bluuebunny/crossref_metadata_2025_split huggingface dataset:
376-OR: Chronic Pancreatitis Does Not Induce Specific Alterations in Beta-Cell Function
Authors: CICCARELLI GEA , DI GIUSEPPE GIANFRANCO , CINTI FRANCESCA , MARI ANDREA , MEZZA TERESA , GIACCARI ANDREA 
Published: June 2023

Chronic pancreatitis (CP) is the most frequent cause of diabetes due to pancreatic diseases, known as type 3c diabetes mellitus (T3cDM). Although the specific alterations of T3cDM are not completely understood, individuals with T3cDM are considered affected by pancreatic endocrine insufficiency and often treated with insulin. To investigate the functional alterations of T3cDM, we evaluated differences in beta-cell function in patients with and without CP, classified according to their glucose tolerance (NGT, IGT, DM). We recruited 50 patients with CP and 96 individuals without CP (NCP). All participants underwent OGTT, hyperglycemic clamp (HC), hyperinsulinemic euglycemic clamp and mixed meal test (MMT) with measurement of GLP-1 and glucagon. Basal insulin secretion rate (ISR), total ISR, rate secretion and β-cell glucose sensitivity (RS and GS) were estimated by mathematical models from OGTT, MMT and HC. Comparing individuals classified into NGT, IGT or DM based on OGTT-derived glucose tolerance, we did not find any difference in beta-cell function derived by OGTT and MMT within the same category (e.g.: NGT-CP vs. NGT-NCP). GLP-1 and glucagon secretion during MMT was not significantly different between CP vs. NCP. Of note, we found that insulin secretion after arginine stimulus in HC, an indirect measure of beta-cell mass, was reduced only in DM-CP vs. DM-NCP (ARG CP 397 (132; 662) pmol/l vs NCP 795 (604; 1134) pmol/l; p= 0.023). No difference was found in insulin sensitivity evaluated as glucose uptake during euglycemic clamp. At equivalent levels of glucose tolerance, patients with CP had similar beta-cell function, GLP-1 and glucagon secretion to individuals without CP. People with T3cDM have less beta-cell mass than patients with DM without CP, but analogous residual beta-cell function, so they could benefit from other therapies apart from insulin. Future studies are warranted to investigate differences in beta-cell function decline between type 2 diabetes mellitus and T3cDM.

Disclosure
G.Ciccarelli: None. G.Di giuseppe: None. F.Cinti: None. A.Mari: Consultant; Eli Lilly and Company. T.Mezza: None. A.Giaccari: Speaker's Bureau; Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi.
379-P: Don’t Ask, Don’t Tell—How Primary Care Is Failing to Address Fear of Hypoglycemia
Authors: PILLA SCOTT J. , MEZA KAYLA , LONG JUDITH A. , GORDON HOWARD S. , BATES JEFFREY T. , WASHINGTON DONNA , BOKHOUR BARBARA G. , TUEPKER ANAIS , SAHA SOMNATH , MARUTHUR NISA M. , CATHERINE BEACH MARY 
Published: June 2023

Fear of hypoglycemia (FOH) contributes to medication nonadherence and lower quality of life, and may be unrecognized by clinicians. We conducted the first multicenter study examining how primary care providers (PCPs) address FOH. This mixed methods study examined audio-recorded visits between patients using hypoglycemia-causing medications (N=237) and their PCPs (N=50) at 4 geographically diverse Veterans Affairs medical centers from 2017-2020. Two investigators independently coded transcripts to identify discussions related to FOH and analyzed the dialogue using a directed content analysis approach. Results: participants’ mean age was 67 years, 89% were male, and 66% and 42% used insulin and sulfonylureas, respectively. FOH was not assessed by the PCP in any of the 237 visits. FOH was reported by 16 patients (6.8%) unprompted (“I met a lady coming the other day, her sugar dropped and she didn't make it. So that's why I was scared”). Among patients who expressed FOH, 88% reported a recent hypoglycemic event, and half stated that it prevented them from taking their medications (“I’m scared to take my medicine because I don’t want it to go down too low”). In response to FOH, most PCPs gathered hypoglycemia history (n=13) or counseled for prevention (n=11). Some PCP’s responded by moving to a new topic (n=2), or by chastising the patient (n=2) (“You're just using the insulins erratically⋯ It's dangerous, Mr. [name]. We keep reminding you”). Two PCPs provided validation (“It’s very scary probably”); no PCP explored the impact on the patient’s life. In conclusion, FOH is likely under-recognized in primary care as PCPs do not assess for it. Patients reporting FOH often struggle to take their diabetes medications as directed. PCPs respond to FOH by appropriately seeking to prevent recurrent events, but there are missed opportunities to provide support and empathy. Greater awareness, routine assessment, and empathy for at-risk patients who fear hypoglycemia is needed to improve diabetes management in primary care.

Disclosure
S.J.Pilla: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. M.Beach: None. K.Meza: None. J.A.Long: None. H.S.Gordon: None. J.T.Bates: None. D.Washington: None. B.G.Bokhour: None. A.Tuepker: None. S.Saha: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK128572); U.S. Department of Veterans Affairs (IIR 14-007)
385-P: A More Accurate Method to Diagnose Impaired Awareness of Hypoglycemia (IAH) in People with Type 1 Diabetes (T1D)
Authors: MACON ERICA L. , WAHL MATTHEW , SHARMA ANU , GHAITH SARAH , PENUMALA SUDHA , FISHER SIMON 
Published: June 2023

Traditional questionnaires used to define IAH have been criticized for high variability, recall bias, and lack of sensitivity. This study in T1D subjects sought to compare awareness of hypoglycemia determined with self-reported questionnaires (Gold Score (GS)) with actual symptom scores (SS) assessed during hyperinsulinemic, stepped-hypoglycemic clamps (blood glucose (BG) lowered to 100, 65, 55, and 45 mg/dL). Neurogenic and neuroglycopenic symptoms were assessed at each BG level as were counterregulatory hormone responses (CRR). There was no statistically significant correlation (R2=0.27, p=0.37) between GS and SS assessed during the hypoglycemic clamp (Figure 1A) indicating that self-reported hypoglycemia awareness questionnaires do not accurately reflect symptoms of hypoglycemia. Receiver-operating curves indicated a cutoff value for peak SS of &lt; 25 as accurately identify IAH in T1D subjects (sensitivity 88%, specificity 83%)(Figure 1B). Epinephrine levels were correlated with SS (R2=0.57, p&lt;0.0001) but not GS (R2=0.02, p=0.59) suggesting SS, but not GS, appropriately identified subjects with impaired CRR. It is concluded that 1) hypoglycemia questionnaires have major limitations in accurately identifying T1D subjects with IAH and impaired CRR, and 2) though more labor intensive, accurate diagnoses of IAH should be based on low peak SS obtained during a hypoglycemic clamp.

Disclosure
E.L.Macon: None. M.Wahl: None. A.Sharma: None. S.Ghaith: None. S.Penumala: None. S.Fisher: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK118082)
39-OR: Circulating Foamy CD36hi Ly6Clo Monocytes in Mouse Models of Diabetic Dyslipidemia
Authors: CERVANTES JOCELYN , KRAMER FARAH , BORNFELDT KARIN , KANTER JENNY E. 
Published: June 2023

Diabetes increases the risk for cardiovascular disease (CVD) and diabetic kidney disease (DKD). Increased levels of triglyceride-rich lipoproteins (TRLs), a hallmark of diabetic dyslipidemia, associate with CVD and DKD. Monocytes become lipid-laden in response to hypercholesterolemia, but it is unclear if and how diabetic dyslipidemia induces monocyte lipid accumulation. To test if diabetes promotes foamy monocytes in circulation, we examined monocyte lipid-loading in three mouse models of diabetes with varying degrees of dyslipidemia and increases in TRLs: two mouse models of type 1 diabetes [streptozotocin (STZ)-induced diabetes (STZ-D) and viral mimicry-induced diabetes (LCMV-D)], and a model of type 2 diabetes (BTBR Lep ob;OB), all with human-like dyslipidemia generated by LDL receptor deletion. Diabetes resulted in elevated lipid loading of Ly6Clo blood monocytes in all models of diabetes, as determined by flow cytometry staining for perilipin-2 (PLN2), a marker of mature intracellular lipid droplets or BODIPY. PLN2 mean fluorescence intensity (MFI) in STZ-D was increased 1.4 ± 0.2-fold compared with nondiabetic (ND) mice, n=8-13, p=0.029, and 1.6 ± 0.1-fold in LCMV-D compared with ND mice, n=11-13, p&lt;0.0001, while BODIPY was increased 2.2 ± 0.1-fold in BTBR OB vs. ND BTBR controls, n=6-11, p&lt;0.0001. Moreover, Ly6Clo monocytes exhibited higher MFI of the scavenger receptor CD36 in the presence of diabetes (1.6 ± 0.2-fold in LCMV-D vs. ND, n=6, p=0.015). To further explore if diabetes increases monocyte lipid-loading via CD36, monocytes from ND and D mice were cultured with VLDL in the presence or absence of an CD36 inhibitor (sulfo-N-succinimidyl oleate). Diabetes augmented ex vivo lipid loading by VLDL, and VLDL monocyte lipid-loading was prevented by blocking CD36. These findings suggest that diabetes increases Ly6Clo monocyte CD36 levels, allowing increased lipid uptake in circulation, which may contribute to atherosclerosis and DKD.

Disclosure
J. Cervantes: None. F. Kramer: None. K. Bornfeldt: Advisory Panel; ESPERION Therapeutics, Inc. Other Relationship; American Heart Association. J.E. Kanter: None.

Funding
National Institutes of Health (R01DK121756)
399-P: Dapagliflozin Is Protective in a Murine Model of Balkan Nephropathy
Authors: OE YUJI , CHUL KIM YOUNG , SIDORENKO VIKTORIYA S. , KANOO SADHANA , LOPEZ NATALIA , GOODLUCK HELEN A. , VALLON VOLKER 
Published: June 2023

Episodes of acute kidney injury (AKI) increase the risk of chronic kidney disease (CKD). Proximal tubular uptake of aristolochic acid (AA) induces aristolactam (AL)-DNA adducts, which induce a p53-mediated DNA damage response and acute tubular injury. Recurrent exposure to AA causes kidney function loss and fibrosis in humans (Balkan nephropathy), and is a model of AKI to CKD transition. SGLT2 inhibitors protect against CKD progression regardless of the presence of diabetes, however, the underlying mechanism is still unclear. Here we elucidated the effects of SGLT2 inhibition on AA-induced kidney injury. 15-week-old C57BL/6J female and male mice were administered vehicle or AA every 3 days for 3 weeks at a dose of 10 and 3 mg/kg i.p., respectively. Application of dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. Urine/plasma were collected after completion of AA injections and 3 weeks later together with kidneys (n=7-11/group). AA-induced increases in plasma creatinine and urinary albumin excretion were robustly attenuated by dapa independent of sex. These effects of dapa were associated with lower urinary levels of kidney-injury molecule 1 (KIM1, normalized to creatinine) after injection and lower kidney mRNA expression of p53 and KIM1 at harvest. Renal up-regulation of pro-inflammatory and pro-fibrotic genes as well as collagen staining by AA were likewise significantly attenuated by dapa. Dapa caused a minor numerical reduction in kidney AL-DNA adduct formation when assessed one day after a single AA injection (by ~10%; P=0.084). In conclusion, dapa attenuated the AA-induced p53-mediated DNA damage response and subsequent nephropathy. SGLT2 inhibitors may protect the kidneys by improving the tubular response to nephrotoxins.

Disclosure
Y.Oe: None. Y.Kim: None. V.S.Sidorenko: None. S.Kanoo: None. N.Lopez: None. H.A.Goodluck: None. V.Vallon: Research Support; NIH - National Institutes of Health, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Maze Therapeutics, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca.

Funding
National Institutes of Health (R01DK112042, R01DK132690, R01AG061296, P30DK079337)
4-LB: Norepinephrine-Stimulated Glutamate Release in the Ventromedial Hypothalamus Is Important to Enhance the Counterregulatory Response during Hypoglycemia
Authors: NELSON IRVANE E. , APPADURAI DANIEL A. , UZO CHUKWUEMEKA , CHAN OWEN 
Published: June 2023

We previously showed that norepinephrine acts through β2-adrenergic receptors to stimulate the release of glutamate in the ventromedial hypothalamus (VMH) and the secretion of counter-regulatory hormones under basal non-stimulated conditions. The current study investigates the importance of this interaction during hypoglycemia and more specifically, whether norepinephrine is an absolute requirement for glutamate secretion in the VMH in response to hypoglycemia and/or whether glutamate neurons respond to hypoglycemia independent of this input. To address this question, we locally delivered the β2-adrenergic receptor blocker, ICI-118,551, into the VMH and evaluated glutamate release in the VMH using microdialysis, as well as its effects on the counter-regulatory hormone responses during a hypoglycemic clamp. These responses were compared to control animals given artificial extracellular fluid. Our data shows that β2-adrenergic receptor blockade reduced VMH glutamate levels, and this was accompanied by a 38% reduction in plasma epinephrine secretion during hypoglycemia (P&lt;0.05 vs Control). Our data suggest that during hypoglycemia, noradrenergic inputs may help drive the release of neurotransmitter glutamate in the VMH that in turn, enhances the release of counter-regulatory hormones.

Disclosure
I. E. Nelson: None. D. A. Appadurai: None. C. Uzo: None. O. Chan: None.
402-P: ENaC Regulation in Mouse Cortical Collecting Duct Cells by EVs Released during the Inactive and Active Cycles of Salt-Loaded Hypertensive Diabetic db/db Mice
Authors: YU LING , GHOLAM MOHAMMED F. , ALLI ABDEL A. 
Published: June 2023

The downregulation of renal epithelial sodium channel (ENaC) activity in response to salt-loading in the diabetic kidney is important to prevent the exacerbation of diabetic kidney disease. An inflammatory response in diabetic db/db mice is associated with constitutively high ENaC activity even after salt-loading. During salt-loading, diabetic db/db mice release extracellular vesicles (EVs) into the urine during the active and inactive cycles that are enriched in bioactive molecules. A vast majority of these EVs are released across the luminal membrane of renal epithelial cells from each segment of the nephron and have the potential to module ENaC activity in recipient collecting duct cells. Our hypothesis was the distinct cargo that is enriched in EVs released during the inactive and active cycles of salt-loaded hypertensive diabetic db/db mice is responsible for increased ENaC membrane protein expression and activity in recipient collecting duct cells. In this study, we measured blood pressure by telemetry during the light (inactive) or dark (active) cycles. In addition, osmolality, electrolytes, and creatinine were measured and EV were isolated from urine samples collected during both cycles. Western blotting and densitometric analysis showed greater ENaC alpha protein expression in membrane fractions of mouse cortical collecting duct (mpkCCD) cells while single-channel patch clamp studies show greater ENaC activity in mpkCCD cells treated with uEVs isolated from the active cycle compared to the inactive cycle of hypertensive diabetic db/db mice. Various proteins and metabolites were found to be enriched in each of the two groups of EVs. Taken together, these data suggest the packaged cargo within EVs released after salt-loading diabetic db/db mice changes over a 24 hour cycle, and various molecules enriched in active cycle EVs contribute to the upregulation of renal ENaC protein expression and activity.

Disclosure
L.Yu: None. M.F.Gholam: None. A.A.Alli: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK123078-01A1 to A.A.A.)
408-P: Associations between Apolipoprotein B (apoB): Apolipoprotein A1 (apoA1) Ratio and Metabolic and Kidney Disease in Youth with Type 1 Diabetes
Authors: REMMERS LAURYN , BIRZNIEKS CARISSA , CARRASCO DIEGO , GROSS SUSAN , SNELL-BERGEON JANET K. , HALL LUCY A. , NADEAU KRISTEN J. , BJORNSTAD PETTER , TOMMERDAHL KALIE L. 
Published: June 2023

ApoA1 is a major protein component of high-density lipoprotein (HDL) and apoB the main protein component of low-density lipoprotein (LDL). The ratio between apoB and apoA1 (ApoB:ApoA1) is often used to measure cardiovascular disease (CVD) risk in adults, yet little is known about its relationship with insulin resistance, central adiposity and early kidney disease, important CVD risk factors, in youth with T1D. In a study of 50 youth with type 1 diabetes, glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed using iohexol and p-aminohippurate clearance, and urine albumin-to-creatinine ratio (UACR) was also measured. Central adiposity was assessed using DXA and insulin sensitivity was estimated (eIS). Intraglomerular pressure was estimated using the Gomez equations. The study participants were 16±3.0 years old, 50% were female, and their average HbA1c was 8.7±1.3%. They had an average T1D duration of 5.7±2.6 years, with UACR levels of 6[5-14] mg/g and GFR of 189±40 ml/min. Concentrations of apoA1 and apoB were quantified by targeted nuclear magnetic resonance spectroscopy. ApoA1 (185±35 vs. 150±36 mg/dl, p=0.001) and apoB (108±29 vs. 90±27 mg/dl, p=0.03) were higher in girls vs. boys, but the apoB:apoA1 ratio was similar between the sexes (p=0.59). ApoB correlated with PGLO (r: 0.42, p=0.01), log UACR (r: 0.33, p=0.02), and trunk mass (r: 0.34, p=0.02), whereas ApoB:ApoA1 correlated with GFR (r: 0.44, p=0.002), PGLO (r: 0.48, p=0.01), log UACR (r: 0.38, p=0.008), trunk mass (r: 0.45, p=0.001), BMI (r: 0.40, p=0.004) and inversely with eIS (-0.44, p=0.001). The ratio of apoB to apoA1 associated with markers of metabolic and kidney disease in youth with T1D. Further research is needed to fully understand the mechanisms behind these associations and to identify potential strategies for preventing or mitigating cardiovascular disease in young persons with T1D.

Disclosure
L.Remmers: None. C.Birznieks: None. D.Carrasco: None. S.Gross: None. J.K.Snell-bergeon: None. L.A.Hall: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. K.L.Tommerdahl: None.
41-OR: The Health Effects of a Behavior Change Program for Prediabetes—Quasi-Experimental Evidence from 2.1 Million Primary Care Patients in England
Authors: LEMP JULIA M. , BOMMER CHRISTIAN , XIE MIN , DAVIES JUSTINE , JANI ANANT , VOLLMER SEBASTIAN , BARNIGHAUSEN TILL , GELDSETZER PASCAL 
Published: June 2023

Introduction: There is an urgent need to implement population-based measures that prevent diabetes, enhance its detection, and avert its progression to complications. However, there remains widespread doubt among clinicians that lifestyle counseling provided in routine care can improve health. This study aims to investigate whether the largest behavior change program for pre-diabetes globally (the English Diabetes Prevention Programme) leads to improvements in key cardiovascular risk factors.
Methods: We exploited the threshold in HbA1c used to decide on program eligibility by applying a regression discontinuity design, one of the most credible quasi-experimental strategies for causal inference, to electronic health data from the Clinical Practice Research Datalink, covering nearly one fifth of all GP practices in England. Using local linear regression, we compared patients lying closely on either side of the threshold for program entry (HbA1c of 42 mmol/mol [6.0%]). The primary outcome was change in HbA1c. Secondary outcomes were body mass index (BMI), weight, blood pressure, and serum lipids.
Results: 2 106 469 adult patients met inclusion criteria in 2017-2018 with follow-up ending June 2020. Program referral led to significant improvement in HbA1c (-0.82 mmol/mol, 95%CI -1.42, -0.21), BMI (-1.34, 95%CI -1.86, -0.81), weight (-2.94 kg, 95%CI -4.33, -1.56), and triglycerides (-0.32 mmol/l, 95%CI -0.53, -0.10). There was suggestive evidence that program referral improved HDL (0.04 mmol/l, 95%CI 0, 0.08). Blood pressure and LDL did not significantly improve. Sensitivity analyses showed that improvements in HbA1c were not attributable to being prescribed medication.
Conclusion: By leveraging a threshold rule induced by public health guidelines, this analysis provides causal, rather than associational, evidence that lifestyle counseling implemented in a national health system can achieve important health improvements.

Disclosure
J.M.Lemp: None. C.Bommer: None. M.Xie: None. J.Davies: None. A.Jani: Advisory Panel; Allergan. S.Vollmer: None. T.Barnighausen: None. P.Geldsetzer: None.

Funding
Chan Zuckerberg Biohub Investigator Award (to P.G.); Alexander von Humboldt Foundation (to T.B.); Ministry of Science, Research, and the Arts Baden-Wuerttemberg; German Research Foundation (INST 35/1314-1 FUGG); State of Baden-Wuerttemberg, Germany
412-P: Trends in Prevalence of Diabetic Kidney Disease in the United States
Authors: CLAUDEL SOPHIE E. , WAIKAR SUSHRUT , SCHMIDT INSA M. , VERMA ASHISH 
Published: June 2023

Background: Diabetes (DM) is the leading cause of kidney disease and disproportionately affects minority populations in the U.S. We hypothesized that racial/ethnic minority adults have higher prevalence of diabetic kidney disease (DKD) than non-Hispanic White (NHW) adults, and that prevalence is increasing.
Methods: Using NHANES 2011-2018 (N=3,360), we calculated weighted, age-adjusted prevalence of DKD among patients with DM. DM was defined as A1c &gt;6.5% or use of hypoglycemic medications. DKD was defined as the presence of DM and eGFR &lt;60ml/min per 1.73m2 or albuminuria ≥30mg/g.
Results: The mean age was 59.9 years and median A1c was 7.0% (IQR 6.4, 8.1). The prevalence of DKD was 29.4% (95% CI 26.7, 32.3). Prevalence increased from 27.7% (95% CI 22.8, 32.6) to 33.1% (95% CI 28.5, 37.7) during the study (p-trend &lt;0.0001). Compared to NHW, DKD prevalence was 1.5, 1.5, and 1.3 times higher among Mexican Americans, non-Hispanic Blacks (NHB), and non-Hispanic Asians (NHA), respectively. DKD prevalence increased for NHW, NHB, and NHA (p-trend &lt;0.05). Among patients with HTN, 39.3% were taking an ACEi/ARB. Among those with albuminuria, 38.8% were taking an ACEi/ARB and 1.3% were taking an SGLT2i.
Conclusions: Rising prevalence of albuminuric DKD and low anti-proteinuric medication use are concerning for future DKD progression. Understanding DKD trends is essential to appreciating the population-level response as new therapies are introduced.

Disclosure
S.E.Claudel: None. S.Waikar: None. I.M.Schmidt: None. A.Verma: None.

Funding
National Institutes of Health (R38HL143584)