bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitophagy Receptor FUNDC1 Links Mitochondrial Quality Control to Muscle–Adipose Dialogue in Alleviating Dietary Obesity
Authors: FU TINGTING , XU ZHISHENG , LIU LIN , LIANG XIJUN , ZHOU DANXIA , GUO QIQI , XIAO LIWEI , GAN ZHENJI
Published: June 2018

The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, using two independent skeletal muscle-specific knockout mouse lines, we demonstrate that FUNDC1, a mediator of mitophagy, plays an essential role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Mice with FUNDC1 deficiency in skeletal muscle (FUNDC1 mKO) showed decreased muscle fat utilization and endurance capacity (∼40%) compared to WT littermates during exercise. Analysis of biochemical markers of mitophagy revealed a marked decrease in mitochondrial localization of LC3-II and P62 protein levels, and this caused impaired mitochondrial respiration capacity. FUNDC1 loss-of-function studies in primary skeletal myocyte recapitulated defective mitophagy and impaired mitochondrial energetic as observed in FUNDC1 mKO muscle. Surprisingly, mice lacking muscle FUNDC1 were resistant to high fat diet (HFD) induced obesity despite reduced muscle mitochondrial energetics. Moreover, glucose and insulin tolerance tests demonstrated that HFD-fed FUNDC1 mKO mice were more tolerant to glucose challenge and more sensitive to insulin stimulation compared to HFD-fed WT controls. This seemingly paradoxical phenotype was due to enhanced fat burning in in adipose tissue. HFD-fed FUNDC1 mKO mice had markedly elevated expression of key thermogenic genes such as Ucp1 (17-fold), Cidea (13-fold), and Dio2 (9-fold) in white adipose. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF-21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality-control in mediating the muscle-adipose dialogue to regulate systemic metabolism.

Disclosure

T. Fu: None. Z. Xu: None. L. Liu: None. X. Liang: None. D. Zhou: None. Q. Guo: None. L. Xiao: None. Z. Gan: None.
Reduced ß Cell SPCA1 Leads to Impaired Calcium Oscillations and Decreased Autophagy
Authors: BONE ROBERT N. , KONO TATSUYOSHI , EVANS-MOLINA CARMELLA
Published: June 2018

The β-cell Golgi, an important site of proinsulin maturation, is a significant store of intracellular Ca2+. However, the contribution of Golgi Ca2+ to diabetes pathophysiology is unknown. The Golgi primarily utilizes the Secretory Pathway Ca2+ ATPase (SPCA1) to maintain intra-Golgi Ca2+ stores. SPCA1 expression was measured in islets from Akita and db/db mice and cadaveric human islets from donors with T1D and T2D. In all cases, SPCA1 levels were significantly lower compared to nondiabetic controls. Proteomics and Reverse Phase Protein Array performed in INS-1 β-cells lacking SPCA1 (SPCA1KO) indicated dysregulated cell death, cell growth, and proliferation pathways compared to WT INS-1 cells. Consistent with this, SPCA1KO cells exhibited increased caspase-3/7 following tunicamycin treatment. SPCA1KO cells also had elevated basal cytosolic Ca2+ levels, decreased organelle Ca2+ reuptake following organelle Ca2+ store depletion, and accelerated Golgi collapse. Despite a significant reduction in GSIS, SPCA1KO cells exhibited a 12-fold insulin content increase. Autophagy has been reported as a key regulator in maintaining β-cell insulin homeostasis. Immunoblot revealed reduced expression of the autophagy marker LC3-II and the autophagosome Atg5/Atg12 complex in SPCA1KO cells, following autophagy induction with Torin. Islets from mice haploinsufficient for SPCA1 (SPCA1+/-) exhibited elevated cytosolic Ca2+ levels and impaired Ca2+ oscillations as reflected by increased phase 1 amplitude and period, compared to WT littermates. In islets, restoration of SPCA1 to normal levels rescued the oscillatory defect. Interestingly, islets from SPCA1+/- mice did not exhibit increased insulin content, however, SPCA1+/- islets had decreased insulin secretion and increased numbers of immature insulin granules. Taken together, we find that β-cell SPCA1 plays an important role in the maintenance of Golgi Ca2+ levels, while loss of SPCA1 led to dysregulated β-cell Ca2+ homeostasis.

Disclosure

R.N. Bone: None. T. Kono: None. C. Evans-Molina: None.
The Association between the Adipokine C1QTNF1 and Type 2 Diabetes Is Significantly Modulated by Obesity
Authors: GEIGER KATHRIN , MUENDLEIN AXEL , LEIHERER ANDREAS , SAELY CHRISTOPH H. , EBNER JANINE , BRANDTNER EVA-MARIA , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2018

C1q and tumor necrosis factor related protein 1 (C1QTNF1) is an adipokine which has recently captured attention as a modulator of various metabolic pathways. As shown in animal and in vitro studies C1QTNF1 enhances glucose and fatty acid oxidation and improves insulin sensitivity. Paradoxically, C1QTNF1 serum levels were found to be elevated in patients with type 2 diabetes (T2DM). To further elucidate the role of serum C1QTNF1 in T2DM, we investigated its association with metabolic parameters linked to T2DM in 542 patients undergoing coronary angiography for the evaluation for established or suspected stable coronary artery disease. In the total study cohort, C1QTNF1 was significantly (p-values <0.001 for all comparisons) increased in patients with T2DM, the metabolic syndrome (MetS), as well as in obese patients (defined as BMI ≥30 kg/m2). Further, C1QTNF1 was positively correlated with BMI, fasting glucose, HbA1c, CRP, and the homeostatic model assessment (HOMA) index of insulin resistance (all p-values <0.001), but not with the HOMA index of beta-cell function (p>0.05). Subgroup analyses with respect to obesity revealed that the association between C1QTNF1 and T2DM was highly significant in obese patients (p<0.001), but not in non-obese subjects (p=0.076). An interaction term obesity x C1QTNF1 was significant (p = 0.018), indicating a significantly stronger association between C1QTNF1 and T2DM in obese patients than in non-obese subjects. Similarly, the association between C1QTNF1 and the MetS was significant only in obese patients (p=0.009), but not in non-obese subjects (p=0.074), We conclude that obesity significantly influences the association between C1QTNF1 serum levels and T2DM and should be considered in further studies evaluating the relationship of C1QTNF1 with metabolic traits.

Disclosure

K. Geiger: None. A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Exenatide and Saxagliptin Do Not Attenuate NFkB-Induced Inflammation in Prediabetic Humans
Authors: GUTIERREZ ABSALON D. , BERMUDEZ KARLA , HAMIDI VALA , RIGGS KAYLA , COVERDALE SARA , DURSTELER AMY , KUMAR NITYA K. , RUSCHEINSKY MONIKA
Published: June 2018

Incretin mimetic medications acutely downregulate inflammation via the NfkB pathway during the fasting state in humans with type 2 diabetes mellitus. Free fatty acids (FFAs) activate TLR4, stimulating NFkB and the production of IL-6, which downregulates insulin signaling via SOCS3. We investigated this pathway in the acute postprandial state—utilizing a high-fat meal and incretin mimetic therapies—in humans with prediabetes. Sixteen humans with prediabetes (age 50 ± 2 years, BMI 32.5 ± 0.4 kg/m2, HbA1c 5.96 ± 0.05%) participated in a randomized, crossover, double-blinded trial comparing exenatide, saxagliptin, and placebo. Blood was drawn at baseline (fasting) and 2 hours for the collection of peripheral blood mononuclear cells (PBMCs) and plasma. After baseline blood draw, subjects were given study medication followed by high-fat test meal. Procedures were repeated for all study arms. Subsequently, seven of these subjects (age 51 ± 2 years, BMI 33.3 ± 0.6 kg/m2, HbA1c 5.86 ± 0.17%) participated in an open-label extension study after the administration of exenatide extended-release (EXR) for six weeks. The above procedures were repeated. In the randomized trial, plasma FFA decreased in all groups (p<0.05), though the magnitude of decrease was smaller for exenatide. Plasma IL6 levels increased in all groups except the saxagliptin (p<0.05). Western blots of PBMCs showed no significant changes in levels of NFkB, TLR4, or SOCS3. Plasma insulin did not change in the exenatide group but increased in other groups. In the extension study with EXR, plasma FFA decreased between 0 and 2 hours (p<0.05), and to a greater extent than the prior exenatide group. Plasma IL6 levels decreased (p<0.05) and insulin levels increased (p<0.05). Western blots showed no significant changes in levels of NFkB, TLR4, or SOCS3. These data show that six weeks of EXR significant reduced postprandial FFA levels and IL-6 without any noted changes in NFkB pathway between 0 and 2 hours.

Disclosure

A.D. Gutierrez: Speaker's Bureau; Self; AstraZeneca, Med Learning Group. K. Bermudez: None. V. Hamidi: None. K. Riggs: None. S. Coverdale: None. A. Dursteler: None. N.K. Kumar: None. M. Ruscheinsky: None.
SGLT1 in Pancreatic a Cells Regulates Glucagon Secretion in Mice, Possibly Explaining the Distinct Effects of SGLT2 Inhibitors on Plasma Glucagon Levels
Authors: SUGA TAKAYOSHI , KIKUCHI OSAMU , KOBAYASHI MASAKI , MATSUI SHO , HASHIMOTO HIROMI H. , SASAKI TSUTOMU , KAKIZAKI SATORU , YAMADA MASANOBU , KITAMURA TADAHIRO
Published: June 2018

A recent report described that sodium glucose cotransporter (SGLT) 1 and 2 were expressed in α cells, and dapagliflozin which is a specific SGLT2 inhibitor, increased plasma glucagon levels by inhibiting SGLT2 in α cells. However, it is still controversial whether SGLT2 inhibitors increase plasma glucagon levels in vivo. Here, we showed that dapagliflozin, but not canagliflozin which is a SGLT2/low-potency-SGLT1 inhibitor, increased plasma glucagon levels in mice fed a high-fat, high-sucrose diet (HFHSD) and diabetic db/db mice. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. RT-PCR and whole RNA sequencing revealed that SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells and mouse islets. We showed that canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. We also showed that the SGLT1 effect on glucagon secretion depended on sodium/glucose cotransport, but not on metabolic effect of glucose. Islets from HFHSD and db/db mice displayed higher SGLT1 expression and lower GLUT1 expression than the islets from control mice. These expression levels were associated with glucagon secretion levels. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets. These data suggested that a novel mechanism regulated glucagon secretion, through SGLT1, in α cells. This finding explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.

Disclosure

T. Suga: None. O. Kikuchi: None. M. Kobayashi: None. S. Matsui: None. H.H. Hashimoto: None. T. Sasaki: None. S. Kakizaki: None. M. Yamada: None. T. Kitamura: None.
GLP-1 Integrates the Innate Immune System to Glucose Homeostasis
Authors: DAVIS ELLEN M. , HUTCH CHELSEA , KIM KI-SUK , MAERZ BASMA , ROELOFS KAREN J. , LEHRKE MICHAEL , SANDOVAL DARLEEN A.
Published: June 2018

Glucagon-like peptide-1 (GLP-1) is a gut peptide that increases post prandially and functions to increase insulin secretion and improve glucose homeostasis. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed by intestinal and pancreatic cells. Interestingly, GLP-1 is also increased during sepsis, which is the most common cause of death in intensive care units (ICU). The goal of this study was to determine in a preclinical model of sepsis if the increase in GLP-1 was from intestinal or pancreatic cells. In order to model sepsis, we administered lipopolysaccharide (LPS) to Cre-control mice, to mice devoid of Gcg, and thus GLP-1 (Gcg null), to mice with Gcg expression reactivated only in the intestine (GcgRAδIntestine), and to mice with Gcg expression reactivated only in the pancreas (GcgRAδPancreas). LPS significantly increased GLP-1 in the control mice, as well as in the two reactivated genotypes compared to saline. However, the degree of the increase in both GcgRAδIntestine and GcgRAδPancreas mice was about 50% of control animals. LPS first increased, then significantly decreased blood glucose in control, pancreatic and intestinal reactivated mice but was significantly lower across all time points in Gcg null mice. These data suggest that both intestinal and pancreatic sources contribute to the increase in plasma GLP-1 seen in our model of sepsis. However, either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS.

Disclosure

E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. K.J. Roelofs: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..
Chronic Fractalkine Administration Exerts Durable Effects to Improve Glucose Tolerance with Specific Effects to Pancreatic Endocrine Function
Authors: LEE YUN SOK
Published: June 2018

Previously we reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and beta cell function. In this study, we examined whether chronic administration of FKN can exert durable effects to improve glucose tolerance in obese rodent models and performed a series of comprehensive mechanistic studies. Chronic administration of a long acting form of FKN (FKN-Fc fusion protein) into obese and insulin resistant mice improved glucose tolerance with improved beta cell function. Unexpectedly, FKN-Fc administration also led to decreased plasma glucagon levels. At the molecular level, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism in both alpha and beta cells. This led to enhanced glucose-stimulated action potential (AP) firing in beta cells, while it decreased alpha cell AP amplitude. Consistent with these results, FKN-Fc treatment increased GSIS and decreased glucagon secretion in beta and alpha cells, respectively. In addition to these effects in islet cells, chronic FKN-Fc treatment also decreased hepatic glucose production. In vitro and ex vivo experiments with normal and obese hepatocytes demonstrated that FKN treatment decreases glucagon-stimulated cAMP levels and CREB phosphorylation in a pertussis toxin-sensitive manner. Taken together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.

Disclosure

Y. Lee: None.
Improvement of Insulin Resistance and Cardiovascular Risk Factors with Treatment of Subclinical Hypothyroidism in Patients with Autoimmune Thyroiditis
Authors: NEVES CELESTINO , OLIVEIRA SOFIA C. , NEVES JOÃO SÉR , PEREIRA MIGUEL G. , SOKHATSKA OKSANA , OLIVEIRA ANA , MEDINA JOSÉ LUIZ , DELGADO LUIS , CARVALHO DAVIDE M.
Published: June 2018

Introduction: Subclinical hypothyroidism (SCH) seems to be associated with increase in cardiovascular risk factors and insulin resistance. The effect of the treatment of SCH with L-thyroxine on cardiovascular profile is not yet clear.

Methods: We evaluated the effects of L-thyroxine therapy in 120 patients (mean age 45.7 ± 12.2 years, 80 women) with SCH due to autoimmune thyroiditis that had no prior treatment for thyroid or cardiovascular disease. The treatment was titrated to TSH levels between 0.4 and 4.0mIU/L. The laboratory data obtained, before and at least 6 months after thyroid function normalization, included thyroid function, antithyroid antibodies, lipid profile, and HOMA-IR (Homeostasis Model Assessment for insulin resistance), HISI (Hepatic Insulin Sensitivity Index), and IGI (Insulinogenic Index). Statistical analysis was performed with Mann-Whitney test, and Spearman’s correlation coefficient.

Results: After treatment L-thyroxine, we observed a significant decrease of TSH (6.43±0.53 to 1.23±0.42 mIU/L, p=0.03) and a significant increase of fT4 (0.74±0.12 to 1.25±0.14 ng/mL, p<0.05). We also observed a decrease of LDL (116.1±34.2 to 91.2±16.3 mg/dL, p<0.01) and Lp(a) (32.0 ±19.1 mg/dL to 21.4±18.1 mg/dl, p<0,01). HDL and Apo A1 increased significantly after treatment (45.2±15.2 to 58.5±18.1 mg/dL, p <0.01; 124.5±43.3 vs. 136.5±56.4 mg/dL, p<0.01, respectively). Treatment with L-thyroxine significantly reduced HOMA-IR (0.24±0.17 to 0.17±0.10, p=0.03) and HISI (334.9±92.9 to 703.8±97.1, p=0.02). At baseline, TSH was positively correlated with total cholesterol (r=0.38, p=0.01), LDL (r=0.38, p=0.01), TG (r=0.28, p=0.01) and IGI (r=0.22, p=0.05). FT3 was negatively correlated with Lp(a) (r =-0.41, p=0.04).

Conclusions: The treatment of SCH in patients with autoimmune thyroiditis is associated with a significant improvement of insulin resistance and cardiovascular risk.

Disclosure

C. Neves: None. S.C. Oliveira: None. J. Neves: None. M.G. Pereira: None. O. Sokhatska: None. A. Oliveira: None. J. Medina: None. L. Delgado: None. D.M. Carvalho: None.
Glucagon-Receptor Signaling Regulates Mitochondrial Bioenergetics via Hepatic Farnesol X Receptor
Authors: KIM TEAYOUN , NASON SHELLY , ANTIPENKO JESSICA P. , VESTRI CATHERINA S. , SMITH-JOHNSTON KELLEY , PEPIN MARK E. , WENDE ADAM R. , FINAN BRIAN , DIMARCHI RICHARD , PEREZ-TILVE DIEGO , MOELLERING DOUGLAS R. , HABEGGER KIRK M.
Published: June 2018

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss. We have identified that the hepatic Farnesol X Receptor (FXR) plays an important role in an anti-obesogenic effect of glucagon receptor (GcgR) agonism. Chronic administration of IUB288, a potent GcgR agonist, significantly reduced diet-induced obesity (DIO) in wild type (WT, 17%) mice compared to (FXR∆liver, 6%) liver-specific FXR knock-out mice. Weight loss was associated with increased energy expenditure (p<0.05) and fat oxidation (reduced RQ, p<0.05). We hypothesized that GcgR agonism alters mitochondrial bioenergetics, at least in part, through hepatic FXR signaling. IUB288 treatment increased body temperature (p<0.05) and [14C]-palmitate oxidation capacity of liver homogenate (p<0.05) to a greater extent in DIO WT mice than in FXR∆liver mice. RNA-Seq analysis of DIO liver samples revealed that the mitochondrial oxidative phosphorylation pathway, fatty acid metabolism, and bile acid metabolism were enriched in WT treated with IUB288, but not in FXR∆liver mice. Liver slices isolated from WT mice treated with IUB288 for two days significantly increased state 3 respiration rates compared to FXR∆liver mice using high resolution respirometry. Respiration was increased utilizing both carbohydrate (pyruvate, malate, glutamate, and succinate) and lipid substrates (palmitoyl-carnitine), suggesting GcgR-agonism modulates hepatic mitochondrial respiration via FXR. Our study elucidates a molecular mechanism of the anti-obesogenic effect of GcgR signaling. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in therapeutic strategies for multiple components of the metabolic syndrome.

Disclosure

T. Kim: None. S. Nason: None. J.P. Antipenko: None. C.S. Vestri: None. K. Smith-Johnston: None. M.E. Pepin: None. A.R. Wende: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. D.R. Moellering: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..
Vitamin D3 Alleviates High-Fat Diet–Induced Endoplasmic Reticulum Stress and Insulin Resistance in Mice
Authors: LIU LU , LI XIAOHUA
Published: June 2018

Endoplasmic reticulum stress (ERs) may be a key mechanism for the connection of obesity, chronic inflammation, and insulin resistance (IR). As we know, vitamin D3 deficiency is prevalent in obese patients, and it may be an independent risk factor for obesity-induced IR and type 2 diabetes mellitus (T2DM). However, the effects of vitamin D3 on ERs, inflammatory response, and IR were still unknown. This study investigate the effects of vitamin D3 on ERs, inflammatory response, and IR in high-fat-diet (HFD) induced obese mice. Eighty male C57BL/6 mice were randomly divided into four group, including control group (n = 20), HFD group, HFD + low dose (50 IU/kg) of vitamin D3 group (VitD-L), HFD + high dose (250 IU/kg) of vitamin D3 group (VitD-H). The control group was fed with common feed, and the other groups were fed with HFD. After the establishment of the obesity model, the mice in experimental group was fed with different dose of vitamin D3 for 1 week. Then western blot was used to detect the protein expression level of Bip, IRE1, PERK and NF-κB in adipose tissue; serum levels of TNF-α, IL-6, serum 25-hydroxyvitamin D3, fasting blood glucose, glycosylated hemoglobin, triacylglyceride and fasting insulin were measured and the insulin resistance index was calculated. The results indicated that vitamin D3 in both low and high dose could significantly down-regulate the expression level of Bip, IRE1 and PERK, and decrease the expression levels of NF-κB, TNF-α, and IL-6 (p < 0.05). It could also significantly decrease the levels of fasting blood glucose, glycosylated hemoglobin, triacylglyceride and fasting insulin in obese mice (p < 0.05), and significantly alleviate the insulin resistance phenomenon in obese mice. The results indicated that vitamin D3 supplementation could reduce the synthesis and release of inflammatory factors, alleviate endoplasmic reticulum stress and insulin resistance.

Disclosure

L. Liu: None. X. Li: None.
Mortality Risk in Adults With and Without Type 2 Diabetes after 18 Years of Follow-up in Northern Spain—The Asturias Study
Authors: ARES JESSICA , VALDES SERGIO , BOTAS PATRICIA , SÁNCHEZ-RAGNARSSON CECILIA , MENÉNDEZ-TORRE EDELMIRO , DELGADO ELIAS
Published: June 2018

Objective: People who develop type 2 diabetes (T2D) have higher mortality risk. Regarding Asturias Study, after 18 years of follow-up, we have estimated all-cause, cardiovascular and cancer mortality-risks according to categories of impaired glucose metabolism.

Research Design and Methods: Asturias study (launched in 1998) included a mortality follow-up of 18 years of its regionwide sample representative of population aged 30-75 years. Age and sex- stratified hazard ratios (HR) were calculated for 48 participants with diagnosed T2D (self reported diagnosis or antidiabetic medication), 83 with undiagnosed T2D (no diagnosed T2D, glycated hemoglobin A1c ≥6,5%, fasting glycemia≥126 mg/dL or glycemia after 75g glucose load ≥200 mg/dL), 296 with prediabetes (glycated hemoglobin A1c 5,7-6,4%, fasting glycemia 100-125 mg/dL or glycemia after 75g glucose load 140-199 mg/dL) and 607 with normoglycemia.

Results: Over 18,612 person-years, 204 people died (32 with undiagnosed T2D, 30 with diagnosed T2D, 62 with prediabetes and 80 with normoglycemia). HR for all cause mortality, adjusted by previous cardiovascular disease, history of high blood pressure, LDL cholesterol level, age, sex, BMI and estimate glomerular filtration rate, was 2.22 (1.42-3.48) for diagnosed T2D, 1.57 (1.03-2.39) for undiagnosed diabetes. Adjusted hazard ratio for cardiovascular mortality was 3.12 (1.55-6.29) for diagnosed T2D and, for cancer mortality, was 1.83 (0.79-4.22) vs. normoglycemia. Women with T2D have higher age-standarized cardiovascular-mortality risk than men with T2D (7.36 (2,84-19.09) vs. 1.58 (1.45-5.56)). People with prediabetes have similar mortality risks as people with normoglycemia.

Conclusions: In Asturias, age and sex-standardized all-cause mortality is more than two times higher for adults with T2D than for adults without T2D. HR for cardiovascular mortality is highly increased in women with T2D comparing with men with the same condition.

Disclosure

J. Ares: Research Support; Self; Sanofi. S. Valdes: None. P. Botas: None. C. Sánchez-Ragnarsson: None. E. Menéndez-Torre: Speaker's Bureau; Self; Sanofi, AstraZeneca, Novo Nordisk A/S. E. Delgado: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Research Support; Self; Sanofi-Aventis. Speaker's Bureau; Self; Esteve, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Lilly. Research Support; Self; Menarini Group.
Bofutsushosan Improves Gut Barrier Function with a Bloom of Akkermansia Muciniphila and Improves Glucose Metabolism in Diet-Induced Obese Mice
Authors: FUJISAKA SHIHO , USUI ISAO , NAWAZ ALLAH , IGARASHI YOSHIKO , KADO TOMONOBU , OKABE KEISUKE , YAGI KUNIMASA , NAKAGAWA TAKASHI , TOBE KAZUYUKI
Published: June 2018

Bofutsushosan (BFT), an oriental herbal medicine, has been clinically used for obese patients. To explore the impact of BFT on glucose metabolism, male C57BL6 mice were fed on high-fat diet (HFD) for 12 weeks and administered either BFT (25 mg /day) or saline for the last 8 weeks. Oral glucose tolerance test and insulin tolerance test revealed improved glucose metabolism with improved insulin sensitivity in BFT treated mice, which was associated with decreased inflammatory gene expressions and improved insulin signaling in the adipose tissue. Whereas the weight of liver and adipose tissue was not changed, cecum weight was significantly increased by BFT. 16S rRNA sequence analysis of fecal samples showed that microbial composition was markedly changed. BFT reduced the relative abundance of Bacteroidetes from 52% to 34%, whereas it increased Verrucomicrobia from 3.4% to 24%. An increase in Verrucomicrobia was mainly associated with Akkermansia mucuniphila (Akk). The bloom of Akk was observed at one week of BFT treatment. Consistent with the previous reports that Akk improves gut barrier function and prevents from metabolic endotoxemia in obese subjects, BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, which was associated with increased claudin-1 protein in the colon. Furthermore, plasma endotoxin level and hepatic lipopolysaccharide binding protein expression were significantly decreased in BFT group. Antibiotic treatment canceled the metabolic effect of BFT. Moreover, when the gut microbiota of BFT-treated mice were transferred to HFD-fed mice, glucose metabolism was significantly improved with decreased diet -induced inflammation with AKK bloom. These data demonstrate that BFT increases Akk in the gut, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to improved diet-induced inflammation, thereby controlling glucose metabolism.

Disclosure

S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. I. Usui: None. A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. Y. Igarashi: None. T. Kado: None. K. Okabe: None. K. Yagi: None. T. Nakagawa: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co.
Over 22 kg/m2 of BMI at Young Age Is a Risk Factor for Future Diabetes in Japanese Men
Authors: SOMEYA YUKI , TAMURA YOSHIFUMI , KOHMURA YOSHIMITSU , AOKI KAZUHIRO , SUZUKI KOYA , KAWAI SACHIO , DAIDA HIROYUKI
Published: June 2018

Type 2 diabetes (T2DM) is easily developed in Asian adults with normal body mass index (BMI), compared with other ethnicities with similar BMI. For example, it has been shown that slightly increased BMI level (>23 kg/m2) in middle age (around 50 years old) is a risk for development of T2DM in Asians. However, it is still unclear whether slightly elevated BMI at young age within normal BMI range (<25 kg/m2) also increases the risk of T2DM later in life. To clarify this, we investigate the impacts of BMI at young age on development of T2DM later in life by historical cohort study. The study subjects are male alumni who were graduated physical education school in Japan from 1971 to 1991. From 2007 to 2017, a self-administered follow-up questionnaire was sent by mail to the subjects to ask their previous medical diagnosis of diabetes. This study analyzed 657 male alumni and covered 32-year follow-up period (interquartile range: IQR: 27-36) which included 20,607 person-years of observation. Subjects were 22 (22-22) years old at graduated college and 54 (50-59) years old at final follow-up investigation. Median BMI was 22.0 (21.1-23.0) kg/m2 at college age and 23.9 (22.3-25.6) kg/m2 at first follow-up investigation. During the period, 57 men developed diabetes. Then, the participants were categorized into four categories: BMI at college age of <21.0 kg/m2 (n=155), 21.0-22.0kg/m2 (n=172), 22.0-23.0kg/m2 (n=170), and ≥23.0kg/m2 (n=160), and the incidence of diabetes was compared. The prevalence rates of diabetes for lowest to highest BMI categories were 4.5%, 7.6%, 11.2%, and 11.3%, respectively (p=0.10), and their hazard ratios were 1.00 (reference), 1.65 (95% CI: 0.66-4.14), 2.45 (1.02-5.87), and 2.51 (1.05-6.03), respectively (p=0.02 for trend). This trend was similar after adjustment for age, year of graduation, smoking and participation in college sports club. These data suggested that over 22.0kg/m2 of BMI at young age might be a risk factor for future T2DM in Japanese men.

Disclosure

Y. Someya: None. Y. Tamura: None. Y. Kohmura: None. K. Aoki: None. K. Suzuki: None. S. Kawai: None. H. Daida: None.
Zinc Alpha2 Glycoprotein Promotes Browning in Adipocytes
Authors: XIAO XIN-HUA , QI XIAO-YAN , WANG YA-DI , XU CAN-XIN , LIU JIANG-HUA
Published: June 2018

Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called “browning”) would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important fat-adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.

Disclosure

X. Xiao: None. X. Qi: None. Y. Wang: None. C. Xu: None. J. Liu: None.
LRP1 Regulates Adiposity by Controlling Energy Balance in MC4R Neurons
Authors: KANG MIN-CHEOL , SEO JI A. , CHO HYUNSOO , LEE HYUNNA , KIM YOUNG-BUM
Published: June 2018

Hypothalamic low-density lipoprotein receptor-related protein 1 (LRP1), a member of LDL receptor family, plays a pivotal role in the regulation of food intake and body-weight homeostasis. However, the role of LRP1 in MC4R-expressing neurons remains unknown. This study was to determine whether deleting LRP1 from MC4R-expressing neurons affects adiposity and energy balance in mice. Here we show that MC4R neuron-specific LRP1 deletion results in decreased body weight in mice fed a normal chow diet (control 30.4±0.8g vs. MC4R-LRP1 deficient mice 27.2±0.5g, p<0.05). Consistent with this, MRI analysis indicated that fat mass in MC4R-LRP1 deficient mice significantly decreased by ∼64% without changes in lean mass, compared with control mice. This occurred despite the fact that MC4R-LRP1 deficient mice are hyperphagic (control 3.99±0.17g vs. MC4R-LRP1 deficient mice 4.71±0.18g, p<0.05). In addition, MTII’s ability to suppress food intake was impaired in MC4R-LRP1 deficient mice. These effects are mainly due to increased energy metabolism, as evidenced by the fact that oxygen consumption for 24 hours increased in MC4R-LRP1 deficient mice compared with control mice (control mice 6002±287 ml/kg/hour vs. MC4R-LRP1 deficient mice 7121±1947 ml/kg/hour, p<0.01), along with exhibiting insulin sensitivity and glucose tolerance. However, locomotor activity was normal in these mice. The current data demonstrate that LRP1 signaling in MC4R neurons is required for the homeostatic regulation of energy expenditure and adiposity. Thus, LRP1 is a key player of energy balance in MC4R-expressing neurons.

Disclosure

M. Kang: None. J.A. Seo: None. H. Cho: None. H. Lee: None. Y. Kim: None.
Hypothalamic Glucose Concentrations Are Higher in Subjects with Type 1 Diabetes (T1D) and Impaired Awareness of Glycemia (IAH) than in T1D without IAH
Authors: MOHEET AMIR , DEELCHAND DINESH , KUMAR ANJALI , OZ GULIN , SEAQUIST ELIZABETH R.
Published: June 2018

IAH occurs commonly in patients with T1D but its pathogenesis remains uncertain. Previous investigation has suggested that recurrent hypoglycemia leads to an upregulation of brain glucose transport thereby assuring that the brain will have better fuel delivery during subsequent episodes of hypoglycemia. If so, subjects with T1D and IAH should have higher hypothalamic brain glucose concentrations than subjects with T1D without IHA when studied at the same level of glycemia. Here we used 1H-magnetic resonance spectroscopy at 7 T to measure (Glucose+Taurine)/ total Creatine in a 13x12x10 mm3 hypothalamic voxel in such patient groups while they were maintained at euglycemia and then hypoglycemia using a glucose clamp. Since taurine and creatine do not change with glycemia, this is a valid measure of brain glucose concentrations. IAH was defined using the Clarke questionnaire with subjects found indeterminate further classified using the Gold questionnaire. We found that hypothalamic (Glucose+Taurine)/ total Creatine was significantly higher in T1D with IAH at both euglycemia and hypoglycemia when compared to T1D without IAH. These data support the hypothesis that a change in glucose transport may contribute to the pathogenesis of IAH.

T1D with IAH (n=9)T1D without IAH (n=9)Age (years)47.6 ± 1729.2 ± 8Hemoglobin A1c (%)7.3 ± 0.97.3 ± 0.7Glycemia at euglycemia (mg/dl)98 ± 495 ± 7Glycemia during hypoglycemia (mg/dl)48 ± 348 ± 5Epinephrine during hypoglycemia (pg/ml)250 ± 155711±442*Symptom score during hypoglycemia8 ± 936 ± 14**Hypothalamic glucose at euglycemia (Glucose+Taurine)/ total Creatine (mM)0.43 ± 0.110.27 ± 0.08**Hypothalamic glucose at hypoglycemia (Glucose+Taurine)/ total Creatine (mM)0.23 ± 0.040.15 ± 0.02***p=0.03, **p < 0.001.

Disclosure

A. Moheet: None. D. Deelchand: None. A. Kumar: None. G. Oz: Research Support; Self; Takeda Pharmaceuticals U.S.A., Inc. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..
Compound C Protects Mice from Diet-Induced Obesity and Hepatosteatosis
Authors: WANG FANG , YANG WENJUN , XIANG RONG , YUAN JINGJING , LIU YUXING , CHEN KEZHU , MO ZHAOHUI
Published: June 2018

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of nonalcoholic fatty liver disease (NAFLD). Comound C has been demonstrated to be not only an inhibitor of AMPK, but also has some actions independent of AMPK inhibition. In our previous studies, we unexpectedly found compound C is an anti-inflammatory and anti-NLRP3 inflammasome agent in vitro. The aim of this study was to investigate the effects of compound C on a mouse model of high-fat diet (HFD) (60 kcal% fat)-induced obesity and hepatosteatosis in vivo.

Methods: C57BL/6 mice were fed with either a standard or a HFD for 14 weeks. These mice were divided in three groups [Normal chow, HFD + Vehicle, and HFD + compound C (6 mg/kg i.p., once a day)] and treated for an additional 4 weeks. All animals were weighed weekly and food intakes measured twice weekly. Liver histology as well as pro-inflammatory gene expression in liver and white adipose tissue (WAT) were examined.

Results: There was a significant reduction in body-weight gain and daily food intake in compound C-treated group compared with HFD group (P < 0.05). Glucose tolerance test and insulin tolerance test showed that compound C increased glucose metabolism and alleviated insulin resistance compared with the HFD group. Histology analysis showed a significant reduction of hepatic steatosis and ballooning by compound C. To further characterize the activity of compound C, quantitative RT-PCR analysis of pro-inflammatory markers were performed, demonstrating that compound C significantly reduced IL-1β, IL-18, IL-6 and TNF-a gene expression in the liver as well as in the WAT (P < 0.01). Moreover, NLRP3 inflammasome which plays an important role in obesity and NAFLD was significantly decreased by compound C using western blot assay.

Conclusions: Taken together, these results suggest that compound C offers the potential as a novel therapy for obesity and NAFLD, probably by impairing NLRP3 inflammasome activation and the related inflammasion.

Disclosure

F. Wang: None. W. Yang: None. R. Xiang: None. J. Yuan: None. Y. Liu: None. K. Chen: None. Z. Mo: None.
The Ldb1 Transcriptional Coregulator Is Required for Brown Adipose Development and Function
Authors: KEPPLE JESSICA , LIU YANPING , KIM TEAYOUN , ROWE GLENN C. , HABEGGER KIRK M. , HUNTER CHAD S.
Published: June 2018

Brown adipose tissue (BAT) is critical for thermogenesis and glucose homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Exploiting the energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many tissues, including the brain and pancreatic islets. However, direct roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. We developed a mouse model in which Ldb1 was deleted in thermogenic adipocytes using an Uncoupling protein 1 (Ucp1)-driven Cre recombinase, termed Ldb1δBAT. These knockout mice had reductions in BAT-selective mRNAs, including Ucp1 and Elovl3, a result similarly observed in X9 beige cell lines lacking Ldb1. Ldb1δBAT mice were unable to defend body temperature during a cold challenge, suggesting thermogenic defects. We also observed glucose intolerance in Ldb1δBAT mice via intraperitoneal glucose challenge. Ldb1 deletion in preadipocytes resulted in reduced Ucp1 expression upon induction to mature adipocytes. These data suggest a direct role for Ldb1 in maintaining thermogenic and metabolic function in BAT, as well as a developmental role in preadipocytes. Additional metabolic and transcriptional profiling of the Ldb1δBAT model will interrogate the mechanisms underlying Ldb1 control of BAT function, potentially leading to novel obesity and diabetes therapeutic targets.

Disclosure

J. Kepple: None. Y. Liu: None. T. Kim: None. G.C. Rowe: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. C.S. Hunter: None.
miR-34a Aggravates Obesity-Induced Adipose Inflammation and Metabolic Dysfunction via Blocking Polarization of Anti-inflammatory M2 Macrophage
Authors: PAN YONG , HUI HANNAH , HOO RLC , FENG TIANSHI , LAM KAREN S. , XU AIMIN
Published: June 2018

Adipose tissue-resident macrophages are an important contributor to systemic chronic inflammation and cardiometabolic abnormalities associated with obesity. However, the etiological factors that alter the number and polarization of adipose-resident macrophages remain poorly characterized. As our previous clinical study has identified microRNA (miR)-34a as one of the most significantly elevated genes in visceral fat of obese patients, we investigated the roles of miR-34a in obesity-related adipose tissue inflammation and metabolic disorders by generated adipose tissue-specific miR-34a knockout (KO) mice. After feeding with high fat diet (HFD), adipose miR-34a KO mice exhibited significant attenuation of HFD-induced glucose intolerance, insulin resistance, hyperlipidemia, steatohepatitis and systemic inflammation compared to HFD-fed wild type (WT) controls. These benefits of miR-34a deficiency were mainly attributed to the reduced number of total macrophages and polarization of adipose macrophages towards the pro-inflammatory M1 phenotype. Mechanistically, we found that miR-34a directly repressed the expression of the transcription factor Klf4, thereby enhancing macrophage polarization to the M1 phenotype. Silencing of Klf4 in the adipose-specific miR-34a KO mice suppressed M2 macrophage polarization. In visceral fat from obese patients, the expression of Klf4 was significantly decreased and negatively correlated with miR-34a level. These data demonstrated that increased miR-34a in adipose tissues exacerbates obesity-induced adipose tissue inflammation by suppressing the expression of Klf4, thereby leading to increased accumulation of pro-inflammatory M1 macrophages.

Disclosure

Y. Pan: None. H. Hui: None. R. Hoo: None. T. Feng: None. K.S. Lam: None. A. Xu: None.
A Systematic Review of Cases of Diabetes Mellitus following Immune Checkpoint Inhibitor Therapy for Cancer
Authors: MIZOKAMI-STOUT KARA R. , GIANCHANDANI ROMA , MACEACHERN MARK , IYENGAR RAVI M. , YENTZ SARAH , SHEN LIYAN , REDMAN BRUCE G. , TAN MENG
Published: June 2018

Introduction: Immune checkpoint inhibitors (ICI) [anti-PD-1, anti-PD-L1, and anti-CTLA-4] are novel drugs increasingly used to treat solid tumor malignancies. Immune-related adverse events (irAE) occur with such therapy. We conducted a systematic review of case reports on endocrine irAE following ICI therapy. Here, we focus on the diabetes mellitus (DM) irAE case reports.

Method: In July 2017 we searched Medline, Embase, Cochrane Central Register and Web of Science for articles related to endocrine irAE and ICI. From 815 citations retrieved, 241 mentioned DM. From these, 32 articles reported 43 cases (had close temporal relationship of immunotherapy and development of DM IrAEs and clinical, biochemical, and/or treatment data). A hand-search in Jan 2018 found 8 more papers with 8 cases. These 51 cases were reviewed independently by 2 co-authors for quality of data, using a standardized form.

Results: Thirty-five patients presented in DKA (21 with fulminant T1DM), 15 with hyperglycemia, and 1 with lab data not reported (NR). The median age of the 31 males and 20 females was 63 years. Median time to onset of DM was 7 weeks after treatment initiation. Anti-GAD65, IA2, or ZnT8 were positive in 53% and negative or NR in 47%. Top 2 cancer treated were melanoma (n=23) and non-small cell lung cancer (n=11). The ICIs used were anti-PD-I (n=34); anti-PD-L1 (n=4); anti-PD-1 + CTLA-4 (n=7); and anti-CTLA-4 then anti-PD-1 (n=6). When DM occurred, ICI was stopped in 16, continued in 12, and NR in 23. At onset, 3 cases with known T2DM continued with oral meds, but all were treated with insulin and fluids. All patients recovered - 38 remained on insulin, 1 stopped insulin 81 days after ICI was stopped; and 12 NR.

Conclusion: Reported cases of T1DM irAE are rising - 9 in 2015, 13 in 2016 and 28 in 2017. Most (69%) presented in DKA. All were treated with anti-PD-1/PD-L1 drugs with the majority on monotherapy. All recovered and 38 were insulin-dependent. Endocrinologists and oncologists should collaborate in managing such patients.

Disclosure

K.R. Mizokami-Stout: None. R. Gianchandani: None. M. MacEachern: None. R.M. Iyengar: None. S. Yentz: None. L. Shen: None. B.G. Redman: None. M. Tan: Other Relationship; Self; Eli Lilly and Company.
Index60 Is More Strongly Associated with the Highest Type 1 Diabetes (T1D) Risk HLA DR3-DQ2/DR4-DQ8 (DQ2/DQ8) Genotype than Glucose Measures
Authors: REDONDO MARIA J. , GEYER SUSAN , ISMAIL HEBA M. , HEROLD KEVAN C. , PUGLIESE ALBERTO , PALMER JERRY P. , SOSENKO JAY ,   TYPE 1 DIABETES TRIALNET STUDY GROUP
Published: June 2018

Dysglycemia (i.e., fasting glucose=110-125 mg/dl; 30, 60, or 90-minutes glucose ≥200 mg/dl; and/or 2-h glucose=140-199 mg/dl, from oral glucose tolerance test [OGTT]) is used both as a predictive marker and pre-diagnostic endpoint in T1D prevention trials. However, recent evidence suggests that Index60 (based on fasting C-peptide, 60-minutes glucose and 60-minutes C-peptide, from OGTT) at a 1.00 threshold may be superior to dysglycemia. We thus hypothesized that Index60 is more strongly associated with T1D-linked genetic factors than glucose measures alone. We compared autoantibody-positive TrialNet Pathway to Prevention Study participants (n=1,098) with or without DQ2/DQ8 for associations with Index60, fasting glucose, 2-h glucose and dysglycemia. Participants with DQ2/DQ8 (n=159) compared to those without it (n=912) had higher Index60 values (median [interquartile range, IQR]=0.6 [-5.6 to 2.6] vs. 0.25 (-4.4 to 2.9]; p=0.001). In contrast, neither fasting glucose (p=0.51) nor 2-hour glucose p=0.07) were significantly different between the groups. The percentage with Index60≥1.00 was significantly higher in participants with (37.6%) than without (22.8%) DQ2/DQ8 (p=0.0001), whereas the percentages with dysglycemia were not significantly different (32.7% vs. 26.1%; p=0.11). Among those with normal OGTTs, Index60≥1.00 was more frequent among participants with DQ2/DQ8 (23.8%) than without it (12.0%; p=0.001), while among participants with Index60<1.00, the frequency of dysglycemia was similar in those with and without DQ2/DQ8 (17.5% vs. 16.0%; p=0.70).

In conclusion, Index60, a metabolic marker based on glucose and C-peptide, is more strongly associated with the highest T1D risk HLA DQ2/DQ8 genotype than glucose measures, including dysglycemia. This suggests that Index60 has higher pathogenic specificity for T1D than glucose measures and should be considered for use in T1D prevention trials.

Disclosure

M.J. Redondo: None. S. Geyer: None. H.M. Ismail: None. K.C. Herold: None. A. Pugliese: None. J.P. Palmer: None. J. Sosenko: None.