bluuebunny/crossref_metadata_2025 huggingface dataset:
333-OR: What Motivates People to Enroll in the National Diabetes Prevention Program Lifestyle Change Program
Authors: PAPALII MICHELLE , ELY ELIZABETH
Published: June 2023

In 2021, the Centers for Disease Control and Prevention (CDC) began collecting data on what motivates people to enroll in the National Diabetes Prevention Program (National DPP) lifestyle change program (LCP). Upon enrolling in the LCP, participants are asked, “Who/what motivated you the most to sign up for this program?” Participants may choose health care professional, blood test results, prediabetes risk test, someone at a community-based organization (CBO), family/friends, current/past participant in the LCP, employer/employer’s wellness plan, health insurance plan, and media advertisements. By October 2022, these data had been collected on 128,116 eligible participants, of whom 25% reported that the prediabetes risk test motivated them the most, followed by their employer/employer’s wellness plan (23%), and health care professional (14%). Motivators were similar in men and women, with the prediabetes risk test and employer/employer’s wellness plan being the top 2 motivators. Across age groups, the prediabetes risk test and employer/employer’s wellness plan motivated adults aged 18-64 years the most, while health care professionals motivated individuals aged 65 years and over the most. Motivators varied across racial/ethnic groups, with family/friends, current/past participants, and someone at a CBO motivating some groups more than others. Though more participants were motivated by the prediabetes risk test, they did not stay in the program as long as those who were motivated by their employer/employer’s wellness plan, family/friends, or someone at a CBO (180 mean days vs. 278, 264, and 261 days, respectively). What might motivate participants to enroll in the LCP may not be what helps them stay in the program longer and may influence their risk reduction outcomes, including weight loss and engagement in physical activity. Understanding motivators can help organizations focus recruitment and enrollment efforts and support participants in achieving their goals.

Disclosure

M.Papalii: None. E.Ely: None.
337-OR: Hyperglycemia Lowers Lactate Clearance during Exercise in Type 1 Diabetes
Authors: ROMERES DAVIDE , YADAV YOGESH , RUCHI FNU , CARTER RICKEY , COBELLI CLAUDIO , BASU RITA , BASU ANANDA
Published: June 2023

To determine the role of hyperglycemia on lactate metabolism during exercise in type 1 diabetes (T1D), we studied 7 T1D participants during two visits (EuLoI; euglycemia, low insulin; HyLoI: hyperglycemia, low insulin) in random order. 7 nondiabetic (ND) subjects were studied on one occasion (EuLoI). Lactate turnover was measured using [1-13C] lactate before, during and after 60 min of exercise at 65% VO2 max. While lactate clearance was lower (p=0.031) during exercise at HyLoI than EuLoI in T1D, it was not different between T1D and ND subjects at EuLoI (p=0.707). In contrast, rate of lactate appearance during exercise was not different between EuLoI vs. HyLoI in T1D (p=0.129), demonstrating that higher plasma lactate concentration during exercise in HyLoI (p<0.001) was due to reduced lactate clearance in T1D. The results from this pilot study indicates that hyperglycemia modulates lactate metabolism during exercise by lowering lactate clearance in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner, in type 1 diabetes.

Disclosure

D.Romeres: None. Y.Yadav: None. F.Ruchi: None. R.Carter: None. C.Cobelli: None. R.Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A.Basu: None.

Funding

National Institutes of Health (DK29953 to R.B.), (DK85516 to A.B.)
34-LB: Effectiveness of Combination Use of a Lifestyle Improvement Support App and a Wearable Device on Glycemic Control in Japanese People with T2DM—STEP-DM
Authors: TAKAHASHI AKIKO , ISHII MANABU , KINO YURIKA , SASAKI KAZUYO , HASHIMOTO TAKAFUMI , MATSUI TAKAHIRO , ARAKAWA KENJI , KUNISAKI MAKOTO
Published: June 2023

Despite the availability of various therapeutic agents for T2DM, about half of patients do not achieve their glycemic control targets in Japan. In recent years, apps and wearable devices supporting diabetes treatment have rapidly spread. However, evidence of their impact, especially in combination, is limited. This is the first study to explore the effectiveness of combination use of a lifestyle improvement support app (TOMOCOTM Mitsubishi Tanabe Pharma Co.) and a wearable device (Fitbit) in Japanese people with T2DM under insufficient glycemic control (jRCT1070220007).

Of 61 patients enrolled, 59 completed (HbA1c: 7.57 ± 0.42%, Body weight: 69.12 ± 13.36 kg; at baseline). The participants used TOMOCOTM and Fitbit in addition to conventional diet/exercise and antidiabetic drug therapy for 12 weeks, and were provided feedback/advice based on TOMOCOTM and Fitbit records from health care providers (Fig). At the end of the observation period, HbA1c was significantly decreased (-0.41 ± 0.41%; range -1.9 to 0.7, p<0.001) and body weight was also reduced (-0.88 ± 1.58 kg; range -5.7 to 2.1, p<0.001), and the trend was consistent across the pre-specified patient background.

In conclusion, combination use of a lifestyle improvement support app and a wearable device with conventional therapy may be effective for glycemic control in people with T2DM.

Disclosure

A. Takahashi: Employee; Mitsubishi Tanabe Pharma Corporation. M. Ishii: Employee; Mitsubishi Tanabe Pharma Corporation. Y. Kino: Employee; Mitsubishi Tanabe Pharma Corporation. K. Sasaki: Employee; Mitsubishi Tanabe Pharma Corporation. T. Hashimoto: Employee; Mitsubishi Tanabe Pharma Corporation. T. Matsui: Employee; Mitsubishi Tanabe Pharma Corporation. K. Arakawa: Employee; Mitsubishi Tanabe Pharma Corporation. M. Kunisaki: Research Support; Mitsubishi Tanabe Pharma Corporation, Novo Nordisk.
340-OR: ADA Presidents' Select Abstract: Structural Neuroimaging and Cognitive Function in Long-Duration Type 1 Diabetes
Authors: SHAH HETAL , DESALVO MATTHEW , HAIDAR ANASTASIA , VISHVA TEJA JANGOLLA SURYA , GREGORY YU MARC , GAUTHIER JOHN , ZIEMNIAK NOLAN A. , WU I-HSIEN , BILLAH TASHRIF , NING LIPENG , ADAM ATIF , RATHI YOGESH , KING GEORGE L.
Published: June 2023

Cognitive decline is an increasingly important complication in people with type 1 diabetes (T1D) as they age. We previously reported that compared with nondiabetic people, those with long-duration T1D have impaired cognitive function, similar to people with type 2 diabetes. To characterize factors associated with cognitive decline in people with T1D, 52 participants of the Joslin Medalist Study (“Medalists”) with T1D≥50 years, and 20 age-matched nondiabetic controls, underwent clinical evaluation, cognitive assessments, and neuroimaging (Alzheimer Disease Neuroimaging Initiative-3 protocol). Compared to controls, Medalists had 49.4 (±21.9) cm3 (p=0.03) lower total brain volume, and 2.7 (±0.8) cm3, 3.0 (±1.5) cm3 and 3.1 (±1.5) cm3 lower volumes (p<0.05), respectively, in the deep gray matter region (thalamus, putamen, caudate and globus pallidus), the Alzheimer disease signature region (hippocampus, parahippocampus, entorhinal cortex, inferior parietal lobule, precuneus and cuneus), and the occipital lobe. No significant differences were observed in frontal, temporal, or parietal lobe volumes. In assessing small vessel disease, the number of white matter hyperintensities (WMHs) or microvascular hemorrhages did not differ between Medalists and controls, nor did regional cerebral blood flow measures (via arterial spin labeling). Among Medalists, reduced total and all regional brain volumes were associated (p<0.05) with worse motor skills, female sex, lower education status, increased age, and longer diabetes duration. Increased WMHs were associated with worse renal function and higher coronary artery calcification scores. Volumes did not associate with other cognitive domains (recall, working memory, or executive function). These findings suggest that cognitive decline in people with long-duration T1D is related mainly to abnormalities in parenchymal CNS rather than neurovascular changes. Definitive confirmation of this finding by brain histopathology is underway.

Disclosure

H. Shah: None. M. Desalvo: None. A. Haidar: None. S. Jangolla: None. M. Yu: None. J. Gauthier: None. N.A. Ziemniak: None. I. Wu: None. T. Billah: None. L. Ning: None. A. Adam: None. Y. Rathi: None. G.L. King: Research Support; Janssen Research & Development, LLC.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (3P30DK036836-34S1); Thomas J. Beatson, Jr. Foundation
344-OR: Post-translational Modification of SHDA Regulating Macrophage Polarization and Inflammation in Obesity
Authors: WU RUI , JIANG HAOWEN
Published: June 2023

The succinate dehydrogenase enzyme (SDH) catalyzes the oxidation of succinate into fumarate in the tricarboxylic acid cycle. Among the four subunits, SDHA and SDHB carry the catalytic activity. Mounting evidence implicates the link between the catalytic subunit SDHA expression and mitochondrial energy metabolism. However, the molecular mechanisms regulating SDH subunits stabilization in macrophages remain largely unknown. Here, we showed that AMPK, an energy sensor, could be a key regulator of SDHA ubiquitination through directly binding to sentrin-specific protease in adipose tissue macrophages, thus contributing to obesity-induced inflammation. Our study identified that SDHA expression was significantly downregulated in AMPKα siRNA RAW264.7 cells. Moreover, MG132 could significantly rescue AMPKα knockdown-induced SDHA degradation in cells, indicating that AMPK regulates SDHA stabilization via proteasomal degradation. However, AMPK protein interaction analyses by yeast two-hybrid showed that SDHA is not AMPK downstream target. Instead sentrin-specific protease was identified as a novel, putative AMPK substrate. To further clarify the potential interaction between AMPK, SDHA, and sentrin-specific protease, Co-IP experiment was included, and results indicated that AMPK directly binds with sentrin-specific protease instead of SDHA. As a desumoylating enzyme, SENP catalyzes hydrolysis peptide bond of SUMO. How the SUMOylation of SDHA impacts its ubiquitination still needs more investigations. In our scenario, we identified a new regulatory mechanism of SDHA stabilization, AMPKα-induced SUMOylation, that partially impacts the ubiquitination level of SDHA in activated macrophages. AMPKα-induced SUMOylation level change of SDHA is directly involved in the regulation of macrophage polarization, which may contribute to adipose inflammation.

Disclosure

R.Wu: None. H.Jiang: None.
347-OR: Methionine Restriction Differentially Protects against High-Fat Diet-Induced Neuroinflammation and Central Insulin Resistance in Male and Female Mice
Authors: LAIL HANNAH L. , LAWRENCE ROWAN , WANDERS DESIREE
Published: June 2023

High-fat diets (HFD) promote central inflammation and insulin resistance (IR). Methionine restriction (MR) improves peripheral insulin sensitivity, lipid metabolism, and cognitive function, at least in part by increasing fibroblast growth factor 21 (FGF21). However, the ability of MR to protect against neuroinflammation and central IR during adolescence has not been examined. Moreover, whether MR depends on FGF21 to protect against HFD-induced changes in central insulin signaling or neuroinflammation is unknown. We sought to determine whether MR protects against HFD-induced neuroinflammation and central IR during adolescence in males and females and whether MR’s effects are dependent on FGF21. Male and female wild-type (WT) and FGF21 knockout (KO) mice, aged 5 to 6 wk, were fed normal (18.9% fat-derived kcal) or high-fat (60% fat-derived kcal) versions of control (0.86% methionine) or MR (0.17% methionine) diets for 5 wk. To investigate insulin action, ITTs were performed after 4 wk on the diet, and saline or insulin (0.6U/kg body weight) was administered 15 min prior to sacrifice.

MR significantly decreased weight gain of HFD-fed mice regardless of sex or genotype (p < 0.05). MR increased serum FGF21 of all males and HFD-fed females (p < 0.05), and strongly tended to increase FGF21 in female mice on the normal-fat diet. HFD feeding tended to promote inflammatory gene expression in the hippocampus of WT males, while MR trended to mitigate inflammation independent of FGF21. MR also significantly reduced fasting blood glucose and improved peripheral insulin response in an FGF21-dependent fashion (p < 0.05). Though, neither HFD nor MR had a notable impact on markers of IR in the hypothalamus or hippocampus. Our findings indicate that short-term MR improves metabolic parameters of adolescent mice fed normal or high-fat diets. In addition, MR acts in an FGF21-independent and sex-dependent manner to improve neuroinflammation.

Disclosure

H.L.Lail: None. R.Lawrence: None. D.Wanders: None.
349-OR: Selected DYRK1A Inhibitors Simultaneously Drive Both Human Beta-Cell Proliferation and Differentiation
Authors: WANG PENG , KUMAR KUNAL , LIU HONGTAO , WOOD OLIVIA , KARAKOSE ESRA , CHOLEVA LAURYN , LAMBERTINI LUCA , GARCIA-OCANA ADOLFO , DEVITA ROBERT J. , STEWART ANDREW F.
Published: June 2023

Small molecule DYRK1A inhibitors induce adult human beta cell proliferation and expand human beta cell mass. Harmine also enhances differentiation and function in human beta cells in vitro and in vivo, increasing expression of key beta cell genes. It is unknown whether this “pro-differentiation effect” is a feature of all DYRK1A inhibitors. We compared harmine, 2-2c, 5-Iodotubericidin (5-IT), GNF4877, INDY, CC-401 and Leucettine-41 at doses that maximally drive human beta cell proliferation. As anticipated, harmine, 2-2c and 5-IT all increased expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC30A8, and ENTPD3. These effects were observed in normal human islets as well as in islets from donors with T2D. Surprisingly, in simultaneous experiments, the DYRK1A inhibitors GNF4877, INDY, CC-401 and Leucettine failed to induce these beta cell differentiation markers. The pro-differentiation effect of harmine was independent of DYRK1A inhibition: silencing DYRK1A in human islets induced beta cell proliferation, but had no effect on differentiation; harmine treatment in DYRK1A-silenced islets restored beta cell pro-differentiation effects. The pro-differentiation effect was also independent of NFAT signaling and DREAM Complex effects, since NFAT overexpression, or p130, p107, E2F4 and E2F5 silencing had no effect on beta cell differentiation. Similarly, silencing other known harmine targets (DYRK2, 3, 4, the CLK and HIPK family) had no effect on either human beta cell differentiation nor proliferation.

In summary, harmine, 2-2c and 5-IT are unique among the DYRK1A inhibitor family in their simultaneous ability to enhance both beta cell proliferation and differentiation. While the beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor drug development.

Disclosure

P. Wang: None. K. Kumar: None. H. Liu: None. O. Wood: None. E. Karakose: None. L. Choleva: None. L. Lambertini: None. A. Garcia-Ocana: Consultant; Sun Pharmaceutical Industries Ltd. R.J. DeVita: None. A.F. Stewart: None.
352-OR: Regulation of Melanocortin Receptor 4 (MC4R) Ciliary Trafficking
Authors: NACHURY MAXENCE
Published: June 2023

The primary cilium, a hair-like projection at the surface of nearly every cell, functions as a signaling antenna in processes as diverse as vision and body weight homeostasis. Obesity is a cardinal symptom of many ciliopathies including Bardet-Biedl Syndrome (BBS). While we are beginning to understand how cilia participate in body weight homeostasis, the molecular pathway that leads to obesity in BBS patients remains unclear.

We now know that the melanocortin receptor 4, a GPCR that regulates feeding behavior, localizes to cilia in hypothalamic neurons. Meanwhile, most BBS proteins assemble or regulate the BBSome, a protein complex that removes activated signaling receptors from cilia.

To characterize the stimuli and mechanisms that regulate MC4R trafficking in and out of cilia, we recapitulated MC4R trafficking in ciliated cell lines amenable to rapid manipulation. Surprisingly, levels of MC4R in cilia remain under the detection limit in most cells unless treated with an inverse agonist of MC4R. In addition, interference with BBSome function also increases ciliary MC4R levels in all cells. Thus, the tonic activity of MC4R promotes the constitutive clearance of MC4R from cilia via BBSome-mediated exit.

These results suggest that artificially increasing the ciliary levels of MC4R may augment its signaling activity. To selectively recognize activated GPCRs, the BBSome relies on specific ubiquitin chains linked at lysine 63 (K63Ub chains) that become attached onto activated GPCRs via β-arrestin-associated ubiquitin ligases. Depletion of β-arrestin blocked the constitutive exit of MC4R from cilia and mutation of ubiquitin acceptor lysines from MC4R and MRAP2 results in a measurable increase in the ciliary levels of MC4R. In addition, targeting a protease that specifically cleaves K63Ub chains to cilia completely blocks the exit of MC4R from cilia.

We conclude that the tonically active MC4R is ubiquitinated in cilia and actively removed by the BBSome.

Disclosure

M.Nachury: None.

Funding

American Diabetes Association (1-20-VSN-03)
354-OR: Attenuation of Obesity-Induced Vascular Inflammation by microRNA-485 in Endothelial Cells
Authors: BESTEPE FURKAN , PAL-GHOSH RUMA , FRITSCHE COLETTE , LAKHOTIYA KARTIK , SMOLGOVSKY SASHA , WESTON JAMES , STEPANIAN ALEC , ALVARADO FERNANDA , CATALANO PATRICK , O'TIERNEY-GINN PERRIE F. , ALCAIDE PILAR , JAFFE IRIS Z. , ICLI BASAK
Published: June 2023

Obesity induced endothelial dysfunction contributes to the vascular inflammation. MicroRNAs (miRNAs) are implicated in the epigenetic regulation of inflammatory pathways. However, relevant miRNAs in the microvasculature, and their relation to chronic inflammation and metabolic dysfunction are poorly understood. Using micro-RNA Seq approach to profile microRNAs from the endothelial cells (ECs) of brown adipose tissue (BAT) of mice with diet-induced obesity (DIO), we identified microRNA- 485-5p (miR-485-5p) as one of the most differentially regulated miRNA. MiR-485-5p was rapidly induced in ECs in response to TNFα, highly enriched in the BAT vascular endothelium of mice with DIO, and was increased by 1.97 fold in human plasma samples with obesity. MiR-485-5p inhibition decreased TNF-α-induced NF-kB-responsive adhesion molecules VCAM-1 (32.6%) and ICAM-1 (34.7%) and phosphorylation of IKBα in ECs in vitro. Gain and loss-of-function studies revealed that neutralization of miR-485-5p potently inhibited leukocyte adhesion to EC monolayers by 20.8% while the overexpression had the opposite effects. Mechanistically, miR-485-5p inhibited the expression of its target gene PCF11 (~40.3%), a polyadenylation factor subunit, an effect that increased VCAM-1 (2.51 fold) and ICAM-1 (1.43 fold) expression as well as leukocyte adhesion to EC monolayers by 18.6% in vitro. Systemic neutralization of miR-485-5p in mice decreased leukocyte adhesion and rolling by 55.1% and 46.7% respectively by intravital microscopy. Finally, systemic delivery of LNA-anti-miR-485-5p inhibitor resulted in improved glucose and insulin tolerance and energy expenditure in mice with DIO while decreasing Ly6Chigh proinflammatory monocytes in blood as measured by FACS. Our findings indicate that miR-485-5p plays a key regulatory role in controlling vascular inflammation in diet-induced obesity, an effect that could be exploited for therapeutic intervention in obesity-induced chronic inflammation.

Disclosure

F.Bestepe: None. P.F.O'tierney-ginn: None. P.Alcaide: None. I.Z.Jaffe: None. B.Icli: None. R.Pal-ghosh: None. C.Fritsche: None. K.Lakhotiya: None. S.Smolgovsky: None. J.Weston: None. A.Stepanian: None. F.Alvarado: None. P.Catalano: None.

Funding

American Diabetes Association (1-16-JDF-046 to B.I.); National Institutes of Health (HL149999)
359-OR: Variation in Utilization of Continuous Glucose Monitoring in Patients with Type 1 Diabetes
Authors: LACY MARY E. , FOWLKES JOHN , HEIER KORY , SOHN MIN-WOONG , KRUSE-DIEHR AARON J. , WATERS TERESA , MOGA DANIELA C.
Published: June 2023

Background: Continuous glucose monitoring (CGM) is recommended by the American Diabetes Association for patients with type 1 diabetes (T1D) but remains underutilized. Prior studies suggest ~30% of patients with T1D use CGM with variation by race/ethnicity reported.

Methods: We used electronic health record data from an academic medical center (1/1/2018-12/31/2021) to examine variation in CGM utilization in patients with T1D and describe demographic factors associated with CGM use via multivariate logistic regression adjusted for clinical variables outlined in Table 1.

Results: Among 3,382 patients with T1D (aged 28.6 ± 17.8 y; 51% female; 83% non-Hispanic White), 52% used CGM during study period. CGM utilization was significantly lower in older (age 65+) versus younger patients (age 0-13; OR=0.15, 95% CI: 0.09, 0.26), Hispanic versus non-Hispanic White patients (OR=0.44, 95% CI: 0.21, 0.94) and patients with commercial versus government-issued insurance coverage (Medicaid, OR=0.44, 95% CI: 0.37, 0.52; Medicare, OR=0.42, 95% CI: 0.30, 0.50).

Conclusions: In this population of patients with T1D, 1 in 2 patients used CGM to manage their diabetes but there was significant variation. Identifying populations with lower-than-expected utilization is a necessary first step in developing targeted interventions to increase CGM uptake and, ultimately, improve short and long-term T1D-related outcomes.

Disclosure

M.E.Lacy: None. J.Fowlkes: None. K.Heier: None. M.Sohn: None. A.J.Kruse-diehr: None. T.Waters: None. D.C.Moga: None.

Funding

National Institutes of Health (UL1TR001998, KL2TR001996)
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 < 25 as accurately identify IAH in T1D subjects (sensitivity 88%, specificity 83%)(Figure 1B). Epinephrine levels were correlated with SS (R2=0.57, p<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<0.0001, while BODIPY was increased 2.2 ± 0.1-fold in BTBR OB vs. ND BTBR controls, n=6-11, p<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<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 >6.5% or use of hypoglycemic medications. DKD was defined as the presence of DM and eGFR <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 <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 <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)
414-P: Multiomic Plasma Markers of Diabetic Kidney Disease in Type 1 Diabetes
Authors: SNELL-BERGEON JANET K. , JOHNSON RANDI K. , PYLE LAURA , CHEN GUAN-YUAN , WELDEMARIAM MEHARI M. , ZHANG QIBIN
Published: June 2023

Diabetic kidney disease (DKD) is a major complication of type 1 diabetes (T1D). We investigated whether metabolomic, lipidomic and proteomic plasma markers were associated with albuminuria in the Coronary Artery Calcification in Type 1 Diabetes cohort. Two timed overnight urine collections were performed, and albumin excretion rates (AER) were averaged. If overnight samples were unable to be obtained, a spot urine sample was collected and albumin/creatinine ratio (ACR) was used to determine albuminuria status. Albuminuria was defined as an AER ≥ 20 ug/min or an ACR ≥ 30mg/g. Plasma samples from the baseline examination were assayed by LC-MS for multiple omics markers in 225 participants with T1D. Moderated t-tests using false discovery rate (FDR) adjustment for multiple comparisons were used to examine the markers associated with albuminuria presence. An FDR adjusted p-value <0.05 was considered to be statistically significant. Average ± SD for age was 36 ± 9 years and for diabetes duration was 23 ± 9 years, and 58% [n = 120] were female. The prevalence of albuminuria at baseline was 20.4% (n = 46). There were 15 metabolite markers (3 metabolites of symmetric dimethylarginine, 2 of glycyl-glycine, and one each of aspartyl-glycine, glycyl-aspartate and 1-methylhistidine, 7 uncertain) with higher expression in participants with DKD than in those without DKD. There were 7 lipid markers in the acylcarnitine family that were elevated in participants with DKD compared to those without DKD, and 19 glycated peptides (16 in fibrinogen, 1 in kininogen and 1 in hemopexin) showed higher expression in participants with DKD than in those without DKD. None of the unmodified proteins differed by DKD status. Multiple omics markers were higher in T1D participants with albuminuria than in people without any sign of DKD. These findings may suggest changes in lipids, metabolites and glycated proteins early in the course of DKD, and these markers should be explored as potential predictors of worsening DKD.

Disclosure

J.K.Snell-bergeon: None. R.K.Johnson: None. L.Pyle: None. G.Chen: None. M.M.Weldemariam: None. Q.Zhang: None.