bluuebunny/crossref_metadata_2025_split huggingface dataset:
206-OR: Insulin Gene Mutation in Family with Monogenic Diabetes Leads to Smaller Pancreas
Authors: WRIGHT JORDAN J. , WILLIAMS JONATHAN M. , GREELEY SIRI ATMA W. , POWERS ALVIN C. , VIROSTKO JOHN , MOORE DANIEL J. 
Published: May 2022

Individuals with new-onset type 1 diabetes (T1D) and those at risk for T1D have a smaller pancreas. The reason for the reduced pancreas size and acinar cell number in T1D is not known, with possible explanations being a direct effect of insulin deficiency, acinar cell-directed autoimmunity, or cytokine-mediated inflammation. To test the hypothesis that insulin deficiency leads to reduced pancreas size, we measured pancreas volume in a family with monogenic diabetes due to an INS-gene mutation using a standardized MRI protocol developed as part of the Multicenter Assessment of the Pancreas in Type 1 Diabetes program (MAP-T1D, www.map-t1d.com, PMID: 34428220) . Pancreas volume was normalized to body weight to calculate pancreas volume index (PVI) . The family, carrying a heterozygous c.94G&gt;C (p.Gly32Arg) INS mutation, was identified as part of the Monogenic Diabetes Registry at the University of Chicago. All family members with diabetes, including the father, diagnosed at age 22, and three children, diagnosed before 8 months, have clinical insulin deficiency and are treated with insulin. All four family members with diabetes (age 30, 30, 34, and 62 yrs; BMI 23-28; PVI 0.23, 0.42, 0.53, and 0.48 mL/kg) had small PVI compared to those without diabetes (age 32, 38, and 60 yrs; BMI 19-23; PVI 1.07, 1.17, and 0.92, p&lt;0.01) . The pancreas of family members with diabetes was similar to those seen in individuals with new-onset T1D (age 13.4 ± 4.1 years, BMI 20.5 ± 4.1, PVI 0.68 ± 0.22) , and pancreas of family members without diabetes was similar to those of unrelated controls (age 15.9 ± 6.7 years, BMI 21.4 ± 4.4, PVI 0.97 ± 0.22 ml/kg; PMID: 30552135) . Studies in this family indicate that insulin is a determinant of pancreas size either directly as a trophic factor or indirectly through control of other islet-derived growth factors. This relationship suggests that reduced pancreas volume in T1D may be an earlier indicator of local insulin loss rather than a reflection of immune or inflammatory factors.

Disclosure
J.J.Wright: None. J.M.Williams: None. S.W.Greeley: None. A.C.Powers: None. J.Virostko: None. D.J.Moore: None.
21-LB: Transdermal Microneedle Device Delivery of Adipocyte-Specific AAVs to Overexpress Adipose Tissue Neurotrophic Factors in the Treatment of Diabetic Peripheral Neuropathy
Authors: BLASZKIEWICZ MAGDALENA , TOWNSEND KRISTY L. 
Published: May 2022

Diabetes is the leading cause of peripheral neuropathy (PN) , which results in loss of nerve supply in tissues like skin, adipose and muscle. While there are currently few treatments for PN, early mitigation in the pre-diabetic state with tissue neurotrophic factors may improve nerve function in metabolically important tissues like adipose. We used an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors directly to scWAT using a transdermal microneedle device that we developed. This approach avoids potential off-target effects and aberrant axon outgrowth in skin that may increase pain. Using both the BTBRob/ob and C57BL/6J diet-induced neuropathy mouse models, we have demonstrated that AAVRec2-BDNF (brain derived neurotrophic factor, which we have implicated in controlling adipose innervation) delivery to scWAT with our device increased tissue innervation 14 days after treatment, marked by increased protein expression of pan-neuronal marker PGP9.5 and sympathetic nerve marker tyrosine hydroxylase (TH) . Longer periods of dietary obesity (25+ wks vs 16 wks) blunted the ability of AAVRec2-BDNF to increase innervation in scWAT, despite these mice showing an initial decrease in body weight compared to controls. This indicates there may be a critical window for therapy delivery during the progression to diabetic neuropathy during which interventions are more advantageous. Treatment with AAVRec2-NGF (nerve growth factor) also increased scWAT innervation in obese mice at 8 weeks post-treatment, as evidenced by increased protein expression of PGP9.5, TH and markers of axon outgrowth (Gap43, Vasp) . Thermal imaging above inguinal scWAT revealed an increase in temperature only in AAVRec2-NGF treated mice, supporting the idea that NGF-responsive nerves drive tissue browning and/or thermogenesis. Taken together, we have developed a novel treatment approach for delivering adipocyte-tropic AAVs to overexpress neurotrophic factors as a means to mitigate diabetes-associated PN.

Disclosure
M. Blaszkiewicz: None. K. L. Townsend: Other Relationship; Neuright, Inc.
214-OR: Effects of Polyphenols on Cholesterol Efflux and Insulin Secretion in MIN6 Cells
Authors: MATSUKI KOTA , KIMURA YUKI , MATSUMURA KOKI , TANABE JUTARO , MURAKAMI HIROSHI , DAIMON MAKOTO 
Published: May 2022

Background: Diabetic dyslipidemia is characterized by elevated levels of triglyceride-rich lipoproteins and reduced levels of HDL-cholesterol (HDL-C) . Low levels of HDL-C are associated with an increased risk of atherosclerotic cardiovascular disease, because HDL protects against atherosclerosis through multiple mechanisms include removal of excess cholesterol from macrophages. HDL can also influence cholesterol homeostasis in pancreatic β-cell. It is noteworthy that absence of ATP-binding cassette transporter A1 (ABCA1) , which is a cellular cholesterol transporter and regulates islet cholesterol efflux, results in islet cholesterol overload and impaired insulin release in mice. We examined the associations of cholesterol efflux and insulin secretion in MIN6 cells with polyphenols that is reported to increase cholesterol efflux.
Methods: Murine MIN6 cells were labeled with 3H-cholesterol and incubated with ApoA1 (μg/ml) or HDL (25 μg/ml) for 24 hours. The percentage cholesterol efflux was calculated by dividing the media-derived radioactivity by the sum of the radioactivity in the media and the cells. The effect of polyphenols on the cholesterol efflux was studied, adding that into the medium before the analysis of the cholesterol efflux. Insulin secretion was assessed by ELISA as the concentration of insulin in the culture medium. The mRNA expression of ABCA1 and ABCG1 were determined by real-time Quantitative RT-PCR.
Results: Under the existence of polyphenols (isorhamnetin) , the ApoA1 or HDL-mediated cholesterol efflux had significantly increased by 1.4% or 1.8%, respectively (n=4, p&lt;0.01) . Isorhamnetin had increased insulin secretion by 882 ng/mg protein/h (n=3, p&lt;0.05) and significantly decreased ABCA1 and ABCG1 expressions.
Conclusion: These data suggest that isorhamnetin increases cholesterol efflux and insulin secretion in MIN6 cells. Isorhamnetin could be the interesting candidate to investigate the new treatment for patients with diabetes mellitus.

Disclosure
K.Matsuki: None. Y.Kimura: None. K.Matsumura: None. J.Tanabe: None. H.Murakami: None. M.Daimon: None.

Funding
JSPS KAKENHI Grant Number 20K11549
222-OR: Effectiveness, Safety, and Treatment Adherence of Follow-On Insulin in Diabetes Management
Authors: CHEN XIAOXUE , PHAM TIMOTHY , BARRON JOHN J. , HART RICHARD A. , ABARCA JACOB , DEVRIES ANDREA 
Published: May 2022

Background: The high insulin costs have associated with underuse and poor adherence among patients with types 2 diabetes (T2D) . Basaglar was approved by FDA in 2015 as a follow-on insulin to reference insulin Lantus. It presents an opportunity to reduce costs and improve adherence to insulin treatment. The study assessed the change in HbA1c after initiation of follow-on insulin (Basaglar) or reference insulin (Lantus) among patients with T2D. We also compared treatment adherence, safety events, and costs at 1-year after initiation of insulin.
Methods: Using claims data from a large U.S. health plan during 2016-2020, we identified adults with T2D who initiated either Basaglar or Lantus. Generalized linear regression modeling assessed the differences in outcomes between the groups. A 0.4% margin was used to determine non-inferiority for HbA1c .
Results: The study included 1,136 Basaglar users and 6,3Lantus users. The mean age was 54.0 years in Basaglar users and 56.3 years in Lantus users (p&lt;0.001) . Both groups showed more than 1% reduction in HbA1c over 6 months and over 12 months. Reduction in HbA1c with Basalgar was similar (noninferior) to that with Lantus, with an adjusted difference of Basaglar to Lantus of 0.14% (95% CI -0.02 to 0.30, p=0.084) over 6 months and 0.17% (95% CI 0.02 to 0.32, p=0.024) over 12 months. Rates of adverse events were similar for both hypoglycemia and vascular events. The Basaglar group showed higher adherence in terms of proportion of days covered (adjusted difference 0.06, 95% CI 0.to 0.08, p&lt;0.001) . Medical costs were similar, but the cost of Basaglar was lower (adjusted mean cost difference -$462, 95% CI -$556 to -$363, p&lt;0.001) after adjustment.
Conclusions: Basaglar provided similar glycemic control compared to Lantus, had similar safety profile and more favorable adherence in patients with T2D. The findings highlight the potential that biosimilar/follow-on biologics offer in terms of expanding patient access and improving treatment affordability.

Disclosure
X.Chen: None. T.Pham: Employee; Anthem, Inc. J.J.Barron: None. R.A.Hart: None. J.Abarca: None. A.Devries: None.
223-OR: ADA Presidents' Select Abstract: Novel Ligand and Kinase-Independent Signaling by the Insulin Receptor
Authors: NAGAO HIROFUMI , CAI WEIKANG , PAN HUI , BATISTA THIAGO M. , BRANDAO BRUNA , KAHN C. RONALD 
Published: May 2022

Insulin acts through the insulin receptor (IR) tyrosine kinase and two major canonical post-receptor signaling pathways (the IRS-1/PI3K/Akt pathway and the Shc/Ras/MAP kinase pathway) to exert its classic metabolic and mitogenic actions. To create a detailed map of how different domains of the receptor might be linked to different insulin actions, we created cells in which endogenous IR and IGF1R had been genetically inactivated, after which the cells were reconstituted with either the wild-type IR, a kinase-dead mutant of IR (K1030R-IR) , a truncated IR lacking just the C-terminus of IR (∆CT-IR) and a truncated IR with the juxtamembrane domain only inside the cell (JMO-IR) . Using these cells and a multi-omics approach, we have uncovered a second novel IR signaling pathway that is dependent on the intracellular domain of IR but is ligand and tyrosinekinase-independent (LYK-I for short) . We find that the LYK-I actions of the IR are mediated by changes in a phosphorylation of a network of proteins involved in cell cycle/mitosis, ATM signaling, extracellular matrix organization, and cellular senescence. These actions result in upregulation of expression of multiple extracellular matrix-related genes and proteins, and down-regulation of immune/interferon-related and cellular senescence related genes and proteins. Functionally, LYK-I signaling results in increased cell proliferation and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent signaling, the IR regulates a second, novel ligand and tyrosine kinase-independent (LYK-I) pathway which regulates the cellular machinery involved in cellular senescence, extracellular matrix interaction and apoptotic sensitivity.

Disclosure
H.Nagao: None. W.Cai: None. H.Pan: n/a. T.M.Batista: None. B.Brandao: n/a. C.Kahn: Advisory Panel; Kaleido, Consultant; Cellarity, Flagship Pioneering, Sana Biotechnology Inc.
227-LB: Elevated Plasma Lactate and the Risk for Metabolic Syndrome—Is Skeletal Muscle a Producer or Consumer?
Authors: BROSKEY NICHOLAS T. , JONES TERRY E. , TANNER CHUCK J. , ZHENG DONGHAI , JEVTOVIC FILIP , KRASSOVSKAIA POLINA , MATARESE LAURA E. , CORTRIGHT RONALD N. , HICKNER ROBERT , DEMARIA ERIC J. , PORIES WALTER J. , HOUMARD JOSEPH A. , DOHM LYNIS 
Published: May 2022

Background: The incidence of metabolic diseases is rising and there is a dire need for early detection to implement prevention. Fasting plasma lactate concentrations have been shown to be elevated in individuals with obesity and predictive of type 2 diabetes. An elevated fasting lactate concentration could possibly be the product of a reduction in muscle oxidative capacity and increased muscle lactate output. However, it is unknown how early this is evident, as are the mechanisms involved. Aim: The aim of this study was to determine if fasting lactate concentrations were linked with a reduction in skeletal muscle oxidative capacity in a cohort without metabolic disease.
Methods: Young (age 28 ± 7; N=21) overweight (BMI (27.1 ± 0.4 kg/m2) men (n=12) and women (n=9) were recruited for this study. Blood biomarkers were measured in the fasted state and body composition was determined by DXA. Muscle oxidative capacity was measured in skeletal muscle homogenates (vastus lateralis biopsy) using 14C-labeled labeled palmitate and pyruvate. Muscle lactate output was determined by microdialysis during a hyperinsulinemic euglycemic clamp procedure.
Results: Elevated lactate was associated with elevated visceral adiposity (R2=.40, p=.003) , elevated triglycerides (R2=.56, p=.0001) , as well as elevations in systolic blood pressure (R2=.39, p=.003) . Subjects with higher lactate had lower ratio of fatty acid oxidation to pyruvate oxidation (ratio R2=.49, p=.002) . Muscle lactate uptake in the basal state of the clamp positively associated with plasma lactate (R2=.92, p=&lt;.0001) ; however, in the insulin phase net lactate output was near zero.
Conclusion: Individuals who are overweight but otherwise healthy have elevated plasma lactate that associates with parameters of the metabolic syndrome. Lactate was associated with a shift from lipid to carbohydrate oxidation. Muscle is a consumer of lactate in the fasted state, whereas adipose tissue may be the source of production postprandially.

Disclosure
N. T. Broskey: None. E. J. Demaria: None. W. J. Pories: None. J. A. Houmard: None. L. Dohm: None. T. E. Jones: None. C. J. Tanner: None. D. Zheng: None. F. Jevtovic: None. P. Krassovskaia: None. L. E. Matarese: None. R. N. Cortright: None. R. Hickner: None.

Funding
NIH (R01DK120296)
23-OR: Loss of the Transcription Factor Tcf21 in Adult Podocytes Leads to Susceptibility in Diabetic Kidney Disease
Authors: TERAMOTO NAOYA , MAEZAWA YOSHIRO , MINAMIZUKA TAKUYA , KOSHIZAKA MASAYA , YOKOTE KOUTARO 
Published: May 2022

Background: Diabetic kidney disease (DKD) is the most common cause of dialysis induction in the United States. Tcf21 is a basic helix-loop-helix transcription factor that is essential for the development of the lungs, heart, and kidneys. Previously, we reported that Tcf21 regulates podocyte development. However, the precise role of Tcf21 in mature individuals and DKD remains unclear.
Method: We generated mice that lacked Tcf21 only in podocytes after birth (iKO) using a doxycycline induction system. We also constructed a diabetes mouse model using streptozotocin injections. In addition, we used cultured human podocytes to investigate the effects of Tcf21 overexpression and the factors that regulate Tcf21 expression.
Results: When the Tcf21 gene was deleted specifically in podocytes in 3-week-old mice, urinary protein was not observed. In contrast, when diabetes was induced in these mice, massive urinary protein and strong glomerulosclerosis was present in 60% of iKO mice. Ultrastructural analysis revealed glomerular basement membrane thickening and podocyte foot process effacement, suggesting that iKO mice are susceptible to DKD. In addition, RNA-seq analysis of Tcf21-overexpressing podocytes showed accumulation of genes involved in the interferon pathway, extracellular matrix production, senescence, and autophagy in gene ontology analysis. Analysis of individual genes showed upregulation of interferon-related genes such as IFI6 and IFI27, increased expression of PAI-1, which is one of the senescence-associated secreted phenotypes, and decreased expression of HMGA2, whose SNIP is known to correlate with susceptibility to DKD. In addition, Tcf21 expression was suppressed by 58% and 27% after TGF-β and high glucose plus insulin stimulation, respectively.
Conclusion: Our results suggest that Tcf21 protects against DKD in mature individuals. Elucidation of the mechanism by which Tcf21 prevents DKD may lead to the identification of novel therapeutic targets.

Disclosure
N.Teramoto: None. Y.Maezawa: None. T.Minamizuka: None. M.Koshizaka: None. K.Yokote: None.
230-LB: Amino Acid–Induced Glucagon Secretion and Glucagon Enhancement of Amino Acid Catabolism Is Independent of Glucose
Authors: MARUSZCZAK KATHARINA , RASMUSSEN CHRISTINE , CEUTZ FREDERIK R. , ØRGAARD ANNE , CHRISTENSEN EMILIE E. , RICHTER MICHAEL M. , HOLST JENS J. , WINTHER-SOERENSEN MARIE , WEWER ALBRECHTSEN NICOLAI J. 
Published: May 2022

Amino acids (aa) stimulate the secretion of glucagon (gcg) and gcg receptor signaling controls aa catabolism, constituting the liver-alpha cell axis. Impairment of the liver-alpha cell axis is observed in diabetes, but how glucose (glc) levels affect this axis is unknown. We investigated the role of glc on the liver-alpha cell axis by 1) isolated perfused pancreas, 2) isolated perfused liver, and 3) a randomized in-vivo study in male mice. The isolated perfused pancreas was used to evaluate the direct effect of low (3.5mM) and high (15mM) glc levels, respectively on aa (10mM arginine) -induced gcg secretion. High glc levels significantly lowered basal gcg secretion, but aa-induced gcg responses were comparable to those at low glc levels (p=0.38) . The direct effect of glc on gcg induced ureagenesis was assessed by isolated single pass perfused liver stimulated with 10mM mixture of 18 aa + 10nM gcg for two periods of 15 min with glc infused at either 1 or 18 mmol/L. The order of glc addition was randomized. Aa and gcg significantly increased urea production compared to baseline, and this was independent of low or high glc levels (p=0.95) . Whole-body effects of glc on the liver-alpha cell axis were assessed in-vivo including four groups receiving an intraperitoneal injection of either Glc-Saline (2 g/kg, Glc/S, n=8) , Glc-Aa (2 g/kg, + 14 g/l, respectively Glc/Aa, n=10) , Saline-Aa (S/Aa, n=10) and saline-saline (volume-matched, S/S, n=10) . Blood samples were obtained at 0,2,4,10 and 20 minutes and levels of glc, gcg, insulin (ins) , and aa were measured. Glc levels did not differ significantly between Glc/S and Glc/Aa groups, but ins and gcg were significantly higher in the G/Aa group. The gcg:ins ratio did not differ between groups. Plasma levels of gcg and aa were not significantly different between the G/Aa and S/Aa groups (p=0.28) . These results suggest that aa overrule the inhibitory effect of glc on gcg secretion and the actions of glucagon on aa catabolism may be independent of glc in mice.

Disclosure
K. Maruszczak: None. C. Rasmussen: None. F. R. Ceutz: None. A. Ørgaard: Employee; Novo Nordisk A/S. E. E. Christensen: None. M. M. Richter: None. J. J. Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M. Winther-soerensen: None. N. J. Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Merck & Co., Inc., Mercodia AB.

Funding
NNF Excellence Emerging Investigator Grant ? Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and Independent Research Fund Denmark Sapere Aude Program (1052-00003B) .
235-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Exerts Potent and Sustained Body Weight Loss in Rodent Obesity Models
Authors: LIM SEYOUNG , KIM DO-HOON , YANG JIEUN , KYEONG JU MI , KIM SUKYUNG , RA SIM BO , KIM JUNHWAN , OH SE-WOONG 
Published: May 2022

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with a unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an engineered GDF15 variant-Fc fusion protein to have extended half-life and potent functional activity by enhancing binding affinity to GDF15 receptors (GFRAL/RET) . Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in humans. In efficacy studies using obese mouse models, YH34160 demonstrated a potent and sustained weight-lowering effect. After a single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight (BW) reduction compared to long-acting glucagon like peptide-1 receptor agonist (GLP-1RA) . Following a 6-week multiple-dose study in DIO mice, YH34160-treated groups exhibited a greater and more prolonged BW loss compared to the group of GLP-1RA. Marked BW reduction and improved lipid profile by YH34160 were also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. In addition, YH34160 caused significantly better anti-obesity effects, and a much more improved metabolic profile than that of albumin-GDF15, and dual GLP-1/Glucagon receptor agonist. Interestingly, YH34160 in combination with GLP-1RA or dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) achieved more potent and greater BW loss compared to each mono-treated group. Overall, these findings indicate that YH34160 would be a promising therapeutic candidate, as well as in combination with GLP-1-based therapeutics, for the treatment of obesity and obesity-related comorbidities.

Disclosure
S. Lim: None. D. Kim: None. J. Yang: None. M. Ju: None. S. Kim: None. B. Sim: None. J. Kim: None. S. Oh: Employee; Yuhan, Stock/Shareholder; Yuhan.
237-OR: Platelet-Derived Protein Responses Differ According to Severity of Hypoglycemia
Authors: MOIN ABU , KAHAL HASSAN , AL-QAISSI AHMED , SATHYAPALAN THOZHUKAT , ATKIN STEPHEN , BUTLER ALEXANDRA E. 
Published: May 2022

Introduction: Severe hypoglycemia is associated with an increased risk of cardiovascular (CV) death, and platelet responses to hypoglycemia (hypo) have been described. The impact of a transient severe hypo versus prolonged less severe hypo is unclear.
Methods: 2 hypo studies were compared; firstly, in 18 subjects (type 2 diabetes (T2D) : 8 controls) blood glucose lowered to 3.5mmoL/L (90mg/dL) for 1-hour; secondly, in 46 subjects (23 T2D: 23 controls) blood glucose lowered to &lt;2.2mmoL/L (&lt;40mg/dL) transiently. The platelet-related protein (PRP) responses from baseline to after 1-hour of hypo (study-1) or at severe transient hypo (study-2) were compared, and at 24-hours post-hypo. Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement was used to determine platelet-related protein changes for 13 proteins.
Results: In T2D, from baseline to hypo, differences were seen for 4 PRPs, three showing increased percent change in study-2 (plasminogen activator inhibitor-1 (PAI-1) , platelet glycoprotein VI (PGVI) and Tissue factor) , one showing increased percent change in study-1 (CD40 ligand (CD40LG)) ; at 24-hours in T2D, percent change for CD40LG remained increased, together with von Willebrand factor (vWF) , in study-2. In controls, from baseline to hypo, differences were seen for four PRPs, three showing increased percent change in study-2 (PAI-1, CD40LG and Protein S) , one showing increased percent change in study-1 (vWF) ; at 24-hours in controls, percent change for Protein S remained increased in study-2, whilst percent change for vWF and plasminogen were increased in study-1.
Conclusion: Thrombogenic potential was enhanced in T2D versus controls, as evidenced by an increased thrombogenic protein expression profile in both mild and severe hypoglycemia, that showed persistent changes at 24-hours in severe hypo.

Disclosure
A. Moin: None. H. Kahal: None.