bluuebunny/crossref_metadata_2025 huggingface dataset:
Sarcolipin, an Uncoupler of SERCA, Protects against Lipotoxicity and Insulin Resistance
Authors: MAURYA SANTOSH K.
Published: June 2018

Obesity is strongly associated with insulin resistance and type 2 diabetes, and increased consumption of high-caloric diet combined with decreased physical activity have made type 2 diabetes a worldwide epidemic. Excess accumulation of lipid and fatty acid metabolites has been shown to interfere with insulin signaling in skeletal muscle. Increasing energy expenditure and mitochondrial metabolism in muscle is an attractive strategy to protect against fat-induced insulin resistance. We have previously shown that sarcolipin (SLN), an uncoupler of SERCA pump, promotes futile cycling, increases ATP utilization and heat generation thereby contributing to muscle thermogenesis. When fed with high-fat diet (HFD), Sln-KO mice developed massive obesity whereas SLN overexpression (SlnOE) mice showed resistance to obesity. In this study, we investigated if SLN based uncoupling mechanism can be targeted to enhance muscle energy expenditure and protects against fat-induced lipotoxicity and insulin resistance in skeletal muscle. Here we show that SLN overexpression increases fatty acid oxidation in skeletal muscle by reprogramming mitochondria and upregulation of enzymes involved in fatty acid transport and oxidation. Interestingly, SlnOE mice fed on high-fat diet did not show intramuscular lipid accumulation and display improved insulin sensitivity. On the other hand, Sln-KO mice show excessive lipid accumulation in muscle and defects in insulin-stimulated glucose uptake, a sign of insulin resistance. Insulin resistant phenotype of Sln-KO muscle was associated with the increased intramuscular concentration of diacylglycerols (DAG), ceramides and acylcarnitines. These results suggest that sarcolipin mediated uncoupling of SERCA is a novel therapeutic target to increase energy expenditure and prevent insulin resistance in skeletal muscle.

Disclosure

S.K. Maurya: None.
Enterohepatic Circulation of Bile Acids Is Activated by Bariatric Surgery before Weight Loss Becomes Apparent
Authors: KITAHARA YOSHIRO , KAWANABE HARUKA , HASUMURA MAI , IWAI YUSUKE , OKAMATSU YORIKO
Published: June 2018

Bariatric surgery induces metabolic improvement before weight loss occurs. Plasma levels of bile acids (BA) are increased after bariatric surgery and this change is reported to contribute significantly to metabolic improvement. In this study, we investigated rats with duodeno-jejunal bypass (DJB) surgery to assess the mechanism underlying the increase in plasma BA after bariatric surgery, especially before weight loss was detectable. Sprague-Dawley rats were fed a high-fat diet for 10 weeks and then were subjected to DJB surgery. Significant weight loss was noted in the DJB rats from 4 weeks after surgery. However, plasma triglycerides (TG) and the hepatic TG content were reduced at 2 weeks after surgery, although food intake was comparable between DJB rats and sham-operated rats. Plasma levels of total BA were elevated from 2 weeks after DJB surgery. In week 2, plasma levels of cholate and chenodeoxycholate were about 5-fold higher in DJB rats than in sham-operated rats, while cecal levels of both BA were lower in DJB rats compared with sham-operated rats. The increase in plasma BA was suppressed by administration of one of bile acid sequestrants, colestimide. Intestinal expression of BA transporters (ASBT, ABCC3, and OSTα) was up-regulated in DJB rats, and hepatic expression of Cyp7A1 was also up-regulated in DJB rats at 2 weeks after surgery. These findings suggest that activation of de novo biosynthesis and increased enterohepatic circulation of BA contribute to elevation of plasma BA levels after DJB surgery before weight loss becomes apparent. These changes led to alteration of gut microbiota in DJB rats, and the resting core body temperature of DJB rats was increased over that of sham-operated rats from 2 weeks after surgery. Therefore, elevation of plasma BA levels early after bariatric surgery by activation of de novo BA synthesis and enterohepatic circulation may play an important role in postoperative metabolic improvement and weight loss.

Disclosure

Y. Kitahara: Employee; Self; Ajinomoto Co., Inc. H. Kawanabe: Employee; Self; Ajinomoto Co., Inc. M. Hasumura: Employee; Self; Ajinomoto Co., Inc. Y. Iwai: Employee; Self; Ajinomoto Co., Inc. Y. Okamatsu: Employee; Self; Ajinomoto Co., Inc..
Impairment of M2a-Subtype Macrophage Activation by Il-4-Irs2 Pathway in Obesity
Authors: KUBOTA TETSUYA , INOUE MARIKO , KUBOTA NAOTO , TAKAMOTO ISEKI , UEKI KOHJIRO , YAMAUCHI TOSHIMASA , KADOWAKI TAKASHI
Published: June 2018

Introduction: M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood.

Methods: We found that the phosphorylation levels of Irs2 by IL-4 were significantly reduced along with decreased Irs2 expression in macrophages of high-fat (HF) diet-fed mice. To investigate the role of Irs2 in the macrophages, we then generated myeloid cell-specific Irs2-deficient (MIrs2KO) mice.

Results: HF diet-fed MIrs2KO mice showed impairment of IL-4-induced M2a-subtype macrophage activation, resulting in insulin resistance. Expressions of the maker genes for M2a-subtype macrophages were downregulated by stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex via impairment of the IL-4/Irs2 pathway. Furthermore, Irs2 expression was significantly suppressed by insulin treatment in macrophages, suggesting that chronic hyperinsulinemia downregulates macrophage Irs2 expression via insulin receptor (IR). Indeed, in myeloid cell-specific IR-deficient mice, the IL-4-Irs2 pathway was preserved in the macrophages due to the lack of IR-mediated downregulation of Irs2, resulting in a reduced degree of inflammation and insulin resistance.

Conclusion: These data suggest that in obesity, downregulation of macrophage Irs2 is induced by hyperinsulinemia, resulting in impaired IL-4-induced M2a-subtype macrophage activation, and insulin resistance.

Disclosure

T. Kubota: None. M. Inoue: None. N. Kubota: None. I. Takamoto: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
Adipocyte-Selective Deletion of ß-Arrestin-1 in Mice Causes Adiposity, Impaired Glucose Tolerance, and Reduced Insulin Sensitivity
Authors: PYDI SAI PRASAD , WESS JÜRGEN
Published: June 2018

In obese individuals, excess fat accumulates in adipose tissue (AT), leading to altered AT metabolism and increased insulin resistance, a key feature of type 2 diabetes (T2D). Therefore, it is of great importance to understand the signaling pathways that regulate AT function. Activation of certain G protein-coupled receptors (GPCRs) in AT has been reported to have beneficial effects on whole body glucose homeostasis. GPCR signaling is modulated by β-arrestin-1 and -2 (barr1 and barr2, respectively), two intracellular proteins which can terminate GPCR signaling and/or mediate G protein-independent signaling. The two β-arrestins are known to regulate many important physiological functions, primarily based on work with whole body knockout (KO) mice. The potential roles of barr1 and barr2 in regulating adipocyte function in vivo remain unexplored. To address this issue, we used Cre-lox technology to generate mutant mice that lacked barr1 selectively in adipocytes (adipo-barr1 KO mice). Interestingly, adipo-barr1 KO mice maintained on a high-fat diet showed significantly increased body weight and adiposity, impaired glucose tolerance, and reduced insulin sensitivity. Moreover, blood glucose and plasma insulin levels were elevated in adipo-barr1 KO mice, indicative of peripheral insulin resistance. RNA-seq analysis revealed the down regulation of key genes involved in glycolysis, glycogen synthesis and insulin signaling. More detailed studies into the mechanisms through which barr1 regulates adipocyte function may identify novel signaling pathways that can be targeted for therapeutic purposes.

Disclosure

S. Pydi: None. J. Wess: None.
Impact of Obesity on Outcomes of Diabetic Ketoacidosis—Results from the National Inpatient Sample
Authors: ELSHEIKH ARWA , ABDULLAH ABDULLAH , WAHAB ABDUL , EIGBIRE GEORGE E. , SALAMA AMR , RAJAMANI KRISHNAKUMAR
Published: June 2018

Introduction: Obesity is associated with better outcomes in patients with myocardial infarction and sepsis among other conditions a phenomena being described as obesity paradox. The impact of obesity and morbid obesity in DKA is not well studied.

Objective: To estimate the impact of obesity and morbid obesity on in-hospital mortality in patients hospitalized for diabetic ketoacidosis (DKA).

Methods: Data from the National Inpatient Sample (NIS) for the years 2012 to 2014, Health Care Utilization Project were reviewed. Patients with a diagnosis of DKA were included using the relevant ICD 9 codes. The primary outcome measured was in-hospital mortality. The Odds Ratio (OR) adjusted for age, gender, Charlson index and sepsis was calculated for obesity and morbid obesity respectively.

Results: A total of 4,468,339 individuals with a diagnosis of DM were reviewed in this retrospective study. 132,362 patients (2.96%), who had a diagnosis of DKA were included. In patients with DKA, obesity (BMI 30-40) was present in 7,635 (5.77%). Morbid obesity was present in 5,290 (4%). Mortality was 1.8% vs. 1.9%, p=0.65 in patients with obesity and (3.5% vs. 1.9%, p<0.001) in patients with morbid obesity. In multiple logistic regression and after adjustment to age, gender, Charlson index and sepsis, morbid obesity was associated with increased OR for mortality: 1.37 (95% CI, 1.18-1.61).

Conclusion: In patients with DKA, morbid obesity was associated with increased mortality. A BMI of (30-40) was not associated with increased mortality. No protective effect of obesity or morbid obesity (obesity paradox) was observed in our study.

Disclosure

A. Elsheikh: None. A. Abdullah: None. A. Wahab: None. G.E. Eigbire: None. A. Salama: None. K. Rajamani: None.
Racial Differences in Insulin Resistance, Secretion, and Clearance
Authors: KIM SUN H.
Published: June 2018

Hispanics and Asians have a higher risk for type 2 diabetes than non-Hispanic whites (NHW); however, the mechanisms remain unclear. We evaluated differences in insulin physiology and the relationship between obesity and insulin action between NHWs (n=68) compared with Hispanics (n=33) and Asians (n=36). All participants were part of our ongoing registry. All were nondiabetic and had the following measurements: 1) insulin resistance (steady-state plasma glucose, SSPG, using the insulin suppression test, IST); 2) insulin secretion rate (using the graded-glucose infusion test, GGIT); and 3) insulin clearance rate (GGIT). Relationships were compared between measures of obesity (BMI, waist circumference) and SSPG, and between SSPG and insulin secretion rate and clearance rate using multivariate regression. Compared with NHWs, both Hispanics and Asians had higher degrees of insulin resistance than predicted by BMI or WC (Figure, p<0.01). Thus, to achieve the same SSPG concentration, the BMI equivalent of 30 kg/m2 in NHWs was 26 in Hispanics and Asians. Insulin secretion and clearance rates were similar for degree of insulin resistance.

In conclusion, higher risk for diabetes in Hispanics and Asians may relate to greater risk for obesity-associated insulin resistance.

Disclosure

S.H. Kim: None.
Ctgf Promotes Differentiation, Regeneration, and Proliferation of ß Cells
Authors: TOWNSEND SHANNON E. , PASEK RAYMOND , COTTAM MATTHEW A. , GANNON MAUREEN A.
Published: June 2018

One potential model of type 2 diabetes etiology is that those with the disease were born with less β-cell mass making them susceptible to stressors such as obesity. Thus, it would be of therapeutic potential to find mechanisms that increase functional β-cell mass. One candidate that has been studied in our lab is Connective tissue growth factor (Ctgf). Ctgf is a secreted protein known to be involved in cell adhesion, migration and, in some cell types, proliferation. Previous studies in our lab have shown that Ctgf is crucial for β-cell development, with loss of Ctgf resulting in fewer β-cells and decreased β-cell proliferation, thus decreased β-cell mass at birth. Ctgf is also important in situations of metabolic stress, such as pregnancy or β-cell loss. Haploinsufficiency during pregnancy results in decreased maternal β-cell proliferation while in contrast, over-expression of Ctgf results in increased β-cell proliferation and regeneration in a model of partial β-cell ablation. Treatment of human and mouse islets ex vivo with recombinant human Ctgf (rhCTGF) has resulted in increased β-cell proliferation. To determine whether smaller fragments of the 40 kD Ctgf protein can promote proliferation, mouse and human islets were treated with either an N-or C-terminal fragment independently.

Results show that N-terminal Ctgf is responsible for promoting β-cell proliferation in both mouse and human islets. Further studies will elucidate the mechanisms by which Ctgf promotes β-cell proliferation as well as through what receptor it acts on β-cells.

Disclosure

S.E. Townsend: None. R. Pasek: None. M.A. Cottam: None. M.A. Gannon: None.
Adverse Impact of Hashimoto's Thyroiditis on Pancreatic Beta-Cell Function in Type 2 Diabetic Patients
Authors: ZHANG YUANYUAN , SUN RONGXIN , ZHANG LIJIE , FANG YUAN , YU CAIGUO , YUAN SHASHA , FENG YINGMEI , ZHAO DONG
Published: June 2018

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease and often complicated with other metabolic disorders. It has been shown that HT patients have higher levels of antibodies against proinsulin than controls. The incidence of HT in T2DM patients is unclear and has never been studied whether beta cell function differ between T2DM patients alone and complexed with HT.

Methods: 8T2DM patients who were recruited between November 2015 till June 2016 to Endocrinology Center in Lu He hospital were analyzed. HT was diagnosed if either serum TPO antibody or TG antibody exceeded the normal range. After a 12-hour overnight fast, venous blood samples were obtained to measure total cholesterol, triglyceride, HDL-c, FBG, insulin and Scr. Oral glucose tolerance test (OGTT) was examined in the patients and serum c-peptide levels were quantified at 0, 1, 2, and 3 hours after glucose administration.

Results: 8T2DM patients were included in the study. 249 patients were diagnosed HT.Compared with non-HT subjects, T2DM with HT were more males (44.7% vs. 35.2%, p=0.02) and had higher values of systolic blood pressure (133.8 mm Hg vs. 131.1 mmHg, p=0.03). Although age, body mass index, HbA1c, serum cholesterol and serum triglyceride did not differ between two groups (p≥0.17 for all), fasting C-peptide levels were lower in T2DM complicated with HT than T2DM alone (1.09 ±0.90 nmol/L vs. 1.28±0.98 nmol/L, p=0.004). To further compare beta cell function, patients were performed OGTT test. Serum C-peptide levels remained lower at 1 and 2 hours after oral administration of 75-g glucose in T2DM with HT than T2DM alone (1 hour: 2.10±1.77 nMol/L vs. 2.33 ±1.84 nMol/L, p=0.03; 2 hours: 3.04±2.56 vs. 3.47±2.77 nmol/L, p=0.02). Serum C-peptide levels were comparable three hours after 75-g glucose intake (3.16±2.45 nmol/L vs. 3.50±2.78 nMol/L, p=0.49).

Conclusion: The prevalence of HT is relatively high in T2DM patients, which was associated with reduced beta cell function.

Disclosure

Y. Zhang: None. R. Sun: None. L. Zhang: None. Y. Fang: None. C. Yu: None. S. Yuan: None. Y. Feng: None. D. Zhao: None.
Canagliflozin Improves Glycemic Control and Beta-Cell Mass in the TallyHo Polygenic Model of Type 2 Diabetes
Authors: POPESCU IULIANA , MUSSMAN GEORGE M. , HUGHES COREY B. , JANES TERRANCE J. , RAY PHIL , CLAY BUNN R. , FOWLKES JOHN , THRAILKILL KATHRYN M.
Published: June 2018

SGLT2 inhibitors reduce insulin resistance and may improve beta-cell function in humans with T2D. We studied the effects of Canagliflozin (Cana) on glucose homeostasis, islet architecture and endocrine cell fate in male TallyHO/JngJ (TH) mice, a new model of T2D, which mimics many aspects of polygenic T2D in humans. By 8 weeks of age, all TH mice developed moderate obesity and hyperglycemia compared to control SWR/J mice; ∼60% of TH mice converted quickly to overt diabetes, characterized by elevated BG values (>400mg/dL) (HG mice), while the remaining cohort maintained lower BG values (250-400mg/dL) until the end of the study (LG mice). Mice from both groups (HG, LG) were then randomized to receive Chow or Chow-containing Cana (100ppm) diet for 10 weeks, prior to sacrifice. Cana treatment significantly decreased the fasting BG levels only in the HG mice (HG/Cana) compared with untreated HG/Chow mice (207.7±34.6 vs. 452.2±163.4mg/dL, p<0.0001), improved glucose and insulin excursion curves during an ipGTT (p<0.0001 for AUC values) and decreased HbA1c values (4.3±0.7 vs. 6.2±0.93%, p<0.0001). Non-fasting plasma insulin and C-peptide levels, pancreatic insulin content and HOMA-B index were all significantly higher in HG/Cana than in HG/Chow mice, suggesting improved beta-cell function by Cana. Immunofluorescence staining for islet hormones showed that, compared to untreated animals, Cana reestablished the islet area and the beta-cell number/islet in HG mice (possibly due to reduced apoptosis of beta-cells), in addition to decreased number of alpha- and delta-cells/islet. In HG/Cana mice, the majority of Ins+ cells expressed the glucose transporter Glut2, while its expression was undetectable in Ins+ cells of the HG/Chow mice, further suggesting an improvement in glucose sensing capability of beta-cells with Cana treatment. Our study shows that Cana has beneficial effects on preserving beta-cell mass, identity and function in a model of early onset T2D.

Disclosure

I. Popescu: None. G.M. Mussman: None. C.B. Hughes: None. T.J. Janes: None. P. Ray: None. R. Bunn: None. J. Fowlkes: None. K.M. Thrailkill: None.
Diabetes-Specific Risk Taking—Psychometric Properties of a Measure for Adolescents with Type 1 Diabetes (T1D)
Authors: WASSERMAN RACHEL M. , PATTON SUSANA R. , CLEMENTS MARK A. , FINCH JONATHAN H. , BOSCHERT KELSEY , SCHWARTZ DAVID D. , ANDERSON BARBARA
Published: June 2018

Among people with T1D, adolescents have the poorest adherence and worst glycemic control of any other age group, despite recent advances in treatment and technology. Clinically, adolescents are known to take risks with their diabetes care (e.g., driving without first checking blood glucose), but these risky diabetes behaviors have not been empirically studied. We report psychometric properties of the new 31-item Diabetes-Specific Risk-Taking Inventory (DSRI) for youth 15-18 years old. On the DSRI, youth report the frequency they engaged in 31 diabetes-specific risk-taking behaviors over the past year. We surveyed a national sample of 224 adolescents (participants in the T1Dx registry) (M age=16.4±1.1, 47% female, M A1c=8.3±1.3, 76.8% on insulin pumps) in a cross-sectional design. Participants completed the DSRI as well as measures of adherence, general risk-taking, executive functioning, depressive symptoms, and incidence of severe hypoglycemia and DKA over the past year, using a secure web portal, RedCap. The DSRI demonstrated excellent internal reliability (internal consistency: α=.90; item-total correlations: r range=.21-.64). Construct validity was demonstrated through significant associations (all p<.01) with validated measures: more frequent diabetes-specific risk-taking was related to poorer adherence (r=-.75), greater general risk-taking (r=.57), greater executive dysfunction (r=.34), more depressive symptoms (r=-26), and report of severe hypoglycemia over the past year (r=.22). The DSRI was not associated with DKA. Overall, initial psychometrics suggest the DSRI reliably and validly captures risks that adolescents take with their diabetes care. This self-report measure has the potential to be an innovative and actionable clinical tool that can be used to screen for high risk behaviors that are not routinely assessed in clinical care and inform transition readiness from pediatric to adult care.

Disclosure

R.M. Wasserman: None. S.R. Patton: None. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. J.H. Finch: None. K. Boschert: None. D.D. Schwartz: None. B. Anderson: Advisory Panel; Self; Sanofi-Aventis.
Endocannabinoid Receptors Activity Modifies Insulin Secretion in Response to Glucose Exposition
Authors: VILCHES-FLORES ALONSO , GARCIA-LUNA GUADALUPE M.
Published: June 2018

Background: Recent studies suggest the participation of the endocannabinoid system in the development of type 2 diabetes mellitus, involved with the regulation of physiological and metabolic processes. The endocannabinoid system is expressed in pancreatic islets and presents a key role in gene expression and regulation of pancreatic hormones secretion. In type 2 diabetes patients and in obesity the blood levels of endocannabinoids are increased, however, little is known about the mechanism of actions in islets and its relation with glucose in media.

Methods: Isolated pancreatics islets of mouse were incubated for 24 hours at 5.5mM and 15mM glucose concentration, in the presence of anandamide or THC as cannabinoid receptors agonists, or with antagonist AM251. Glucose-stimulated insulin secretion and intracellular cAMP were analyzed by ELISA and cytosolic calcium changes were measured by spectrofluorometry with FURA-2.

Results: Activation of endocannabioid receptors significantly increases cAMP levels at low glucose concentration, meanwhile no further changes were observed at high-glucose concentration, correlated with a similar effect in insulin secretion. Shor-time exposure to the antagonist decreases insulin secretion under both glucose conditions. Anandamide does not induce changes in intracellular calcium but THC decreases it at high glucose concentration. Antagonist AM251 enhances calcium fluctuations, suggestion an indirect modulation of insulin secretion.

Conclusions: Endocannabinoid receptors modulation regulates intracellular mechanisms involved in insulin secretion, according to glucose exposure, in isolated pancreatic mouse islets.

Disclosure

A. Vilches-Flores: None. G.M. Garcia-Luna: None.
PRMT1-Orchestrated Fibroblast Activation in Renal Fibrosis Induced by TGFß/Smad3 Signaling Pathway
Authors: ZHU YU ,   SHANGHAI EAST HOSPITAL
Published: June 2018

TGFβ/Smad3 signaling pathway contributes predominantly to fibroblast activation and epithelial trans-differentiation in diabetic nephrology (DN). Our previous study has demonstrated that protein arginine methyltransferase 1 (PRMT1) mediated glomerular fibrosis in DN via phosphorylation of ERK. However, it is far from clear whether PRMT1 plays an important role in renal fibrosis induced by TGFβ1 signaling pathway. To investigate PRMT1 function, we used AMI-1, a novel inhibitor for PRMT1, in fibroblast both in vitro and in murine unilateral ureteral obstruction (UUO). Immunoblot analysis showed that AMI-1 reduced rat fibroblast cells (NRK-49F) and mouse tubular epithelial cells (mTEC) activation and accumulation of extra cellular matrix(ECM) and phosphorylation of Smad3 induced by serum or TGFβ1 (5ng/ml). The TGFβ1 induced deposited ECM and phosphorous Smad3 synthesis were repressed in NRK-49F transfected with small interfering RNA for PRMT1. Through immunoblot, immunohistochemistry and Masson analysis, UUO induced renal architecture and fibrosis were effectively attenuated by AMI-1 (10mg/kg, intraperitoneal injection once a day). α-SMA and PRMT1 were co-expressed in activated fibroblast in renal glomerular and tubular interstitial induced by UUO in mice and IgA nephrology and diabetic nephrology in human kidneys via dual-immunofluorescence staining. Taken together, our data reveals that AMI-1 presents a restrainable protection on TGFβ1 induced signaling, suggesting that its in-vivo application might extend to the treatment of fibrotic diseases.

Disclosure

Y. Zhu: None.
Improvement of Vascular Endothelial Function at an Early Stage by the Original Stretching Exercise Designed in Our Study Group in Patients with Type 2 Diabetes Mellitus
Authors: HARA KENJI , SHINOZAKI HIROYUKI , YAMAUCHI MOTOTAKA , NARUSE RIKA , SUETSUGU MARIKO , TSUCHIYA TAKAFUMI , TAKEBAYASHI KOHZO , INUKAI TOSHIHIKO
Published: June 2018

Background and Aims: Vascular endothelial cells play an important role in protecting and repairing vessels. It is little known that exercise therapy could ameliorate the vascular endothelial function in diabetic patients. In 2015, in collaboration with Tobu Sports Ltd. (Japan), we created the original exercise program including 12 kinds of body-stretching and converted the program to a DVD. The main aim in the present study is whether the exercise therapy using our original DVD would improve the vascular endothelial function in type 2 diabetic patients.

Subjects and Methods: Ten patients with type 2 diabetic mellitus (M/F: 8/2, Age: 58.2±12.7 years) strictly performed the exercise program using the DVD for 12 weeks. Vascular endothelial function was estimated as a reactive hyperemia index (RHI) measured with Endo PAT (Nihon-Koden Ltd. Japan). Body compositions in patients were measured with MC-780 (Tanita Ltd. Japan). We evaluated CAVI or ABI as marker of arteriosclerosis. Various biomedical parameters were assayed in the study.

Results: There was a significant increase in RHI before and after intervention (initiation: 1.63±0.3, after: 2.02±0.5, p<0.01). A marked increase in RHI was shown in 90% of patients (9/10). A single patient who showed a reduction in RHI was observed going up of HbA1c levels on a background of irregularity of diet therapy. Any significant alterations were obtained in neither metabolic markers including HbA1c, FPG and body compositions, nor CAVI and ABI during the study.

Conclusions: The present study suggests that the intervention of exercise composed by various stretching actions could lead to improvement of vascular endothelial function at an early stage, different from alterations of other metabolic markers in diabetic patients. Thereby, we speculate that vascular endothelial function might be relatively sensitive against a stretching-exercise.

Disclosure

K. Hara: None. H. Shinozaki: None. M. Yamauchi: None. R. Naruse: None. M. Suetsugu: None. T. Tsuchiya: None. K. Takebayashi: None. T. Inukai: None.
FGF-21 as a Potential Mediator for the Antidepressant Effects of Physical Exercise
Authors: LIU YAN , YAU SUK YU , WANG YAO , XU AIMIN
Published: June 2018

Major depressive disorder (MDD), a common psychiatric disease co-morbid with obesity and diabetes, has been one of the most important causes of disability worldwide. Physical exercise by far, is the most effective strategy for the prevention and treatment of MDD. Fibroblast growth factor 21 (FGF-21) is critically involved in energy metabolism and a potential therapeutic agent for treating obesity and its related medical complications. Although the brain is known to be a target of FGF-21 actions, its role in neuropsychological disorders remain unclear. Here, we showed that serum FGF-21 increased progressively with physical exercise and peaked at 3 hours after running, which was 1-2 hours later than that of free fatty acids, suggesting that increased free fatty acids might be the natural agonist of PPARα that induces FGF-21 production during exercise. Real-time PCR analysis further demonstrated that exercise-induced elevation of circulating FGF-21 was predominately from the liver. Furthermore, a series of behavior studies, including tail suspension test, forced swimming test and saccharin preference test uniformly showed that exercise training significantly alleviated depressive symptoms in wild type (WT) mice, which were largely diminished in FGF-21 knockout (KO) mice. Likewise, levels of inflammation markers in the hippocampus were significantly decreased, while synaptic plasticity were notably increased in exercised WT, but not in FGF-21 KO mice, suggesting that inhibition of neuroinflammation and neurogenesis might contribute to the antidepressant effects of FGF-21 during exercise.

In conclusion, FGF-21 is a liver-derived exercise responsive factor mediating the anti-depressant effect of exercise in mice.

Disclosure

Y. Liu: None. S. Yau: None. Y. Wang: None. A. Xu: None.
Effect of Low-Available Carbohydrate Diet with High Dietary Fiber Using Okara and Konjac on Blood Glucose Levels in Mice
Authors: SURUGA KOHEI , KADOKURA KAZUNARI , MIYATA AYAKA , TOMITA TSUYOSHI , SEKINO YOSHIHIRO , TERADA KAZUO , HATA SACHIYO , ASAKA SHIGERU , KAMATA KAZUHIKO , YAMADA SATORU
Published: June 2018

Background: Low-carbohydrate diets (LCD) is popular as nutrition therapy since ADA 2013 recommendation. But, for many patients, it may be difficult to obey LCD, especially in noodle lovers. Recently, we have developed low-available carbohydrate noodle with rich-dietary fiber using Okara and Konjac (O-K mix). Thus, in this study, we evaluated the effect of O-K mix on blood glucose levels in mice model.

Methods: Test 1 (single meal test). ICR mice were divided into two groups: (1) administered 3 g of noodle from O-K mix/kg (O-K noodle); (2) administered 3 g of noodle from flour/kg (N noodle). Test 2 (one month test). KK-Ay mice were divided into three groups: group I, fed a standard chow, SC; group II, fed a SC with 30% O-K mix; group III fed a SC with 50% O-K mix, and were allowed free access to each experimental food for 28 days.

Results: Test 1. The increase in the plasma glucose was significantly suppressed at 30 and 60 min after administration in O-K noodle group (Fig. A). Test 2. Even though the sugar volume was lower in diet of the group II and III than those of group I, no significant differences were observed in volume of food intake and body weight among group I, II, and III. On the other hand, in terms of plasma glucose concentration, there were significant difference in group II and III compared with group I (Fig. B).

Conclusions: O-K mix might be useful for patients with diabetes or celiac disease who love noodle.

Disclosure

K. Suruga: None. K. Kadokura: None. A. Miyata: None. T. Tomita: None. Y. Sekino: None. K. Terada: None. S. Hata: None. S. Asaka: None. K. Kamata: None. S. Yamada: None.
Hemochromatosis and Cystic Fibrosis Carriers Identify Risk for GLP-1 Agonist Associated Pancreatitis
Authors: WEST WILLIAM A. , UWAIFO GABRIEL I.
Published: June 2018

GLP-1 agonists are widely used antidiabetic agents. Among their potential associated side effects is acute pancreatitis (AP). Its exact prevalence is unknown as are known predictors for its incidence. We present two cases that suggest that carrier states for hemochromatosis (HC) and cystic fibrosis (CF) are risk factors for GLP-1 agonist associated AP. Case 1 is a 39 year old Caucasian lady with type 2 diabetes diagnosed 2 years ago. She has morbid obesity, hypothyroidism and NAFLD. She had a history of symptomatic AP to liraglutide (Victoza), exenatide (Byetta), dulaglutide and sitagliptin. She is currently managed with Degludec insulin, repagnilide, metformin and prn Lispro insulin with a current HBA1c of 6.5. Work up for mild transaminitis and prior elevated ferritin revealed she is a heterozygous carrier for the C282Y HC mutation despite currently having normal ferrokinetic profile. Her ongoing glycemic care is now without any further use of GLP-1 analogs nor DPP-4 inhibitors. Case 2 is a 62 year old Caucasian lady with type 2 diabetes diagnosed 8 years ago. She has hypertension, hypercholesterolemia and sleep apnea. She had a history of developing symptomatic AP to exenatide ER (Bydureon), dulaglutide and liraglutide (Victoza). Her current antidiabetic regime consists of Detemir insulin, Aspart insulin prn, metformin, repaglinide, and canagliflozin with a current HBA1c of 7.7. Because of a positive history of CF in several grand children she had genetic testing that showed she is a heterozygous carrier of the Delta F5deletion mutation of the CFTR gene. Her ongoing diabetes care is without any further use of GLP-1 analogs. Our case series present two patients with class associated predilection for GLP-1 analog associated AP. Heterozygous carrier states for CF and HC may represent at risk clinical phenotypes for GLP-1 AP. Consideration should be given to genetic screening for these carrier states prior to commencing diabetic patients on GLP-1 analogs and possibly also DPP-4 inhibitors.

Disclosure

W.A. West: None. G.I. Uwaifo: None.
Effect of Lupin Flour on Corn Oil–Induced Insulin Resistance in C57BL/6 Mice
Authors: TERRUZZI ILEANA , VACANTE FERNANDA , SENESI PAMELA , MONTESANO ANNA , CODELLA ROBERTO , LUZI LIVIO
Published: June 2018

As the rate of obesity and type-2 diabetes is constantly increasing, there is a need to develop new therapeutic approaches with better effects and lower side effects at lower prices. The use of traditional foods with beneficial health properties could be a solution. Lupin, a legume rich in proteins, exerts a hypoglycemic effects and positively modifies proteins involved in glucose homeostasis, in both animals and humans. The aim of this study was to investigate the beneficial effects of lupin flour supplementation on glucose homeostasis using an in vivo model. The condition of insulin resistance (IR) was induced by diet containing corn oil (4%). Ten-week-old male C57BL/6 mice were given ad libitum access to a corn bean meal diet for 9 weeks (CD) or a cornbean meal diet enriched with 2% lupine flour (LC). Food intake was evaluated daily and body weight was measured weekly. Intra-peritoneal glucose tolerance test (IPGTT) was performed to assess the body’s ability to metabolize glucose. Food was removed 15 h before the start of IPGTT, and mice body weights after food deprivation were used to calculate glucose doses. Blood glucose and plasma insulin concentrations were measured. The quantity of food ingested was similar between groups. At the 9th week of treatment, the time-course of glucose clearance in both groups remained elevated for 120 min after glucose administration, indicating a glucose intolerance state. However, HOMA-IR was significantly lower (p=0.02) in LC than in CD group: the LC group showed significantly lower plasma insulin (2.09 ± 0.53 ng/mL) (p = 0.002) than the CD group (3.34 ± 0.56 ng/mL) while plasma glucose did not differ between groups (140 ± 24.9 mg/dL vs. 138 ± 35.5 mg/dL). These biological effects of lupine flour strengthen its promising potential as a new therapeutic agent of treatment for human insulin resistance conditions.

Disclosure

I. Terruzzi: None. F. Vacante: None. P. Senesi: None. A. Montesano: None. R. Codella: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.
Diabetes Patients’ Perception of Diet—Facts and Fads
Authors: ERUKULAPATI RAVI S. , YALAMANCHILI SANDHYA , RANI SUDHA
Published: June 2018

Aim: Diet and knowledge of it plays a crucial role in the management of diabetes. The purpose of the study was to survey diabetes patients’ awareness of the basic ingredients of diet and their insights into the facts and fads of their daily dietary constituents.

Methods: An objective qualitative questionnaire-based assessment was performed among outpatient diabetes patients who visited Apollo Sugar diabetes care center in a metropolitan city, India. The questionnaire was answered by patients in a simple ’Yes’ or ’No’ format relevant to their awareness of various foods. The questions were about the protein, carbohydrate, fat constitution, quantity that could be consumed, and myths surrounding various food products they come across in their daily routine. Patients’ perception of diet was categorized into ’correct’ and ’incorrect’ depending on their response to each question mentioned in a 10-point questionnaire. A score of ’1’ was given for each ’correct’ answer and ’0’ for an ’incorrect’ answer. Total maximum score each diabetic patient can score is 10/10 and a minimum of 0/10. Appropriate statistics were applied to test the results at significance p ≤0.05.

Results: Total 581 patients with diabetes were assessed in this study. Patients included were in age range 16 to 85 years with median age of 56 years. Males and females were 60% and 40%, respectively. Among these patients a mean score of 4.5 and median score of 4 was achieved in the questionnaire. 35 (6%) patients achieved the maximum score of 10/10 and 74 (12.7%) patients had a minimum score of 0/10. There was no significant difference in the mean score achieved between males (4.1) and females (3.9). Though it was not statistically significant there was a negative correlation between age and the score (-0.06; p = 0.2).

Conclusion: The survey gave us useful insights into the lack of awareness about daily food products in diabetic patients. Majority of them didn’t have adequate knowledge, which recommends for a thorough diet counseling to improve their dietary patterns for better clinical outcomes.

Disclosure

R.S. Erukulapati: None. S. Yalamanchili: None. S. Rani: None.
eGFR Changes in Overweight/Obese Mexican-American Children
Authors: QUINTANA FERNANDO G. , WANG HONGWEI , CERVANTES-GONZALEZ FRANCISCO J. , PEREZ MAYRA A.
Published: June 2018

Researchers have reported that there is an association between BMI and eGFR. AS BMI increases chronic kidney disease prevalence increases in adults.

Purpose: the aim of this study is to analyze the relationship between eGFR vs. BMI and age for overweight and obese boys and girls visiting a pediatric clinic in South Texas.

Methods: to calculate eGFR the “Bedside Schwartz” formula: eGFR = 0.413 x (height/SCr) height expressed in centimeters was used to estimate kidney function for 583 girls and 650 boys visiting a pediatric clinic from 2001 to 2017. The children were classified as overweight and obese according with CDC BMI percentiles. Age in years were classified as follows. 1-4.9; 5-7.9; 8-10.9; 11-12.9; 13-15.9 and 16+ years. A general linear model: GFR = BMI + Age + Age*Age was used to analyze the data. IRB approval #2016-01-31 was obtained from the TAMIU IRB.

Results: girls: BMI levels were not significantly different. Age was significantly different (df=5, F=11.64, p<0.05), the interaction was not significant. The eGFR means by age were as follows: overweight: 128.19; 138.83; 136.73; 133.69; 120.11; 107.21. Age groups 5 and 6 were different from groups 1, 2, 3 and 4 (p<0.05). Obese: 127.41; 131.71; 130.58; 135.55; 121.00; 112.35. Age groups 5 and 6 were different from groups 1, 2, 3 and 4 (p<0.05), Graph 1. Boys: BMI levels were not significantly different. Age levels were significantly different (df=5, F=20.96; p<0.05), the interaction was not significant. The eGFR means by age were as follows: overweight: 133.84; 134.61; 136.91; 127.91; 120.51; 98.52. Age groups 5 and 6 were different from groups 1, 2, 3, and 4 (p<0.05). Obese: 126.74; 135.12; 140.23; 137.44; 117.64; 96.58 (p<0.05), Graph 2.

Conclusion: The results support that eGFR decreases as age increases for overweight and obese children from age 1 to age 16+. Therefore we can hypothesize that there is a relationship between kidney function and children overweight and obesity as age increases for the population of boys and girls studied.

Disclosure

F.G. Quintana: None. H. Wang: None. F.J. Cervantes-Gonzalez: None. M.A. Perez: None.
Fast Insulin Secretion Blunted by Impaired Insulin Storage of Islet ß Cells in Mice
Authors: ZHAO YINAN , ZHAO TIAN , ZONG AILUN , ZHOU YINGSHENG
Published: June 2018

Purpose: To clarify the effects of cellular insulin content and restoration on fast insulin secretion after acute hyperglycemia challenges.

Methods: To analyze the impairment and recovery mechanisms of acute hyperglycemia on the first phase insulin secretion, we evaluated the function of insulin secretion by glucose tolerance test. To explore the ramification of insulin secretion and storage in pancreatic islets after acute hyperglycemia challenges, we isolated the islet for GSIS and measured insulin content in vitro. HE for pancreas tissues were performed to study morphologic changes of the islets and to assess the impact of acute hyperglycemia on islet histology. EM for β cells were used to study morphologic changes of insulin granules.

Results: The mice with acute hyperglycemia showed, (1) blunted early insulin secretion in impaired glucose tolerance test; (2) disrupted insulin secretion using static islet incubation at low (2.8 mmol/l), high (16.7 mmol/l) glucose, 30 or 40mmol/l Potassium Chloride stimulus; (3) lack of intracellular insulin content. Five days after termination of hyperglycemic treatment, blunted early insulin secretion and glucose levels were completely reversed in the glucose tolerance test, but insulin contents in islet study did not return to the values of the control groups. In morphological study, irregular islets in HE and decreased insulin granules in EM caused by hyperglycemia did not alleviate.

Conclusions: Blunted fast insulin secretion and impaired glucose tolerance caused by acute intravenous hyperglycemia can be reversed, but poor insulin storage remained.

Disclosure

Y. Zhao: None. T. Zhao: None. A. Zong: None. Y. Zhou: None.
Predicting Future Glycemic Trajectories with a Mathematical Model
Authors: HA JOON , CHEN PHIL H. , SHERMAN ARTHUR
Published: June 2018

Diverse pathogenesis pathways to type 2 diabetes make optimal care and prevention challenging. Identifying heterogeneous metabolic parameters of patients would be beneficial for developing personalized therapies and prediction of future glycemia. As such, we developed a mathematical model based on Ha et al. Endo 2016,) to extract metabolic parameters of patients and predict their future glycemic trajectories. We fitted longitudinal Oral Glucose Tolerance Test data from a cohort of Pima Indians to predict future glycemic trajectories. First, we estimated three major metabolic parameters from a single OGTT: peripheral insulin sensitivity, hepatic insulin sensitivity, and beta-cell function. Insulin sensitivity estimated by the fitting algorithm correlated well with insulin sensitivity measured by insulin clamp and MINMOD, R2 =0.5 in both cases. Second, we used the fits to two OGTTs separated in time by several years to estimate capacity of beta-cell function to compensate for insulin resistance. Third, we found a strong correlation between an individual’s BMI and insulin sensitivity, R2 =0.75. Using a range of projected BMIs, the model predicts future glycemia. When measured BMIs from later time points were used, the future glycemic trajectory was accurately predicted. The mathematical model has great potential for clinical application in guiding therapy.

Disclosure

J. Ha: None. P.H. Chen: None. A. Sherman: Other Relationship; Self; Eli Lilly and Company.
CoMac Communication System—A Feasibility Implementation of Language-Centered Intervention for T2DM
Authors: CONNOR ULLA M. , SANDY ROBERT , GROOT MARY DE , MACNEILL ROBERT S.
Published: June 2018

The CoMac Communication System is a scientifically tested set of tools to individualize Diabetes Self-Management Education and Support (DSMES), by speaking to persons with type 2 diabetes (T2DM) using their own language and worldviews.

In this quasi experimental study, conducted in a Midwestern diabetes care clinic with an accredited DSMES, a tablet was provided for patients to complete the CoMac segmentation survey. Altogether 72 patients took the survey and received the tailored communication. An unplanned control group of 48 patients emerged, due to occasional unavailability of the tablet/survey. These patients received the clinic’s standard DSMES, without the use of the CoMac tools. A1C levels from the first visit to the follow-up visit for each group were compared.

Interviews with the healthcare providers (HCPs), conducted during the six-month study, provided evidence about the success of the implementation. Individual psychosocial profiles and language recommendations helped HCPs better align their language. “Words matter” led to more efficient and effective behavioral goal settings with the patients.

The A1Cs of the intervention group decreased from 8.9 to 7.3, the control group’s from 8.3 to 7.6. A multiple regression analysis with the A1C level change as the dependent variable showed that the independent variables of age, gender, and starting weight were not significant predictors of A1C reduction. Statistically significant were the starting value of A1C and the CoMac intervention. Patients with higher initial A1Cs showed a greater decline in A1Cs. The key variable of interest, treated with the CoMac intervention, had a t-value of -1.81, with a prob value of 0.037. Although a cause-and-effect relationship cannot be proven without random assignment, the significantly improved A1Cs of the intervention group are highly encouraging.

As diabetes care teams and delivery models expand, person-centered language tools are an innovation in effective management of DSMES.

Disclosure

U.M. Connor: Other Relationship; Self; CoMac Analytics, Inc..R. Sandy: None. M. de Groot: Consultant; Self; Johnson & Johnson Diabetes Institute, LLC., Eli Lilly and Company. R.S. MacNeill: Other Relationship; Self; comAc analytics inc.