bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&lt;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&lt;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&lt;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&lt;0.05) and lipidomes involved in inflammatory pathways (lysophosphatidylcholine, 126±11 vs. 51±7 nmol/ml, p&lt;0.005; phosphatidylcholine, 385±24 vs. 306±25 nmol/ml, p&lt;0.01; ceramide, 1.7±0.2 vs. 1.2±0.2 nmol/ml, p&lt;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&lt;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&lt;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)&lt;0.001). Adiponectin, a key mediator of FGF21’s therapeutic effects, was increased by FGF21 in males but not females (p(treatment x sex)&lt;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)&lt;0.05, &lt;0.0001, &lt;0.05, &lt;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&lt;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&lt;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&lt;0.05) and were positively correlated with in-situ PI/INS ratio (r=0.6; p=0.01) and colocalization (r=0.5, p&lt;0.05), with in-vivo measurements of glucose intolerance (r=0.6-0.8; p&lt;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&lt;0.01) and negatively with those associated to β cell identity (r=-0.2; p&lt;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
292-OR: Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets
Authors: TRAN DUC T. , LOGUERCIO SALVATORE , LEE KOUTA , POTTEKAT ANITA , BALCH WILLIAM E. , ARVAN PETER , KAUFMAN RANDAL J. , ITKIN-ANSARI PAMELA 
Published: June 2021

It has become increasingly appreciated that inflammatory cytokines promote islet dysfunction in both type 1 and type 2 diabetes. Aberrant secretion of the insulin precursor proinsulin is observed in patients with both types of diabetes and may contribute to proinsulin autoimmunity in T1D, yet the mechanisms responsible for proinsulin release remain obscure. To investigate the effects of inflammation on proinsulin trafficking, human islets were treated ex vivo with the diabetes associated cytokines, Interleukin-1-beta and Interferon-gamma, provoking a four-fold release of proinsulin. To identify proinsulin interacting proteins responsible for aberrant trafficking, intracellular proinsulin was affinity purified and its interactome defined by mass spectrometry. Cytokines altered the identify or magnitude of proinsulin’s engagement with binding partners at every stage of the canonical proinsulin biosynthetic pathway that we recently defined in normal human islets. Of particular relevance to potential avenues of proinsulin escape, cytokines promoted proinsulin interactions with: 1) antigen presentation loading complex components TAP2 and calnexin 2) stress granule assembly factors G3BP1, Ataxin-2 and IGF2BP2, that are also found in secreted exosomes, and 3) the immature insulin granule marker and T1D autoantigen ICA1/ICA169. Pathway analysis further revealed that cytokine treatment increased proinsulin binding, even if indirectly, to multiple KIF family microtubule motor proteins. Given that stress granules and immature granules are sensitive to microtubule dynamics we tested the role of microtubules in cytokine induced proinsulin release. Microtubule destabilization with Nocodazole significantly increased proinsulin release above that provoked by cytokines alone. Together, the data quantitatively map the cytokine reshaped proinsulin interactome and provide new insight into how an inflammatory environment can promote proinsulin escape from human islets.

Disclosure
D. T. Tran: Employee; Self; Encodia Inc. S. Loguercio: None. K. Lee: None. A. Pottekat: None. W. E. Balch: None. P. Arvan: None. R. J. Kaufman: None. P. Itkin-ansari: None.

Funding
JDRF (2-SRA-2015-47-M-R); National Institutes of Health (R24DK110973)
300-OR: Association of Raised Lipoprotein(a) Levels with Micro- and Macrovascular Complications in Patients with Type 1 Diabetes
Authors: VAN HAARE HEIJMEIJER SOPHIE , HERMANS MICHEL P. 
Published: June 2021

Background: Raised levels of lipoprotein(a) [Lp(a)] are causally associated with incident macroangiopathy and aortic valvular calcification in (non)diabetic subjects.
Objective: In type 2 diabetes (T2DM), there is an inverse, J-shaped relationship between elevated Lp(a) and prevalent microangiopathies. This work assessed whether this inverse association also exists in type 1 diabetes (T1DM).
Methods: The cardiometabolic phenotype of 357 patients with T1DM was determined, alongside routine lipids, Lp(a), non-Lp(a)-LDL-C, apolipoprotein B100, apolipoprotein A-I, and atherogenic dyslipidemia. Patients in the 1st tertile of Lp(a) ([TI]; n=119; median Lp(a) 6 nmol/L) were compared to those in the 3rd tertile of Lp(a) ([TIII]; n=119; median Lp(a) 100 nmol/L).
Results: There were no significant differences between [TI] and [TIII] patients regarding gender, diabetes duration, HbA1c, smoking, BMI, hypertension, GFR, (micro)albuminuria, cerebrovascular disease, routine lipids (total C; LDL-C; HDL-C; TG), apolipoprotein B100, apolipoprotein A-I, non-Lp(a)-LDL-C, and frequency/intensity of statin use. Compared to [TIII], [TI] patients were younger (48 vs. 53 years), had lower body fat (24 vs. 27%), and higher muscle mass (36 vs. 34%; all p&lt;0.05). After adjusting for age, [TIII] had more overall microangiopathy (+37%; 57 vs. 45%) and diabetic retinopathy (+34%; 51 vs. 38%; 0.0441). They also had an increased prevalence of overall macroangiopathy (+211%; 19 vs. 9%; p 0.0265) and coronary artery disease (+250%; 15 vs. 6%; p 0.0238). Among [TIII] patients, 35% were in the highest CV risk category, vs. 16% of [TI] (p 0.0008).
Conclusion: In addition to the risk of macrovascular complications, a high level of Lp(a) is associated with an increased frequency of retinal microangiopathy in T1DM patients, contrary to what was observed in T2DM. On the other hand, the frequency of macroangiopathy was increased in T1DM just like in T2DM and nondiabetic patients.

Disclosure
S. Van haare heijmeijer: None. M. P. Hermans: None.
301-OR: Effect of Vitamin D Supplementation on Insulin Sensitivity and Beta-Cell Function in Prediabetes
Authors: RASOULI NEDA , BRODSKY IRWIN , CHATTERJEE RANEE , KIM SUN H. , PRATLEY RICHARD E. , STATEN MYRLENE , NELSON JASON P. , PITTAS ANASTASSIOS G. ,   D2D RESEARCH GROUP
Published: June 2021

Vitamin D is believed to regulate pathways in glucose homeostasis, but effects of vitamin D supplementation on insulin sensitivity and β-cell function in humans remain uncertain. We completed a secondary analysis of the Vitamin D and type 2 diabetes (D2d) study to investigate the effects of vitamin D supplementation on insulin sensitivity and β-cell function. Participants at high risk for type 2 diabetes, meeting at least 2-out-of-3 ADA criteria for prediabetes, were randomly assigned to 4000 IU/day of vitamin D3 or placebo. Insulin sensitivity and β-cell function were estimated using data from 75-gram oral glucose tolerance tests (OGTT). We used the University of Oxford HOMA2 Calculator to estimate insulin sensitivity from simultaneously measured fasting plasma glucose and C-peptide values. Early C-peptide and insulin responses were calculated as the ratio of C-peptide or insulin increment to glucose level changes during the first 30 minutes of the OGTT. The disposition index (DI) as an estimate of β-cell function was calculated as the product of C-peptide response and HOMA2%S. The response to vitamin D3 was evaluated in 1,774 participants over 24 months. Baseline characteristics [mean age 60.5±9.8 years, BMI 31.9±4.4 kg/m2, 56.4% male, 69.1% white, 25-hydroxyvitamin D (25-OH D) 28.2±10.2 ng/ml, HbA1c 5.9%±0.2, FPG 107.7±7.2 mg/dl, 2hrOGTT glucose 137.1±34.1 mg/dl] were similar between the vitamin D and placebo groups. Serum 25-OH D increased from 27.9±10.3 ng/ml to 54.9±14.4 ng/ml at 24 months in the vitamin D group and remained unchanged with placebo (p&lt;0.05 between group changes from baseline). There were no significant differences in changes in HOMA2%S, C-peptide or insulin responses and DI between the two groups.
In conclusion, in this pre-specified analysis from the D2d study, supplementation with vitamin D for 24 months did not alter insulin sensitivity or β-cell function in people with prediabetes who were not selected based on their baseline vitamin D levels.

Disclosure
N. Rasouli: Consultant; Self; Novo Nordisk, Research Support; Self; Allergan plc, Lilly Diabetes, Novo Nordisk. I. Brodsky: None. R. Chatterjee: Research Support; Self; Bristol-Myers Squibb Company, Epigenomics AG, Verily Life Sciences. S. H. Kim: Advisory Panel; Self; Bayer U. S., GI Dynamics, Stock/Shareholder; Spouse/Partner; Dexcom, Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Staten: None. J. P. Nelson: None. A. G. Pittas: None. D2d research group: n/a.

Funding
American Diabetes Association (1-14-D2d-01 to A.G.P.); National Institute of Diabetes and Digestive and Kidney Diseases (U34DK091958); Office of Dietary Supplements (U01DK098245)
313-OR: Disparities in Preventive Care Utilization among Patients with Diabetes in the Diabetes Belt and Surrounding Areas
Authors: SOHN MIN-WOONG , KANG HYOJUNG , MCMURRY TIMOTHY L. , KIM SOYOUN , LOBO JENNIFER M. 
Published: June 2021

Objective: Preventive care has been shown to reduce both the incidence and progression of diabetic complications. American Diabetes Association treatment guidelines recommend annual preventive care such as annual doctor visits and A1c tests. Our objective is to compare utilization rates of four annually recommended preventive services for persons with diabetes in the Diabetes Belt and those in the surrounding area.
Methods: We used 2015 Medicare claims data to identify preventive service utilization using ICD9/10 and CPT/HCPCS codes. Diabetes Belt consists of 644 counties in the Appalachian region and southeastern part of US that had diabetes prevalence over 11% in 2008 compared to ~8.5% in the rest of the country. Surrounding counties include 118 counties that are adjacent but not contiguous to the Diabetes Belt counties.
Results: Patients in the Belt had significantly lower utilization than those in surrounding counties for all four preventive services: foot exam, 81% vs. 88%; eye exam, 53% vs. 58%; microalbuminuria test, 31% vs. 34%; one or more A1c tests, 73% vs. 74%. After adjusting for age, sex, and race/ethnicity, patients in the Diabetes Belt had 38%, 18%, 16%, and 11% lower odds of using foot exams, microalbuminuria tests, eye exams, and A1c tests, respectively, compared to those in the surrounding counties (p for all comparisons &lt; 0.001). Even after adjusting for socioeconomic, access-to-care factors, and service availability, patients in the Diabetes Belt had consistently lower rates of utilization for these four services than surrounding counties.
Conclusion: Patients with diabetes in the Diabetes Belt are doubly jeopardized for diabetic complications because of higher prevalence diabetes and lower preventive care utilization than surrounding counties. Health policy makers may want to pay more attention to the Diabetes Belt in reducing the regional differences in the utilization of these services.

Disclosure
M. Sohn: None. H. Kang: None. T. L. Mcmurry: None. S. Kim: None. J. M. Lobo: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113295)