bluuebunny/crossref_metadata_2025 huggingface dataset:
1692-P: Ablation of Endothelial ROCK2 Promotes Fat Browning and Improves Metabolic Dysfunction
Authors: TAKEDA YUSUKE , MATOBA KEIICHIRO , KAWANAMI DAIJI , NAGAI YOSUKE , KANAZAWA YASUSHI , NISHIMURA RIMEI
Published: June 2020

Intraperitoneal fat is considered a particularly important risk factor for impaired glucose tolerance, dyslipidemia, and coronary heart diseases. However, the underlying mechanisms in obesity are not fully understood. The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and expression of genes. Recent studies have shown that Rho/ROCK signaling is strongly related to diabetic vascular complications. ROCK has two isoforms, ROCK1 and ROCK2. Systemic gene deletion studies in mice suggest that these isoforms have distinctive roles in regulating cellular function. In this study, we investigated specific roles of endothelial ROCK2 in the progression of obesity. We mated ROCK2 floxed mice with VE-cadherin-cre mice to generate endothelial-ROCK2 knockout mice (ER2KO). ER2KO mice are resistant to weight gain and glucose intolerance induced by high fat diet. White adipose tissue (WAT) weight was lower in ER2KO mice compared with wild type mice. Histological analysis revealed that adipose droplets were smaller in ER2KO than wild type mice. Browning, the conversion of WAT to a beige phenotype, activates thermogenic function, suppresses obesity and improves glucose and lipid metabolism. Interestingly, we observed an increase of mRNA expression of browning marker including PPARα, CIDEA, PRDM16, UCP1, and specific markers of M2 macrophages in WAT of ER2KO mice regardless of whether they had been fed a normal chow or high fat diet. Collectively, the present study suggests that endothelial ROCK2 regulates glucose and lipid metabolism by suppressing browning of WAT. ROCK2 could be an important therapeutic target against obesity.

Disclosure

Y. Takeda: None. K. Matoba: Research Support; Self; Sanofi K.K., Takeda Pharmaceutical Company Limited. D. Kawanami: None. Y. Nagai: None. Y. Kanazawa: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.
1694-P: Beta-Arrestin 1 Suppresses Myogenic Reprogramming of Brown Fat to Maintain Euglycemia
Authors: PYDI SAI PRASAD , JAIN SHANU , BARELLA LUIZ F. , MEISTER JAROSLAWNA , WANG LEI , CUI YINGHONG , GAVRILOVA OKSANA , WESS JÜRGEN
Published: June 2020

Background: Adipocyte dysfunction links obesity to type 2 diabetes (T2D). To develop novel antidiabetic drugs, it is essential to delineate the signaling pathways that regulate adipocyte function under physiological and pathophysiological conditions. Recent studies have shown that β-arrestin-1 and -2 (barr1 and barr2, respectively), two intracellular signaling proteins known for their ability to modulate signaling via G protein-coupled receptors (GPCRs), regulate many important metabolic functions, sometimes even in a GPCR-independent fashion.

Objective: To understand the role of barr1 in adipocyte function, obesity, and whole body glucose and energy homeostasis.

Methods: To assess the role of barr1 in regulating adipocyte function, we used Cre-lox technology to generate mutant mice that lacked barr1 selectively in adipocytes(adipo-barr1-KO). These mutant mice, together with their control littermates, were subjected to a series of metabolic tests. Moreover, we used various molecular and biochemical techniques to probe the molecular mechanism through which barr1 modulates adipocyte function.

Results: We found that adipo-barr1-KO mice showed greatly impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet. In contrast, transgenic mice that overexpressed barr1 in adipocytes were protected against the metabolic deficits caused by a high-calorie diet. At the cellular level, barr1 deficiency led to a myogenic re-programming of brown adipose tissue (BAT), causing elevated plasma myostatin levels, which in turn led to impaired insulin signaling in peripheral tissues. Additional in vivo studies indicated that barr1-mediated suppression of myostatin expression by BAT is required for maintaining euglycemia.

Conclusion: Our data suggest that strategies aimed at enhancing barr1 expression or activity in BAT may prove beneficial for the treatment of T2D.

Disclosure

S. Pydi: None. S. Jain: None. L.F. Barella: None. J. Meister: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
1698-P: Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation and Hepatic Insulin Resistance
Authors: DEDUAL MARA A. , WUEEST STEPHAN , CHALLA TENAEGENE DELESSA , LUCCHINI FABRIZIO , AEPPLI TIM , BORSIGOVA MARCELA , MAURACHER ANDREA A. , VAVASSORI STEFANO , SCHMID JANA PACHLOPNIK , BLÜHER MATTHIAS , KONRAD DANIEL
Published: June 2020

Removal of one kidney (uninephrectomy; UniNx) in mice reduced high fat-diet (HFD)-induced adipose tissue inflammation thereby improving adipose tissue and hepatic insulin sensitivity. Such finding was accompanied by increased circulating cystatin C levels in UniNx compared to sham-operated mice. Importantly, cystatin C may have anti-inflammatory properties, and circulating cystatin C levels were reported to positively correlate with obesity as well as type 2 diabetes. However, the causal relationship of such correlation remains unclear. Herein, HFD feeding of cystatin C-deficient (CysC KO) mice aggravated obesity-associated adipose tissue dysfunction and inflammation, as reflected by an accumulation of pro-inflammatory monocytes and elevated expression of pro-inflammatory mediators. Moreover, markers of adipocyte differentiation were decreased. Similarly to findings in adipose tissue, expression of pro-inflammatory cytokines was increased in liver and skeletal muscle of HFD-fed CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in knockout mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide (LPS)-induced adipose tissue inflammation. In people with obesity, circulating cystatin C levels correlated negatively with mRNA expression of pro-inflammatory cytokines such as Hif1α as well as IL-6. Moreover, healthy (i.e., insulin-sensitive) subjects with obesity depicted significantly higher mRNA expression of cystatin C in subcutaneous white adipose tissue.

In conclusion, cystatin C is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism.

Disclosure

M.A. Dedual: None. S. Wueest: None. T. Challa: None. F. Lucchini: None. T. Aeppli: None. M. Borsigova: None. A.A. Mauracher: None. S. Vavassori: None. J. Pachlopnik Schmid: Advisory Panel; Self; Novartis AG, Swedish Orphan Biovitrum. M. Blüher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Amgen, Novartis AG. D. Konrad: Research Support; Self; Novo Nordisk A/S.

Funding

Children’s Research Centre; University Children’s Hospital Zurich; University of Zurich (FK-18-027); Swiss National Science Foundation (310030-160129, 10030-179344); Wolfermann-Nägeli Foundation
1709-P: Increased Adiponectin Levels Are Associated with Impaired Brown Adipose Tissue in Mice
Authors: CHANCLON BELEN , BAUZA-THORBRUGGE MARCO , BENRICK ANNA , WERNSTEDT-ASTERHOLM INGRID
Published: June 2020

Brown adipose tissue (BAT) thermogenesis affects energy expenditure, as well as glucose and lipid clearance. Thus, making BAT an attractive target in obesity/type-2 diabetes. Adiponectin (Apn) regulates whole-body metabolism and lowered Apn levels are associated with obesity and increased type-2 diabetes risk. Apn has been suggested to be required for maintaining normal body temperature in cold environment, but the role of Apn in BAT functionality is not clear. Here, we have studied BAT in adiponectin overexpressing (Apn-Tg) mice. During unchallenged chow-diet conditions, BAT of Apn-Tg mice was enlarged, fibrotic and more whitish. This phenotype was, as judged by tracer experiments, associated with lower lipid and glucose uptake, decreased de novo lipogenesis and decreased fatty acid oxidation in BAT. High-fat diet (HFD)-induced obesity increased these differences between genotypes. The BAT mRNA expression of thermogenesis markers such as UCP-1 and DIO-2 were down-regulated in BAT of obese, but not lean, Apn-Tg mice. Moreover, Seahorse-based analysis revealed reduced mitochondrial function in Apn-Tg BAT in ex vivo-differentiated brown adipocytes. To test whether increased Apn levels affect cold-induced BAT activation, we exposed Apn-tg and littermate control mice to cold temperature (6°C) for four weeks. Under this setting, the BAT lipid and glucose uptake, and body temperature were similar between genotypes. Accordingly, UCP-1 and DIO-2 mRNA levels were not different between Apn-Tg and WT mice, and highly induced by chronic cold exposure. Nevertheless, Seahorse data from isolated BAT mitochondria from cold-exposed animals still indicate mitochondrial dysfunction in Apn-Tg mice. Thus, our data suggest that increased adiponectin levels are associated with metabolic dysfunction in BAT. We propose that the increased BAT expansion in Apn-Tg mice occurs at the expense of the mitochondrial function.

Disclosure

B. Chanclon: None. M. Bauza-Thorbrugge: None. A. Benrick: None. I. Wernstedt-Asterholm: None.
171-OR: Preventing Diabetes: Resource Allocation between Risk-Based and Whole Population–Based Approaches
Authors: NEUWAHL SIMON , HOERGER THOMAS J. , LAXY MICHAEL , SHAO HUI , ALBRIGHT ANN L. , ZHANG PING
Published: June 2020

The national diabetes prevention goal set by CDC is to reduce new type 2 diabetes cases from 1.4 million in 2018 to 1.1 million in 2025 (a 21% reduction). Policymakers often debate the merits of interventions that focus on high-risk individuals vs. whole population-based interventions that benefit a broader spectrum of the population.

To resolve this debate, we use a simulation modeling approach to optimize resource allocation among a risk-based intervention (the lifestyle change intervention specified in the National Diabetes Prevention Program [National DPP]) and three whole-population interventions (e.g., sugar sweetened beverage taxes, worksite health promotion, and bike lanes or walking paths). We use the simulation model to estimate the cost and number of diabetes cases prevented by combinations of risk-based and whole population-based interventions. We then plot the prevention frontier as the least-cost combination of interventions for each prevention target. The optimal allocation of resources across interventions can be selected by choosing a prevention target or specifying the available prevention budget.

We find that neither the National DPP alone nor three whole population-based interventions combined are likely to meet the 2025 goal for type 2 diabetes prevention (Figure). Instead, a combination of the National DPP and whole population-based interventions will be needed.

Disclosure

S. Neuwahl: None. T.J. Hoerger: Research Support; Self; Centers for Disease Control and Prevention, Centers for Medicare and Medicaid Services. M. Laxy: None. H. Shao: None. A.L. Albright: None. P. Zhang: None.

Funding

Centers for Disease Control and Prevention
1719-P: Novel Mass Spectrometry–Based Selected Reaction Monitoring Proteomics for Analysis of Low Abundant Insulin Levels in Cerebrospinal Fluid
Authors: LIU QING-RONG , ZHU MIN , CHIA CHEE W. , O’CONNELL JENNIFER F. , ZHANG PINGBO , EGAN JOSEPHINE M.
Published: June 2020

Circulating insulin levels are routinely measured using Enzyme-linked Immunosorbent Assay (ELISA). However, ELISA is not sensitive enough to measure cerebrospinal fluid (CSF) insulin levels which are 10-100 times lower than those of plasma: yet ELISA results are often reported for insulin analysis in CSF where it serves as a surrogate for brain interstitial fluid insulin levels. We developed a novel LC-MS/MS based selected reaction monitoring (SRM) proteomics assay for quantitative analyses targeting predetermined peptides derived from trypsin digests of insulin; each peptide depends on specific SRM transitions. We determined insulin levels using our novel insulin SRM proteomics method in the matching plasma and CSF samples that were from individuals fasting ≥12 hours and individuals after 2 hours of steady state hyperglycemia by clamp technology (2 hr SS HG). All samples were obtained in individuals with normal fasting glucose and HbA1C levels. Statistically significant differences were observed in both plasma and CSF between fasting and 2 hr SS HG by two tailed and unpaired student t test and 2-way matched ANOVA as shown in Table below. Our results confirmed that peripheral endogenous insulin appears in CSF at least 2 hours after steady state hyperglycemia in subjects with normal glucose tolerance. Our SRM insulin tryptic peptide panel reliably quantified insulin peptide levels in human CSF samples.

Disclosure

Q. Liu: None. M. Zhu: None. C.W. Chia: None. J.F. O’Connell: None. P. Zhang: None. J.M. Egan: None.

Funding

National Institute on Aging
172-LB: Risk of Major Congenital Malformations, Perinatal or Neonatal Death with Insulin Detemir Compared with Other Basal Insulins in Pregnant Women with Preexisting Diabetes: The EVOLVE Study
Authors: MATHIESEN ELISABETH R. , ALIBEGOVIC AMRA CIRIC , HUSEMOEN LISE LOTTE N. , KELKAR PRANAV , MCCANCE DAVID R. , DE VALK HAROLD W. , DAMM PETER ,   ON BEHALF OF THE EVOLVE STUDY GROUP
Published: June 2020

Aim: The EVOLVE study examined the risk of major congenital malformations and perinatal or neonatal deaths when using insulin detemir (IDet) versus other basal insulins in pregnant women with pre-existing diabetes.

Materials and Methods: A prospective, non-interventional, multinational study in pregnant women with type 1 or type 2 diabetes treated with IDet or other insulin treatment. In the present analysis, 727 women using IDet during pregnancy were compared with 730 women using other basal insulin, mainly insulin glargine. The primary endpoint was the number of women completing ≥22 weeks of gestation without any of the following events: major congenital malformations, perinatal or neonatal deaths.

Results: At enrolment 86% of subjects had type 1 diabetes (mean age: 31 years; BMI: 26 kg/m2) and mean A1C was 7.1%. There was no difference between treatment groups in crude or adjusted risk difference for pregnancies without major congenital malformations, perinatal or neonatal deaths (Table).

Conclusion: In pregnant women with pre-existing diabetes, IDet was not associated with excess risk of major congenital malformations, perinatal or neonatal deaths vs. other basal insulin.

Disclosure

E.R. Mathiesen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis. A. Alibegovic: Employee; Self; Novo Nordisk A/S. L.N. Husemoen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Kelkar: Employee; Self; Novo Nordisk Service Centre India Private Ltd. D.R. McCance: None. H.W. de Valk: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S.

Funding

Novo Nordisk A/S
172-OR: Diabetes Care Management (DCM) Under Total Cost of Care (TCOC) Budgeting: Insights from a Medicaid Cohort
Authors: MONTERO ALEX R. , BETLEY CHARLES , BROWN JASON R. , DELIA DEREK M. , FRANCIS NNENIA , SPICER LAURA , MAGEE MICHELLE F.
Published: June 2020

Background: DCM interventions improve glycemic control and readmission. Cost effectiveness studies typically use only system EHR data. We implemented a 3-month technology-enabled DCM intervention (Diabetes Boot Camp (DBC)) for adults with uncontrolled T2DM in a regional health system. Using EHR data, DBC was shown to reduce A1C and hospitalizations compared to matched controls. The aim of this study was a TCOC assessment of DBC among Medicaid participants using claims data.

Methods: Medicaid-enrolled DBC completers and controls were linked to Maryland’s Medicaid Management Information System. The impact of DBC on different components of spending and TCOC at 90 days was evaluated.

Results: Among the 47 cases and 60 controls, average age was 52; 72.9% were Black; and 67.3% were female. DBC was associated with a per person reduction of $197 in ED/inpatient spending but an increase of $1,471 in TCOC, driven primarily by greater pharmacy spending and outpatient visits. Increased pharmacy spending was driven by spending on insulins and newer medication classes (Table 1).

Conclusions: In a TCOC analysis of DBC, estimated savings from reduced hospital use were more than offset by pharmacy and professional service spending. Pharmacy spending change is likely due to improved adherence/regimen intensification. To promote sustainable TCOC payment models for DCM, consideration of medication effects is needed.

Disclosure

A.R. Montero: None. C. Betley: None. J.R. Brown: Employee; Spouse/Partner; LabCorp. D.M. Delia: None. N. Francis: None. L. Spicer: None. M.F. Magee: Consultant; Self; Mytonomy. Employee; Spouse/Partner; U.S. Food and Drug Administration. Research Support; Self; AstraZeneca, Eli Lilly and Company, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; American Diabetes Association, Pri-Med LLC. Other Relationship; Self; Endocrine Society.
1720-P: The Modulation in Glucose Metabolism by B1 Kinin Receptor Does Not Depend in Hepatic Insulin Signaling
Authors: CORREIA POLIANA ESPÍNDOLA , GOMES CLARISSA B. , MERELLO PAULA N. , NATIVIDADE GABRIELLA R. , BARROS CARLOS C. , GERCHMAN FERNANDO
Published: June 2020

Background: The kinin B1 receptor (B1R), an inducible effector of Kallikrein-Kinin System during inflammation, has been blamed also to influence glucose metabolism and leptin sensitivity.

Aim: To investigate the effects of cafeteria diet (CAF) on hepatic glucose metabolism in B1R knockout mice (B1RKO).

Methods: Two months old male C57Bl/6 wild type and B1RKO mice were fed with standard chow (SC) or CAF ad libitumfor 14 weeks (WT-SC n=7; B1RKO-SC n=8; WT-CAF n=7; B1RKO-CAF n =10). We performed glucose tolerance test (GTT) and insulin tolerance test (ITT) at the last week before organs collection. HOMA IR index was calculated. Quantitative PCR was used to determine hepatic expression of glucose-6-phospatase (G6Pase), glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase (FBPase1) and hepatocyte nuclear factor 4 alpha (HNF4A). We also performed western blot to analyze AKT phosphorylation in liver. Two-way ANOVA was used to analyze differences between groups. Values were expressed as mean ± SEM and p ≤0.05 was considered statistically significant.

Results: Although the increment of glucose area under the curve during GTT was lower in B1RKO-CAF than WT-CAF (WT-SC 46.246 ± 4.302 vs. B1RKO-SC 35.699 ± 3.383; p=0.03; and B1RKO-CAF 28.521 ± 5.338 vs. WT-CAF 56.564 ± 3.477; AUC p=0.0001), B1RKO mice presented a similar decay in glucose levels during ITT as well as HOMA-IR values . While there was a decrease in liver mRNA expression of G6Pase and PEPCK, GK expression increased in mice fed with CAF diet, without differences between genotypes. FBPase1 and HNF4A mRNA expression were not different between groups. Liver AKT phosphorylation increased with CAF in both C57Bl/6 wild type and B1RKO mice.

Conclusion: The increased glucose uptake of B1RKO mice during GTT might not be related to insulin signaling in the liver, since no changes were observed in insulin resistance or in the hepatic expression of gluconeogenesis regulatory enzymes.

Disclosure

P. Espíndola Correia: None. C.B. Gomes: None. P.N. Merello: None. G.R. Natividade: None. C.C. Barros: None. F. Gerchman: None.

Funding

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (16-0397)
1722-P: Loss of Foxos in Muscle Maintains Strength and Mitochondrial Function during Aging, but Does Not Alter Glucose or Insulin Tolerance
Authors: PENNIMAN CHRISTIE M. , BHARDWAJ GOURAV , JUNCK TAYLOR , BOYER CIERRA , JENA JAYASHREE , FUQUA JORDAN , LIRA VITOR A. , ONEILL BRIAN T.
Published: June 2020

Muscle mitochondrial decline plays an important role in aging-related muscle weakness and is associated with insulin resistance. FoxO transcription factors are targets in insulin action and are determinants of longevity across species. However, the role of FoxOs in age-related strength and muscle mitochondrial decline is unknown. We measured strength, glucose/insulin tolerance, and muscle mitochondrial bioenergetics in 4.5- month (Young) and 24-month-old (Aged) muscle specific FoxO1/3/4 triple KO (TKO) and littermate control mice. Lean mass and muscle weights were increased 22-48% in young and aged TKO mice compared to age-matched controls. Ad libitum glucose levels were ∼12 mg/dL higher in aged groups compared to young, without differences between TKO and controls. Similarly, glucose and insulin tolerance were unchanged between TKO and control mice in both young and aged groups. While treadmill tests were not different between TKO and controls at either age, the aged control mice show a 20% decrease in max force of ankle dorsi-flexor muscles compared to young controls which was prevented in aged TKOs. Reductions in muscle mitochondrial respiration using glutamate/malate/succinate substrates were also prevented in aged TKO mice compared to aged controls. Mitochondrial Complex I activity was higher in both young and aged TKO compared to their respective controls. We did not see any differences in activity of citrate synthase, and protein expression of subunits from complex I and III, but not other complexes, showed an age-related decline in both TKO and control muscle. These data indicate that loss of FoxOs in muscle prevents age-related mitochondrial dysfunction and muscle weakness, without altering glucose or insulin tolerance, and may be a therapeutic target to prevent muscle atrophy.

Disclosure

C.M. Penniman: None. G. Bhardwaj: None. T. Junck: None. C. Boyer: None. J. Jena: None. J. Fuqua: None. V.A. Lira: None. B.T. ONeill: None.
1723-P: Transcription Factor Foxo1 Mediates TGF-ß1-Induced Apoptosis in Primary Hepatocytes
Authors: AI WEIQI , LIAO WANG , PAN QUAN , YANG WANBAO , SHEN ZHENG , GUO SHAODONG , CHEN YUNMEI
Published: June 2020

Dysregulation of hepatocyte apoptosis or failure is associated with several types of chronic liver diseases. Transforming growth factor β1 (TGF- β1) is a well-known pro-apoptotic factor in the liver, which is constituted by a receptor complex composed of TGFβ receptor type I (TβRI) and TβRII, along with transcriptional factors Smad proteins. As a member of the forkhead box O-class transcription factors, Foxo1 is a predominant regulator for hepatic glucose production. While the role of Foxo1 in functions beyond glucose metabolism is gradually recognized, since there has been increasing evidence showing the potential relationship between TGF-β1 signaling and Foxo1. Here, we investigated whether Foxo1 mediates the pro-apoptotic effect of TGF-β1 in primary hepatocytes. By using hepatocytes isolated from both of wild type (Foxo1fl/fl) and liver specific Foxo1 knockout (LFKO, albumin-Cre+/-:: Foxo1fl/fl) mice, it was found that TGF-β1 induces hepatocytes apoptosis in a Foxo1-dependent manner. We also explored the associated molecular mechanisms and demonstrated that TGF-β1 activates protein kinase A (PKA) through TβRI-Smad3, followed by phosphorylation of Foxo1 at Ser273 to promote apoptosis of hepatocytes. The significant role of pFoxo1-S273 in mediating the pro-apoptotic effect of TGF-β1 was validated by using hepatocytes isolated from Foxo1-S273A mice, which mimics the dephosphorylation of Foxo1-Ser273. The establishment of TGF-β1-PKA-Foxo1axis in this study reveals a novel role of Foxo1 in hepatic functions.

Disclosure

W. Ai: None. W. Liao: None. Q. Pan: None. W. Yang: None. Z. Shen: None. S. Guo: None. Y. Chen: None.

Funding

American Diabetes Association (1-15-CD-09 to S.G., Sr.); National Institutes of Health (R01DK095118, R56DK11833401)
1743-P: Metabolic Characteristics of Diabetes among Low-BMI Individuals in India
Authors: YIMAGOU ERIC LONTCHI , GUPTA RIDDHI DAS , ANOOP SHAJITH , KEHLENBRINK SYLVIA , MOY JOY , MANAVALAN ANJALI , MATHIAS PRIYANKA M. , GOYAL AKANKASHA , CAREY MICHELLE , STEIN DANIEL T. , THOMAS NIHAL , HAWKINS MEREDITH
Published: June 2020

Diabetes among low BMI individuals has been recognized globally for over 60 years, and classified by WHO as malnutrition-related diabetes mellitus in 1985. Despite its prevalence in low and middle income countries, this condition has never been comprehensively studied.

State of the art metabolic studies were performed in 20 South Indian men with Low BMI Diabetes (LD; BMI 18.3 ± 0.9 kg/m2), after excluding monogenic and immune diabetes, and visible pancreatic pathology. Other groups were studied: T1D, T2D, and nondiabetic subjects (BMI-matched to LD and T2D). Insulin secretion was assessed by C-peptide deconvolution following a mixed-meal tolerance test. Peripheral and hepatic insulin sensitivity were analyzed using tracer-based (6,6-deuterated glucose), stepped hyperinsulinemic-euglycemic pancreatic clamps following correction of glucose toxicity.

LD subjects were distinct from both T1D and T2D. Insulin secretion was significantly lower in LD than in T2D subjects, yet higher than in T1D. LD subjects were more insulin sensitive than T2D; glucose uptake and endogenous glucose production did not differ from lean nondiabetic or T1D subjects.

These comprehensive studies are the first to demonstrate that LD individuals are characterized by markedly impaired insulin secretion yet preserved insulin sensitivity. Thus, diabetes in low BMI individuals is a distinct entity that warrants further investigation.

Disclosure

E. Lontchi Yimagou: None. R. Das Gupta: None. S. Anoop: None. S. Kehlenbrink: None. J. Moy: None. A. Manavalan: None. P.M. Mathias: None. A. Goyal: None. M. Carey: None. D.T. Stein: None. N. Thomas: None. M. Hawkins: None.

Funding

National Institutes of Health (R01DK069861)
1752-P: Discovery of Targets for Insulin Resistance by Microfluidic Organ-on-Chip Models
Authors: TANATAWEETHUM NIDA , TRANG ALLYSON , ANNEPUREDDY LAASYA , MEHTA JHALAK , COHEN RONALD N. , BHUSHAN ABHINAV
Published: June 2020

Metabolism of glucose and lipids is essential for nutrient balance and metabolic homeostasis, and is dynamically regulated by adipose tissue and liver. Dysfunction in regulation of these molecules as well as the secreted factors results in metabolic syndrome and insulin resistance (IR), which is a precursor to type 2 diabetes. Studies have shown that as the main site of adaptive thermogenesis, brown adipose tissue (BAT) improves hepatic insulin sensitivity, whereas white adipose tissue (WAT) can induce hepatic IR. However, how these organs communicate to regulate insulin sensitivity is not completely understood due to the lack of representative experimental models. Animals models are useful but suffer from confounding effects from other organs; traditional in vitro models have limited physiological representation.

We have developed an organ-on-chip platform to study the interactions between BAT/WAT and liver under different metabolic states. The adipose-liver organ-chip consists of two interconnected microfluidic devices - brown/white adipocytes were cultured in one device and hepatocytes (insulin sensitive and IR) in the other, both under perfusion. We show that (a) adipocytes exhibited higher intracellular lipid and fatty acid secretion and (b) the hepatocytes secreted higher albumin compared to traditional co-cultures. We found that brown adipocytes secretions restored insulin sensitivity, and improved glucose/lipid metabolism in IR hepatocytes. In contrast, white adipocytes worsened insulin sensitivity and glucose/lipid metabolism. IR hepatocytes lowered Akt-phosphorylation and glucose uptake while upregulated adipocyte fatty acids secretion. Through RNA-seq, we have identified adipose genes responsible for improving hepatic IR.

We have discovered potential new targets for improving hepatic insulin sensitivity. The novel organ-chip platform represented the cells physiologically and will be useful in the discovery and validation of new therapeutic targets for T2D.

Disclosure

N. Tanataweethum: None. A. Trang: None. L. Annepureddy: None. J. Mehta: None. R.N. Cohen: None. A. Bhushan: None.

Funding

DRTC (P30DK020595)
176-OR: The Impact of Chronic Kidney Disease on Commercial Payers in the U.S.
Authors: KAUF TERESA , WANG WEIYING , DILLON ALLISON , SINGH INDERJIT , ODEGARD JOHN T. , RINGEMANN CHRISTIAN , HALDRUP STEFFEN
Published: June 2020

Objectives: While a large proportion of chronic kidney disease (CKD) cost in the U.S. is borne by Medicare, most CKD patients have commercial coverage, either as primary insurance or as a Medicare supplement. This study examines the economic impact of CKD on commercial payers in the U.S.

Methods: A retrospective cohort study using IBM MarketScan® data from January 2010 - December 2018 was conducted. Patients with ≥2 outpatient (≥30 days apart) and/or ≥1 inpatient claims containing a diagnosis code for CKD were eligible for analysis. The earliest CKD diagnosis date served as the index date. Included patients were continuously enrolled for ≥6 months pre- and post-index. Annualized progression rates and direct medical costs per patient per year (PPPY) by CKD stage were analyzed for the overall CKD population and patients with pre-existing type 1 or type 2 diabetes.

Results: Of 753,097 CKD patients identified, 310,837 (41.3%) had diabetes. More CKD patients with pre-existing diabetes had hypertension (81.7% vs. 75.7% for overall CKD). Approximately 45% of patients in both cohorts were diagnosed at Stage 3. PPPY costs for Stages 1-5 were $19,970, $26,248, $32,687, $46,091, and $61,492, respectively. For CKD patients with pre-existing diabetes, PPPY costs were $21,028, $29,941, $37,835, $50,614, and $67,160 for Stages 1-5. The increase in Stage 5 cost over Stage 1 cost was 208% and 219% for CKD overall and CKD with pre-existing diabetes, respecitvely. Annualized CKD progression was higher for CKD patients with pre-existing diabetes compared to CKD patients overall (162 vs. 130 progressions per 1000 patients in a given year).

Conclusions: Annualized rates of CKD progression are high, with the burden of CKD increasing more than 2-fold from Stage 1 to Stage 5. Earlier identification and treatment management of CKD are needed to reduce the burden of disease.

Disclosure

T. Kauf: Consultant; Self; Roche Diabetes Care. W. Wang: Consultant; Self; Roche Diabetes Care. A. Dillon: Consultant; Self; Roche Diabetes Care. I. Singh: Employee; Self; Roche Diabetes Care. J.T. Odegard: None. C. Ringemann: Employee; Self; Roche Diabetes Care. S. Haldrup: Employee; Self; F. Hoffmann-La Roche Ltd.
1760-P: Brain Sh2b1 Protects against Obesity and Insulin Resistance through Multiple Hypothalamic Neural Circuits
Authors: LI YUAN , KIM MIN-HYUN , JIANG LIN , MYERS MARTIN G. , RUI LIANGYOU
Published: June 2020

Sh2b1 is a SH2 and PH domain-containing adaptor protein and enhances signal transduction in response to leptin, insulin, brain-derived neurotrophic factor (BDNF), and other ligands. Leptin, insulin and BDNF are known to activate the hypothalamic neural circuitry that controls energy balance, body weight, and metabolism. Genome-wide studies have identified numerous SH2B1 single nucleotide polymorphisms linked to human obesity and diabetes. SH2B1 nonsense and missense mutations have also been reported to be associated with obesity and type 2 diabetes in humans. We previously reported that global deletion of Sh2b1 results in hyperphagia, obesity, and type 2 diabetes in mice. Here, we attempted to identify Sh2b1 target cells, using conditional Sh2b1 knockout mice. We ablated Sh2b1 in the ventromedial hypothalamus (VMH) of Sh2b1flox/flox mice (Sh2b1ΔVMH) either by transducing the VMH with AAV-Cre vectors or using Sf1-Cre drivers. Both Sh2b1ΔVMH males and females, like global Sh2b1 knockout mice, developed obesity, insulin resistance, and liver steatosis. To further map Sh2b1 neurons, we generated leptin receptor (LepR) neuron-specific Sh2b1 knockout (Sh2b1ΔLepR) mice using LepR-Cre drivers. Sh2b1ΔLepR males and females also developed obesity, insulin resistance, glucose intolerance, and liver steatosis. Brown adipose tissue (BAT) thermogenic programs were severely impaired in Sh2b1ΔLepR mice, leading to decreased core body temperature and cold intolerance. Remarkably, Sh2b1 deficiency completely abrogated the ability of leptin to stimulate sympathetic nerves projecting to BAT in Sh2b1ΔLepR mice, indicating that Sh2b1 mediates leptin actions on sympathetic-controlled energy expenditure and metabolism. Collectively, our data suggest that hypothalamic Sh2b1 influences multiple neural circuits controlling food intake, energy expenditure, and metabolic processes by integrating leptin, insulin, BDNF, and/or other nutritional signals.

Disclosure

Y. Li: None. M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.
1763-P: Acarbose Protects from Central and Peripheral Metabolic Imbalance Induced by Exposure to Benzene
Authors: DEBARBA LUCAS KNIESS , MULKA ADAM , FAKHOURY PATRICK I. , DIDYUK OLESYA , AWADA ABEAR A. , LIMA JULIANA , KOSHKO LISA , KLUEH ULRIKE , SADAGURSKI MARIANNA
Published: June 2020

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Few epidemiological studies suggested an association between adverse health effects of benzene at low doses and the development of insulin resistance. Regardless, a detailed analysis of the metabolic effects of benzene exposure and its target tissues has rarely been done. We assessed the effects of chronic and acute exposure to benzene at 50 ppm in inhalation chambers in mice. We show that exposure to benzene for 4 weeks (5h/day), induced hyperglycemia and hyperinsulinemia, associated with impairment in gluconeogenesis and lipid metabolism in males. Females were completely resistant to the negative metabolic consequences of benzene exposure. Moreover, chronic benzene exposure promoted hypothalamic gliosis, ER stress, and elevation of inflammatory genes in male mice. In support, a global proteome profile has identified inflammatory and ER stress pathways in the hypothalamus of the benzene exposed animals suggesting their role in a benzene-induced metabolic imbalance. In support, benzene exposure triggered alterations in neuron-glia interactions by modulating neuronal sensing under hyperglycemic conditions within hypothalamic glucose-sensing VMH neurons. Mechanistically, acute benzene exposure activated hypothalamic ER stress and neuroinflammatory responses, while pharmacological inhibition of IRE1α-XBP1 pathway alleviated glial inflammatory cytokines production suggesting that this may be the primary mechanism by which benzene causes changes in metabolic status. A diabetes drug, Acarbose that extends animals’ life span in a sex-specific manner, and protected against benzene induced metabolic imbalance, ER stress, and neuroinflammatory responses. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the effect of benzene exposure even at lower levels.

Disclosure

L. Kniess Debarba: None. A. Mulka: None. P.I. Fakhoury: None. O. Didyuk: None. A.A. Awada: None. J. Lima: None. L. Koshko: None. U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None.

Funding

American Diabetes Association (1-18-JDF-063 to M.S.)
1769-P: Microglial Activation and Inactivation via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) Alters Peripheral Glucose Homeostasis
Authors: NESS KELLY M. , DOUGLASS JOHN , VALDEARCOS-CONTRERAS MARTIN , DORFMAN MAURICIO D. , NIRAULA ANZELA , KOLIWAD SUNEIL K. , THALER JOSHUA
Published: June 2020

Obesity, a condition affecting more than one in three American adults, is associated with hypothalamic neuronal injury, inflammation, and gliosis- a process characterized by accumulation of activated microglia. Experimental evidence from our lab suggests that microglial activation and inflammatory signaling play a functional role in obesity pathogenesis and, furthermore, that this inflammation, or the blockade of such, may affect whole-body glucose homeostasis. Microglial-specific NF-kB knock-out mice are protected from diet-induced obesity, but, despite their lean phenotype, develop glucose intolerance similar to wild type controls. We therefore used stimulatory (hM3Dq) and inhibitory (hM4Di) DREADDs to test the hypothesis that microglial activation or inactivation acutely affects systemic glucose homeostasis. We generated novel mouse models that selectively express the hM3Dq- and hM4Di-DREADD transgenes in microglia. Expression was verified via qRT-PCR, flow cytometry, and IHC. Cohorts of mice and littermate controls were maintained on either normal chow diet or high-fat diet (HFD). Glucose tolerance tests were performed on mice following administration of the DREADD receptor agonist clozapine-N-oxide (CNO). Acute microglial activation via CNO administration in hM3Dq-DREADD animals improved glucose tolerance under both chow and HFD conditions. Acute CNO-induced microglial inactivation in hM4Di-DREADD animals increased fasting glucose in chow-fed animals and worsened glucose tolerance in HFD-fed animals. These findings provide the first evidence that peripheral glucose homeostasis is affected by microglial activity and inflammatory signaling and can be manipulated on an acute timescale using DREADD technology.

Disclosure

K.M. Ness: None. J. Douglass: None. M. Valdearcos-Contreras: None. M.D. Dorfman: None. A. Niraula: None. S.K. Koliwad: Consultant; Self; AstraZeneca. Stock/Shareholder; Self; Suggestic, Yes Health. J. Thaler: None.

Funding

National Institutes of Health (T32DK007247, R01DK119754)
1783-P: Effects of DPP-4 Inhibition on the Enteroinsular Axis in Pancreatic Insufficient Cystic Fibrosis
Authors: SHEIKH SABA , KELLY ANDREA , STEFANOVSKI DARKO , PELECKIS AMY J. , NYIRJESY SARAH , EIEL JACK N. , SIDHAYE ANIKET , DE LEON DIVA D. , HADJILIADIS DENIS , RUBENSTEIN RONALD C. , RICKELS MICHAEL R.
Published: June 2020

Impaired incretin secretion may contribute to insulin secretion defects in pancreatic insufficient cystic fibrosis (PI-CF). We hypothesized that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy would increase glucagon-like peptide-1 (GLP-1) and improve insulin secretion in glucose intolerant CF. We conducted a randomized, double blind, placebo-controlled trial in 24 subjects with PI-CF and abnormal glucose tolerance who received the DPP-4 inhibitor sitagliptin 100 mg (n = 12) or matched-placebo (n = 12) for 6 months. Randomization was stratified by oral glucose tolerance. Mixed-meal tolerance tests (MMTT) and glucose-potentiated arginine (GPA) tests were performed at baseline and after 6 months intervention. Incremental area-under-the-curves were calculated for GLP-1 (AUCGLP-1) post meal. Insulin secretory rates (ISR), derived by parametric deconvolution of C-peptide kinetics, were modeled using linear mixed effects models. Acute insulin and glucagon response to arginine were calculated under fasting, 230, and 340 mg/dL hyperglycemic clamp conditions. Subjects in the sitagliptin vs. placebo groups were similar in age (median 24 [range 18-43] vs. 28 [18-43] years), sex (5 females each), and BMI (24 [19-34] vs. 22 [17-24] kg/m2). HbA1c, similar at baseline (5.6 [4.8-6.1] vs. 5.7 [5.4-5.9] %), improved after 3 months of sitagliptin (-0.2 %, 95% CI -0.4- -0.2, P = 0.02). AUCGLP-1 was higher after sitagliptin vs. placebo (1400 pmol·min/L, 95% CI 750-2050, P < 0.001). ISR after sitagliptin showed a faster rise through 60 min post meal (9.1 µU·mL-1·min-1, 95% CI 4.4-13.9, P < 0.001) and returned to baseline faster vs. placebo (-12.0 µU·mL-1·min-1, 95% CI -16.9- -7.2, P < 0.001). Acute insulin responses did not differ between groups, but acute glucagon responses were lower after sitagliptin vs. placebo (P = 0.03). In glucose intolerant CF, six-month therapy with sitagliptin resulted in modest improvement in glycemic control and islet function.

Disclosure

S. Sheikh: None. A. Kelly: None. D. Stefanovski: None. A.J. Peleckis: None. S. Nyirjesy: None. J.N. Eiel: None. A. Sidhaye: None. D.D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc. D. Hadjiliadis: Other Relationship; Self; AstraZeneca. R.C. Rubenstein: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc.

Funding

National Institutes of Health (R01DK97830, K23DK107937, UL1TR001878, P30DK19525, T32 DK007314); Merck & Co., Inc. (MISP50512)
1786-P: The New Insulin Sensitizer MSDC-0602K Synergizes with the GLP-1 Receptor Agonist Liraglutide
Authors: PYLES KELLY D. , KAMM DAKOTA , COLCA JERRY R. , MCCOMMIS KYLE S.
Published: June 2020

First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can preserve beta cell mass and function. GLP-1 receptor agonists work by augmenting glucose-stimulated insulin secretion. Our objective was to assess potential additive effects of the new insulin sensitizer, MSDC-0602K (0602K) when combined with a GLP-1 receptor agonist in db/db mice. Mice were gavaged daily with 30 mg/kg 0602K or vehicle, injected subcutaneously every other day with 200 μg/kg Liraglutide (Lira) or vehicle, or received both drugs. Lira reduced glycemia and plasma fructosamine levels, while 0602K or 0602K+Lira normalized glycemia and fructosamine to lean db/+ mouse levels. Both drugs alone improved glucose tolerance compared to vehicle db/db, while the combination of 0602K+Lira further improved glucose tolerance even compared to lean db/+ mice. Vehicle treated db/db mice displayed elevated insulin and C-peptide levels, which were both reduced by 0602K treatment. C-peptide levels were lowered to a greater degree than insulin, indicating that 0602K treatment exerted a major effect on insulin secretion. In contrast, Lira increased the insulin and C-peptide levels in db/db mice, while the combination of 0602K+Lira displayed reduced levels of insulin and C-peptide similar to 0602K-alone treatment. Pancreas immunohistochemistry of vehicle treated db/db mice showed little islet insulin content, but islet insulin was significantly increased by 0602K or 0602K+Lira treatment. Isolated islets from lean, naïve mice showed no defect in glucose-stimulated insulin secretion with 0602K treatment, suggesting that the lowered insulinemia in vivo is due to corrected insulin resistance rather than direct inhibition of insulin secretion.

In conclusion, the new insulin sensitizer MSDC-0602K improves insulinemia and helps to restore islet insulin content when used alone or in combination with Liraglutide. Glucose tolerance displayed additive effects with combined 0602K+Lira treatment.

Disclosure

K.D. Pyles: None. D. Kamm: None. J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. K.S. McCommis: None.

Funding

National Institutes of Health (R01HL136658)
1788-P: Islet Function in Youth with Cystic Fibrosis with and without Liver Disease
Authors: RAYAS MARIA S. , HUGHAN KARA S. , JAVAID RIDA , LEUNG DANIEL , STEFANOVSKI DARKO , KELLY ANDREA , SALEHI MARZIEH
Published: June 2020

Insulin deficiency largely underlies cystic fibrosis related diabetes (CFRD). CF liver disease (CFLD) is a risk factor for CFRD development, but the mechanisms linking these mortality-increasing comorbidities are unknown. This pilot study sought to characterize prandial glucose metabolism and islet function in youth across glycemia and CFLD spectrums.

Glucose, insulin, c-peptide (CP) and glucagon were obtained during a 3-hr oral glucose tolerance test in youth (9M/11F, ages 12-21y) with pancreatic insufficient CF from two centers. Fasting insulin sensitivity (HOMA-IR) and insulin clearance (CP:insulin), and prandial glucose and glucagon excursion (AUC180), insulin sensitivity (Matsuda index), β-cell sensitivity to glucose, insulin secretory rates (ISR; by parametric deconvolution of CP kinetics) and disposition index (DI, composite of insulin secretion and insulin sensitivity) were calculated. CFLD status was defined using CFLD guidelines: CFLD with portal hypertension (CFLDPH), CFLD without portal hypertension (CFLD) and no liver disease (CFnoLD).

CFLDPH (n=3), CFLD (n=3) CFnoLD (n=14) did not differ in age, BMI-Z, or HbA1c. CFRD was present in 2 CFLDPH, 0 CFLD, 4 CFnoLD. Fasting glucose was greater in CFLDPH vs. CFLD or CFnoLD (p<0.05). HOMA-IR and fasting CP:insulin were reduced in CFLDPH vs. CFLD and CFnoLD, but post-meal glucose-AUC180 and indices of insulin sensitivity and clearance were similar. ISR and DI tended to be lower in CFLDPH vs. CFLD (p=0.008 and p=0.077) and CFnoLD (p=0.071 and p=0.058), respectively. β-cell sensitivity was reduced in CFLDPH vs. CFLD (p<0.05). Fasting and AUC180 glucagon did not differ among groups.

In this limited group of youth, reduced fasting insulin sensitivity and magnified insulin secretory defects are present in CFLDPH, the more severe form of CFLD, and may explain their heightened CFRD risk. Larger studies are warranted to define pathogenesis and inform glycemic treatment targets in individuals with severe CFLD.

Disclosure

M.S. Rayas: None. K.S. Hughan: Research Support; Self; Novo Nordisk Inc. R. Javaid: None. D. leung: None. D. Stefanovski: None. A. Kelly: None. M. Salehi: None.

Funding

Cystic Fibrosis Foundation (RAYAS16GEO, HUGHAN16GE0, MOR16CFF); National Institutes of Health (5T32DK00772923)