Hepatic Triglycerides in a Weight Loss-Independent but Sex-Dependent Manner
Authors: CHAFFIN AKI T.B. , LARSON KARLTON R. , HUANG KUEI-PIN , RYAN KAREN K.
Published: June 2021

Fibroblast growth factor-21 (FGF21) decreases hepatic triglycerides when administered to obese animals and humans, and thus has gained attention as a novel drug target for nonalcoholic fatty liver disease (NAFLD). However, its mechanism of action remains unclear. Furthermore, although NAFLD pathology is well known to be sexually dimorphic, studies of FGF21 have skewed toward males without sufficient consideration of sex as a biological variable. Here we report that FGF21 administration to diet-induced obese mice decreased hepatic triglycerides in a weight loss-independent manner in obese male mice, but this effect was blunted in female littermates (p(treatment x sex)<0.001). Adiponectin, a key mediator of FGF21’s therapeutic effects, was increased by FGF21 in males but not females (p(treatment x sex)<0.01). In agreement with this, FGF21 elicited an increase in hepatic adenosine monophosphate, known to be downstream of adiponectin signaling, and decreased the expression of lipogenic genes Pparg, Cidea, and Cd36 in males but not females (p(treatment x sex)<0.05, <0.0001, <0.05, <0.01, respectively). Finally, we investigated whether the metabolic benefits of FGF21 observed in males are restored in ovariectomized (OVX) females. OVX females did not phenocopy males, as FGF21 did not significantly decrease hepatic triglycerides, increase plasma adiponectin, or decrease lipogenic gene expression in OVX females. These data have immediate clinical implications, and highlight the importance of both sex and reproductive status as a biological variable in ongoing development of FGF21-based therapeutics for NAFLD.

Disclosure

A. T. B. Chaffin: None. K. R. Larson: None. K. Huang: None. K. K. Ryan: None.

Funding

National Institutes of Health (R01DK121035, F31DK124080)
289-OR: Cleavage of Protein Kinase C d by Caspase-3 Mediates Cytokine-Induced ß-Cell Death
Authors: COLLINS JILLIAN , BENNINGER RICHARD K. , FARNSWORTH NIKKI L.
Published: June 2021

In type 1 diabetes (T1D) autoreactive T-cells secrete cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interferon-γ (IFNγ) that can initiate β-cell apoptosis. Protein kinase C delta (PKCδ) plays a role in mediating cytokine-induced β-cell apoptosis. The exact mechanisms of PKCδ regulation in β-cell death and role in T1D are unknown. In cancer cells PKCδ mediates apoptosis by translocating to the nucleus and being cleaved by caspase 3. We hypothesize that PKCδ mediates cytokine-induced β-cell apoptosis by translocating to the nucleus and cleavage by caspase 3. Islets from WT or mice with a β-cell specific PKCδ knockout were cultured for 24hr with cytokines (10ng/ml TNFα, 5ng/ml IL-1β, 100ng/ml IFNγ), caspase 3 inhibitor (Z-DEVD-FMK, 33µg/ml), or adenovirus to produce GFP-PKCδ, GFP with a constitutively active nuclear localization sequence, and a PKCδ mutant that cannot be cleaved by caspase 3 (CM-GFP-PKCδ). Human islets were treated with 10μM PKCδ inhibitor (δV1-1) with cytokines. Apoptosis was determined by fluorescent live/dead staining. PKCδ translocation was determined by GFP colocalization with a nuclear stain and activity was determined with a FRET-based sensor. Decreasing PKCδ activity protected mouse (p<0.01) and human (p=0.02) islets against cytokine-induced apoptosis. Cytokines induced PKCδ translocation to the nucleus at 3 (p=0.05) and 24hr (p<0.01) and increased nuclear PKCδ activity at 3hr (p=0.04). WT islets with Z-DEVD-FMK and CM-GFP-PKCδ islets were protected from cytokine-induced death. Production of PKCδ with an active nuclear localization sequence did not impact apoptosis. Inhibiting PKCδ protected islets from cytokine-induced β-cell death. Pro-inflammatory cytokines induce nuclear translocation and activity of PKCδ. Nuclear localization of PKCδ alone is insufficient for apoptosis but caspase-3 cleavage is required. Our data suggests that targeted inhibition of PKCδ has the potential to prevent or delay β-cell death in T1D onset.

Disclosure

J. Collins: None. R. K. Benninger: None. N. L. Farnsworth: None.

Funding

JDRF (D1671-FAC-2020-891-A-N)
290-OR: Altered In-Situ Expression of Proinsulin-Insulin in Pancreatic Islets Reflects Metabolic and Molecular Defects in Type 2 Diabetic and Glucose-Intolerant Living Donors
Authors: BRUSCO NOEMI , SEBASTIANI GUIDO , LICATA GIADA , GRIECO GIUSEPPINA E. , GIUSEPPE GIANFRANCO DI , NIGI LAURA , FIGNANI DANIELA , MOFFA SIMONA , CINTI FRANCESCA , CEFALO CHIARA MARIA ASSUNTA , CAPECE UMBERTO , IMPRONTA FLAVIA , MARI ANDREA , DOTTA FRANCESCO , GIACCARI ANDREA , MEZZA TERESA
Published: June 2021

Proinsulin (PI) processing is altered in beta-cells during T2D progression. However, the molecular mechanisms driving such alterations are not fully characterized neither their occurrence were correlated with patients’ metabolic profile. To fill this gap, we investigated the correlation between pancreatic proinsulin (PI) expression and phenotypic/functional changes of beta-cells during metabolic stress in extensively clinical characterized impaired glucose tolerant (IGT, n=7) and T2D (n=4) individuals, compared to normal glucose tolerant (NGT, n=4). We analyzed microdissected pancreatic islets collected from surgical pancreas biopsies. The expression of genes associated to ER stress and β cell phenotype were evaluated. Given the high heterogeneity among pancreatic islets, we also performed a single islets analysis in n=88 islets from n=3 NGT, n=3 IGT and n=3 T2D patients. PDIA1, GRP78 and XBP1 genes, involved in unfolded protein response (UPR), were significantly upregulated in pancreatic islets of IGT and T2D patients vs. NGT (p<0.05) and were positively correlated with in-situ PI/INS ratio (r=0.6; p=0.01) and colocalization (r=0.5, p<0.05), with in-vivo measurements of glucose intolerance (r=0.6-0.8; p<0.001) and β cell functional reduction (r=-0.6; p=0.04).Single islets phenotyping approach revealed a progressively increased heterogeneity from NGT to IGT and T2D patients. Of note, in-situ PI/INS ratio and colocalization were positively correlated with the expression of UPR genes (r=0.3; p<0.01) and negatively with those associated to β cell identity (r=-0.2; p<0.01). Our data demonstrated that altered PI processing in β-cell reflected metabolic and molecular defects in IGT and T2D patients. Further, single islet phenotyping analysis revealed a high heterogeneity among pancreatic islets in terms of ER stress and β-cell differentiation profile during metabolic alterations.

Disclosure

N. Brusco: None. C. Cefalo: None. U. Capece: None. F. Impronta: None. A. Mari: Research Support; Self; Eli Lilly and Company. F. Dotta: None. A. Giaccari: None. T. Mezza: None. G. Sebastiani: None. G. Licata: None. G. E. Grieco: None. G. Di giuseppe: None. L. Nigi: None. D. Fignani: None. S. Moffa: None. F. Cinti: None.

Funding

Università Cattolica del Sacro Cuore (FondiAteneo Linea D.1, anno 2020); Italian Ministry of Education, University and Research (GR-2018-12365577); European Foundation for the Study of Diabetes; AstraZeneca