Body Insulin Sensitivity Research Articles

Sleeve Gastrectomy with Bypass of Proximal Small Intestine Provides Better Diabetes Control than Sleeve Gastrectomy Alone Under Postoperative High-Fat Diet.

Sleeve gastrectomy (SG) plus procedures have been developed to strengthen the effect of SG on diabetes control. The aim of this study was to compare diabetes control after SG plus bypass of the proximal small intestine with SG alone under adverse conditions for diabetes remission. SG plus duodenojejunal bypass (SG-DJB), SG plus jejunojejunal bypass (SG-JJB), SG alone, and sham surgeries were performed in diabetic rats. A high-fat diet (HFD) was fed postoperatively to induce diabetes recurrence. Body weight, food intake, glucose tolerance, insulin sensitivity, serum hormones, hepatic function, and lipid profiles were measured postoperatively. SG-DJB, SG-JJB, and SG groups exhibited significant improvement in glucose tolerance and insulin sensitivity compared with the sham-operated group at 2weeks postoperatively. Postoperative HFD induced obvious diabetes relapse and re-impaired insulin sensitivity at 16weeks postoperatively. The SG-DJB and SG-JJB groups exhibited superior glucose tolerance and similar insulin sensitivity to SG alone at 16weeks postoperatively. Compared with the SG alone, the SG-DJB and SG-JJB groups exhibited similar food intake, weight loss, fasting ghrelin, glucose-stimulated insulin secretion, and higher glucose-stimulated GLP-1 secretion. SG-DJB and SG-JJB provided better diabetes control than SG alone in rats fed a HFD postoperatively. Further clinical studies are expected to confirm the superiority of SG plus bypass of proximal small intestine.

A Plant-Based High-Carbohydrate, Low-Fat Diet in Overweight Individuals in a 16-Week Randomized Clinical Trial: The Role of Carbohydrates.

The effects of carbohydrates on body weight and insulin sensitivity are controversial. In this 16-week randomized clinical trial, we tested the role of a low-fat, plant-based diet on body weight, body composition and insulin resistance. As a part of this trial, we investigated the role of changes in carbohydrate intake on body composition and insulin resistance. Participants (n = 75) were randomized to follow a plant-based high-carbohydrate, low-fat (vegan) diet (n = 38) or to maintain their current diet (n = 37). Dual-energy X-ray absorptiometry was used to measure body composition. Insulin resistance was assessed with the Homeostasis Model Assessment (HOMA-IR) index. A repeated measure ANOVA model was used to test the between-group differences from baseline to 16 weeks. A linear regression model was used to test the relationship between carbohydrate intake, and body composition and insulin resistance. Weight decreased significantly in the vegan group (treatment effect −6.5 [95% CI −8.9 to −4.1] kg; Gxt, p < 0.001). Fat mass was reduced in the vegan group (treatment effect −4.3 [95% CI −5.4 to −3.2] kg; Gxt, p < 0.001). HOMA-IR was reduced significantly in the vegan group (treatment effect −1.0 [95% CI −1.2 to −0.8]; Gxt, p = 0.004). Changes in consumption of carbohydrate, as a percentage of energy, correlated negatively with changes in BMI (r = −0.53, p < 0.001), fat mass (r = −0.55, p < 0.001), volume of visceral fat (r = −0.35, p = 0.006), and HOMA (r = −0.27, p = 0.04). These associations remained significant after adjustment for energy intake. Changes in consumption of total and insoluble fiber correlated negatively with changes in BMI (r = −0.43, p < 0.001; and r = −0.46, p < 0.001, respectively), fat mass (r = −0.42, p < 0.001; and r = −0.46, p < 0.001, respectively), and volume of visceral fat (r = −0.29, p = 0.03; and r = −0.32, p = 0.01, respectively). The associations between total and insoluble fiber and changes in BMI and fat mass remained significant even after adjustment for energy intake. Increased carbohydrate and fiber intake, as part of a plant-based high-carbohydrate, low-fat diet, are associated with beneficial effects on weight, body composition, and insulin resistance.

Exposure to antipsychotics, especially olanzapine, associated with increased body fat in young patients

A randomized clinical trial involving youths ages 6 to 18 who received an antipsychotic for symptoms of aggression has found that antipsychotic exposure was associated with adverse changes in body fat and insulin sensitivity. These findings raise concern because these factors are known contributors to early‐onset type 2 diabetes and cardiovascular disease.

Effects of four weeks intermittent hypoxia intervention on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, and Akt activity in skeletal muscle of obese mice with type 2 diabetes.

AimsThe aims of this study were to determine the effects of four weeks of intermittent exposure to a moderate hypoxia environment (15% oxygen), and compare with the effects of exercise in normoxia or hypoxia, on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, Akt-dependent GSK3 phosphorylation and Akt activity in skeletal muscle of obese mice with type 2 diabetes.MethodsC57BL/6J mice that developed type 2 diabetes with a high-fat-diet (55% fat) (fasting blood glucose, FBG = 13.9 ± 0.69 (SD) mmol/L) were randomly allocated into diabetic control (DC), rest in hypoxia (DH), exercise in normoxia (DE), and exercise in hypoxia (DHE) groups (n = 7, each), together with a normal-diet (4% fat) control group (NC, FBG = 9.1 ± 1.11 (SD) mmol/L). The exercise groups ran on a treadmill at intensities of 75–90% VO2max. The interventions were applied one hour per day, six days per week for four weeks. Venous blood samples were analysed for FBG, insulin (FBI) and insulin sensitivity (QUICKI) pre and post the intervention period. The quadriceps muscle samples were collected 72 hours post the last intervention session for analysis of GLUT4 translocation, insulin receptor phosphorylation, Akt expression and phosphorylated GSK3 fusion protein by western blot. Akt activity was determined by the ratio of the phosphorylated GSK3 fusion protein to the total Akt protein.ResultsThe FBG of the DH, DE and DHE groups returned to normal level (FBG = 9.4 ± 1.50, 8.86 ± 0.94 and 9.0 ± 1.13 (SD) mmol/L for DH, DE and DHE respectively, P < 0.05), with improved insulin sensitivity compared to DC (P < 0.05), after the four weeks treatment, while the NC and DC showed no significant changes, as analysed by general linear model with repeated measures. All three interventions resulted in a significant increase of GLUT4 translocation to cell membrane compared to the DC group (P < 0.05). The DE and DH showed a similar level of insulin receptor phosphorylation compared with NC that was significantly lower than the DC (P < 0.05) post intervention. The DH and DHE groups showed a significantly higher Akt activity compared to the DE, DC and NC (P < 0.05) post intervention, as analysed by one-way ANOVA.ConclusionsThis study produced new evidence that intermittent exposure to mild hypoxia (0.15 FiO2) for four weeks resulted in normalisation of FBG, improvement in whole body insulin sensitivity, and a significant increase of GLUT4 translocation in the skeletal muscle, that were similar to the effects of exercise intervention during the same time period, in mice with diet-induced type 2 diabetes. However, exercise in hypoxia for four weeks did not have additive effects on these responses. The outcomes of the research may contribute to the development of effective, alternative and complementary interventions for management of hyperglycaemia and type 2 diabetes, particularly for individuals with limitations in participation of physical activity.

Estrogen replacement enhances insulin-induced AS160 activation and improves insulin sensitivity in ovariectomized rats.

Menopause predisposes women to impaired glucose metabolism, but the role of estrogen remains unclear. In this study, we examined the effects of chronic estrogen replacement on whole body insulin sensitivity and insulin signaling in ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized under anesthesia. After 4 wk, pellets containing either 17β-estradiol (E2) or placebo (Pla) were subcutaneously implanted in the rats. After 4 wk of treatment, the intra-abdominal fat accumulation was greater in the Pla group than that in the E2 group. Hyperinsulinemic-euglycemic clamp analysis and intravenous glucose tolerance test revealed that insulin sensitivity was significantly lower in the Pla group than in the E2 group. In addition, Western blotting showed that in vivo insulin stimulation increased protein kinase B (Akt) phosphorylation to a similar degree in the gastrocnemius and liver of both groups, but phosphorylated Akt2 Ser474 was enhanced in the muscle of the E2 group compared with the Pla group. Moreover, insulin-stimulated phosphorylation of Akt substrate of 160 kDa (AS160) Thr642 was observed only in the E2 group, resulting in the difference between the two groups. Additionally, AS160 protein and mRNA levels were higher in muscle of the E2 group than the Pla group. In contrast, E2 replacement had no effect on glucose transporter 4 protein levels in muscle and glycogen synthase kinase-3β in muscle and liver. These results suggest that estrogen replacement improves insulin sensitivity by activating the Akt2/AS160 pathway in the insulin-stimulated muscle of ovariectomized rats.

Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis

Type 2 diabetes is preceded by a prediabetic stage of impaired glucose tolerance that affects 10-23% of youth and is expected to double over the next decade. The natural history of impaired glucose tolerance and the determinants of β-cell dynamic response have never been investigated longitudinally in young people. We aimed to investigate the clinical and metabolic determinants of longitudinal glucose tolerance changes and β-cell function in a multiethnic cohort of obese youth. We followed up prospectively a multiethnic cohort of overweight and obese (body-mass index >85th percentile) adolescents with baseline normal glucose tolerance (plasma glucose <140 mg/dL) or impaired glucose tolerance (plasma glucose 140-199 mg/dL) at the Yale Pediatric Obesity Clinic (CT, USA). All participants underwent a 3-h oral glucose tolerance test at baseline and after 2 years to estimate insulin secretion (oral disposition index) in the context of body insulin sensitivity. As part of standard care at the clinic, all participants received dietary advice and underwent dietary assessment every 5-6 months. No structured lifestyle or pharmacological intervention was administered. Between January, 2010, and December, 2016, 526 adolescents (mean age 12·7 years, range 10·6-14·2) were enrolled to our study. At baseline, 364 had normal and 162 had impaired glucose tolerance. Median follow-up was 2·9 years (IQR 2·7-3·1). 105 (65%) of 162 with impaired glucose tolerance at baseline reverted to normal glucose tolerance at follow-up, 44 (27%) had persistent impaired glucose tolerance, and 13 (8%) progressed to type 2 diabetes. A feature of reversion to normal glucose tolerance was a roughly four-fold increase in the oral disposition index (from median 0·94 [IQR 0·68-1·35] at baseline to 3·90 [2·58-6·08] at follow-up; p<0·0001) and a significantly higher oral disposition index at follow-up compared with participants who maintained normal glucose tolerance across the study period (median 3·90 [IQR 2·58-6·08] vs 1·59 [1·12-2·23]; p<0·0001). By contrast, a decrease in insulin secretion was seen in participants who had persistent impaired glucose tolerance (median 1·31 [IQR 1·01-1·85]; p<0·0001) or who progressed to type 2 diabetes (0·20 [0·12-0·58]; p<0·0001), compared with participants who maintained normal glucose tolerance across the study period. Non-Hispanic white ethnic origin conferred five times the odds of reversion to normal glucose tolerance compared with non-Hispanic black ethnic origin (OR 5·06, 95% CI 1·86-13·76; p=0·001), with a two times greater annual increase in the oral disposition index (β 2·32, 95% CI 0·05-4·60; p=0·045). Impaired glucose tolerance is highly reversible in obese adolescents. Ethnic origin is the main clinical modifier of the dynamic β-cell response to prediabetic hyperglycaemia and, thus, determines the reversibility of impaired glucose tolerance, or its persistence. Therapeutic interventions for impaired glucose tolerance should target the specific mechanisms underpinning glucose tolerance changes in high-risk ethnic groups. National Institutes of Health (National Institute of Child Health and Human Development, National Center for Research Resources, and National Institute of Diabetes and Digestive and Kidney Diseases), American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, Robert Leet Patterson and Clara Guthrie Patterson Trust, European Society for Pediatric Endocrinology, American Heart Association, and the Allen Foundation.

Association Between Plasma Metabolites and Insulin Sensitivity Indexes in Fat-Tailed and Thin-Tailed Lambs During Negative and Positive Energy Balances

Background: Fatty acid mobilization and inflammatory response of adipose tissues vary in various depots, hence the response of fat-tailed and thin-tailed sheep breeds to different energy balances was hypothesized to be different due to differences in proportion and metabolism of various adipose depots in these breeds which may affect whole body insulin sensitivity. Objective: Current study aimed to evaluated the changes in plasma metabolites including non-esterified fatty acid (NEFA), glucose, insulin, triglyceride (TG) and tumor necrosis factor-alpha in response to negative and positive energy balances and their correlation with insulin sensitivity indexes in Lori-Bakhtiari fat-tailed and Lori-Bakhtiari × Romanov cross breed thin-tailed lambs. Methods: Thirty-six male lambs (18 fat-tailed and 18 thin-tailed lambs) were placed in individual pens and experienced periods of negative (21 d) and positive (21 d) energy balances. Lambs were bled weekly to measure plasma metabolites. Pearson correlation coefficients among variables were generated using Proc Corr of SAS. Results: In thin-tailed but not fat-tailed lambs, plasma NEFA showed a negative correlation with plasma glucose (R = -0.47; P < 0.0003) and insulin (R = -0.46; P < 0.0005) content. Plasma NEFA negatively correlated with revised quantitative insulin sensitivity check index (RQUICKI) and severity of the correlation was higher in fat-tailed (R = -0.58; P < 0.0001) comparing to thin-tailed (R = -0.40; P < 0.003) lambs. In fat-tailed lambs, plasma NEFA and insulin were the most influential factors on RQUICKI, whereas in thin-tailed lambs, insulin was the main factor affecting RQUICKI. Conclusion: The results of current study demonstrate that despite higher basal and negative energy balance induced plasma NEFA content in thin-tailed lambs, the contribution of plasma NEFA to insulin resistance was higher in fat-tailed lambs, whereas negative correlation between plasma NEFA and insulin content in thin-tailed lambs demonstrate higher sensitivity of insulin secretion capacity to plasma NEFA content.

The Role of Physical Exercise in Obesity and Diabetes.

The prevalence of obesity is increasing world-wide. Obesity is associated with a plethora of metabolic and clinical constraints, which result in a higher risk for the development of cardiovascular complications and metabolic disease, particularly insulin resistance and type 2 diabetes. Obesity is an acknowledged determinant of glycemic control in patients with type 1 diabetes and accounts for the majority of premature death due to cardiovascular events. Physical exercise is generally recommended in patients with diabetes in order to prevent the development of or reduce existing obesity, as adopted by every international treatment guideline so far. Regular physical exercise has a beneficial impact on body composition, cardiovascular integrity, insulin sensitivity and quality of life. However, only a minority of patients participates in regular physical exercise, due to individual or disease-related barriers. In type 2 diabetes, there is robust evidence for beneficial effects of physical exercise on glycemic control, cardiovascular health and the development of diabetes-related long-term complications. In type 1 diabetes and patients treated with insulin, a higher risk for exercise-related hypoglycemia has to be considered, which requires certain prerequisites and adequate adaptions of insulin dosing. Current treatment guidelines do only incompletely address the development of exercise-related hypoglycemia. However, every patient with diabetes should participate in regular physical exercise in order to support and enable sufficient treatment and optimal glycemic control.

Parental obesity is associated with the severity of childhood obesity and its comorbidities

The influence of parental obesity on their obese offsprings is acknowledged but insufficiently characterised. Retrospective study of 800 obese patients (45.2% girls; age: 10.35±3.40 years, body mass index [BMI]:+4.22±1.68 standard deviation score [SDS]). Group comparison according to the presence of obesity in none (n=347) or any of the parents (n=453), and then whether the obese parent was the father (n=185), the mother (n=151), or both parents (n=117) were performed. The parameters analysed were: Age at the onset of the obesity and at their first visit, birth weight (BW), BMI-SDS, blood glucose, insulin level, homeostatic model assessment (HOMA) index, total cholesterol (TC), HDL, LDL, triglycerides, 25-OH-vitamin-D, area under the curve (AUC) for insulin in the oral glucose tolerance test (OGTT), whole body insulin sensitivity index (WBISI), LDL/HDL and TC/HDL ratios, and weight loss after 12 month follow-up. No differences were observed between groups as regarding gender, ethnic background, or pubertal stage. Patients with one obese parent showed higher BW-SDS and BMI-SDS (P<.01), more severe impairment of carbohydrate metabolism (blood insulin, insulin-AUC, HOMA, HbA1c [P<.01] and lower WBISI [P<.05]) than those with no obese parent. Among those patients with a single obese parent, higher BW-SDS, insulin, HOMA, and lower 25-OH-vitamin D (P<.05) was observed when obesity was present in the mother. There was a higher prevalence of metabolic syndrome when both parents were obese (χ2=5.96, P<.05). A total of 132 patients reduced their BMI by ≥1.5SDS, or their weight by ≥10%, with no influence of the background of parental obesity. Obesity in any parent determines a higher severity of their offspring obesity and metabolic comorbidities, more importantly when obesity is present in the mother or in both parents, but without interference in the options of therapeutic success.

A long-acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-adiponectin-IL17A pathway.

Non-alcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. However, the disadvantages of FGF21 as a clinically useful medicine include its short plasma half-life and poor drug-like properties. Here, we have explored the effects of PsTag600-FGF21, an engineered long-acting FGF21 fusion protein, in mice with NASH and describe some of the underlying mechanisms. A long-acting FGF21 was prepared by genetic fusion with a 600 residues polypeptide (PsTag600). We used a choline-deficient high-fat diet-induced model of NASH in mice. The effects on body weight, insulin sensitivity, inflammation and levels of hormones and metabolites were studied first. We further investigated whether PsTag600-FGF21 attenuated inflammation through the Th17-IL17A axis and the associated mechanisms. PsTag600-FGF21 dose-dependently reduced body weight, blood glucose, and insulin and lipid levels and reversed hepatic steatosis. PsTag600-FGF21 enhanced fatty acid activation and mitochondrial β-oxidation in the liver. The profound reduction in hepatic inflammation in NASH mice following PsTag600-FGF21 was associated with inhibition of IL17A expression in Th17 cells. Furthermore, PsTag600-FGF21 depended on adiponectin to exert its suppression of Th17 cell differentiation and IL17A expression. Our data have uncovered some of the mechanisms by which PsTag600-FGF21 suppresses hepatic inflammation and further suggest that PsTag600-FGF21 could be an effective approach in NASH treatment.

Lower Hepatic Insulin Sensitivity in a Family with a Recently Described Glucokinase Gene Variant

Mutations in the gene encoding glucokinase (GCK) cause maturity-onset diabetes of the young (MODY) 2, characterized by impaired prandial insulin secretion and hepatic glycogen storage. Recently diagnosed patients with type 1 diabetes (T1D) exhibit impairment of both beta cell function and hepatic energy metabolism. Thus, this study aimed at examining the effect of MODY 2 on hepatic insulin sensitivity and energy metabolism. Carriers of one recently described GCK mutation (D124N; c.370, GAC&amp;gt;AAC in exon 4) were compared to controls (CON) with similar sex, age and body mass index (BMI) (female/male: 1/2 vs. 3/6; 36±4 vs. 35±2 years; 20.1±1.6 vs. 25.7±1.5 kg/m2) from the German Diabetes Study (Registration_Clinicaltrials.gov NCT01409330). Whole body and hepatic insulin sensitivity (IS) were assessed by Botnia-clamp tests with [6,6-2H2]glucose. Beta cell function was determined from incremental AUC(C-peptide)0-60min/δAUC(glucose)0-60min during intravenous glucose tolerance test. Hepatocellular lipid content (HCL), γATP and inorganic phosphate (Pi) were measured with by 1H/31P magnetic resonance spectroscopy. MODY 2 patients had higher hemoglobin A1c (6.1±0.1 vs. 5.2±0.1%, p&amp;lt;0.001) along with approximately 62% lower glucose-stimulated C-peptide secretion than CON (p&amp;lt;0.05). They also had lower hepatic IS (1.8±0.1 vs. 2.3±0.1 mg/(kg*min), p&amp;lt;0.05), but similar whole body IS (12.6±1.9 vs. 13.1±1.5 mg/(kg*min), p=0.87) compared to CON. However, HCL (1.0±0.9 vs. 0.5±0.2%, p=0.46), γATP (3.5±0.3 vs. 3.5±0.6 mmol/l, p=0.99) and Pi (1.9±0.5 vs. 2.9±0.7 mmol/l, p=0.45) in the liver were comparable between both groups. In conclusion, these data show that lower hepatic IS, but not abnormal hepatic energy metabolism, underlies the previously reported reduction in prandial hepatic glycogen synthesis. Moreover, impairment of hepatic IS is not necessarily associated with hepatic mitochondrial function. Disclosure K. Bódis: None. O.P. Zaharia: None. Y. Karusheva: None. P. Bobrov: None. D.F. Markgraf: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Müssig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. J. Szendroedi: None.

Effect of Obesity and Exercise on Amino Acid Metabolites in American-Indian Adolescents at Risk for Diabetes

Circulating amino acids (AA) and their metabolites are biomarkers for insulin resistance and future diabetes in adults, but there are few, and conflicting findings in studies of adolescents. We performed amino acid metabolomic profiling in American Indian adolescents to determine whether specific analytes would vary with body composition and insulin sensitivity, and/or be altered in response to exercise training. Boys and girls, 11-18 years who were normal weight (NW, n=36) or obese (Ob, n=58) completed tests of fitness, body composition, and a fasting blood draw. Forty-two of the Ob group were retested after completing 16 weeks of aerobic exercise training. A panel of 42 plasma amino acids and metabolites were measured by UPLC/MS/MS. The Ob group had several risk factors for future diabetes, including higher body fat, lower aerobic fitness, and lower insulin sensitivity (iHOMA2). The Ob group had 16 analytes that were higher and 8 lower than the NW group. Among those that were higher in the Ob group were branched chain AAs (Val, Leu, Ile, +13-17%) and aromatic AAs (His, Phe, Tyr, +15-34%); those AAs were also correlated with body fat (r=0.32 to 0.53) and insulin sensitivity (r=-0.32 to -0.60). The Lys metabolite, α-aminoadipic acid, a predictor of diabetes in adults, was 46% higher in the Ob group and correlated with insulin sensitivity (r=-0.43). β-aminoisobutyric acid, a myokine related to insulin resistance in adults, was 29% lower in the Ob vs. the NW group and correlated with insulin sensitivity (r=0.32). Exercise training resulted in a 10% increase in aerobic fitness, but body composition and insulin sensitivity were unchanged. Only two AAs were changed (His, Cys) after training. These novel findings in adolescents demonstrate that several plasma AAs are altered by obesity and serve as biomarkers of insulin action, but are not altered with this exercise intervention. Disclosure K.R. Short: None. J. Chadwick: None. M.A. Tullier: None. L.D. Wolbert: None. C.L. Coleman: None. K.C. Copeland: Other Relationship; Self; Novo Nordisk Inc..

Increased Gluconeogenesis Is Not an Early Feature of Whole-Body Insulin Resistance in Black Women—The Federal Women Study

In contrast to white women, fasting hyperglycemia is not an early diabetes risk marker in black women. The etiology of this racial difference in risk is unknown but could be related to differences in rates of gluconeogenesis and hepatic fat in black women. Using stable isotope tracers [2H2O], [6,62H2]glucose, and ([2H5]glycerol), we partitioned basal glucose production into its two components (gluconeogenesis and glycogenolysis) and measured basal whole body lipolysis. Whole body (SI), hepatic (HIS) and adipose tissue insulin sensitivity were calculated in two groups of federally employed pre-menopausal women, without diabetes: 24 black and 19 white; age 37±6 (mean±SD), range 25-50y; BMI 33±6, range 24.9-45.2 kg/m2. Hepatic and visceral fat were measured by proton MRS. The prevalence of prediabetes (17% vs. 26%), age and BMI were similar in blacks and whites, all P&amp;gt;0.4). Black women had less fasting hyperglycemia (4% vs. 22%, P=0.1), lower visceral and hepatic fat (P&amp;lt;0.01) but similar SI, adipose tissue insulin sensitivity and whole body lipolysis (all P&amp;gt;0.5). Basal glucose, insulin and FFA concentrations were similar in both groups (P&amp;gt;0.05). Blacks had lower glucose production (2.52±0.34 vs. 2.75±0.28 mg·kglbm-1·min-1, P&amp;lt;0.05), fractional gluconeogenesis (57.6±10.6 vs. 66.3±11.4%, P=0.02), and absolute gluconeogenesis (1.44±0.28 vs. 1.77±0.31 mg·kglbm-1·min-1, P&amp;lt;0.01). HIS correlated with SI and hepatic fat (both r=0.5, P&amp;lt;0.01) and the relationship did not differ by race (P&amp;gt;0.05). However, at the same SI blacks had higher HIS (intercepts P&amp;lt;0.01). In summary, black women had relatively preserved HIS and lower hepatic fat, while white women had higher gluconeogenesis and hepatic fat associated with fasting hyperglycemia. Fasting glucose may be a poor early diabetes marker in black women because gluconeogenesis was low despite whole-body insulin resistance. Disclosure S.T. Chung: None. M.W. Haymond: Advisory Panel; Self; Zealand Pharma A/S. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. A. Onuzuruike: None. L. Mabundo: None. H. Garraffo: None. P.J. Walter: None. A.B. Courville: None. A.M. Gharib: None. S. Chacko: None. A.E. Sumner: None.

DNA Repair Enzyme Ogg1 Regulates Hepatic Insulin Resistance in High-Fat Diet-Fed Obese Mice

Mitochondrial DNA (mtDNA) damage has been implicated in the development of insulin resistance. The mtDNA is highly specialized and encodes for proteins essential for energy metabolism. Also, mtDNA damage heightens mitochondrial oxidative stress, which is very critical for insulin resistance. OGG1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that Ogg1 deficiency results in an increased susceptibility to high fat diet (HFD)-induced obesity, metabolic dysfunction and insulin resistance in mice, suggesting a crucial role of Ogg1 in glucose metabolism. In the current study, we performed a 2-hour hyperinsulinemic-euglycemic clamp to measure tissue-specific insulin sensitivity in wild type (WT) and Ogg1-/- (KO) mice after chronic feeding of low fat diet (LFD as controls) or HFD. On LFD, both WT and KO mice showed comparable body weight and insulin sensitivity. After 16 weeks of HFD, the KO mice were more obese than WT mice with significant increases in whole body fat mass. There was a strong trend of increased insulin resistance with lower glucose infusion rates and whole body glucose turnover and glycogen synthesis in HFD-fed KO mice compared to HFD-fed WT mice. Hepatic insulin action was significantly lower in the HFD-fed KO mice which was consistent with recent evidence showing Ogg1 regulation of hepatic gluconeogenesis in the fed state. This is the first evidence demonstrating that Ogg1 contributes to HFD-induced insulin resistance in liver. Our findings suggest that protecting mtDNA from damage might be crucial to prevent insulin resistance and further identify therapeutic strategies for stimulating OGG1 as potential treatment of insulin resistance. Disclosure L. Yuzefovych: None. M. Schuler: None. H. Noh: None. S. Suk: None. J.K. Kim: None. L. Rachek: None.

Early Effects of Sleeve Gastrectomy (SG) on Systemic and Organ-Specific Dietary Fatty Acid Uptake, Postprandial Free Fatty Acids (FFA), and Glucose Metabolism in Type 2 Diabetes (T2D)

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve days after SG, whole body and hepatic insulin sensitivity increased significantly whereas fasting and postprandial EGP decreased. Postprandial GLP-1, GIP, PYY and glucagon were higher after vs. before SG. Postprandial AUC of FFA (175 vs. 228 mmol/Lx min; p&amp;lt; 0.05) and total FA oxidation were higher (p&amp;lt; 0.02 from 180 min to 360 min), but dietary FA oxidation was reduced after SG (p&amp;lt; 0.002 from 180 min to 360 min). After SG, uptake of dietary FA 6 hours after the meal was reduced in the myocardium (mean SUV 2.07± 0.66 vs. 1.36± 0.44; p=0.06) and was increased in visceral AT (mean SUV 0.24± 0.2 vs. 0.42± 0.2; p=0.03), without changes in other organs. In conclusion, there is reduced myocardial and increased visceral AT uptake of dietary FA associated with reduced dietary FA oxidation and increased FFA mobilization and oxidation, concomitant with reduced EGP and insulin sensitization in patients with T2D early after SG. Disclosure A. Carreau: None. C. Noll: None. B. Guerin: None. L. Biertho: Advisory Panel; Self; Novo Nordisk Inc.. Consultant; Self; Johnson &amp; Johnson Services, Inc., Valeant Pharmaceuticals International, Inc.. E.E. Turcotte: None. A. Tchernof: Research Support; Self; Johnson &amp; Johnson Services, Inc., Medtronic. A. Carpentier: Consultant; Self; UniQure, Janssen Pharmaceuticals, Inc., Siemens. Research Support; Self; Caprion, Merck Sharp &amp; Dohme Corp., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, AstraZeneca, Bristol-Myers Squibb Company, Sanofi-Aventis, Pfizer Inc., Novo Nordisk Inc., Exelixis, Amgen Inc..

Deletion of SLC4A4 in Pancreatic ß Cells Protects from High-Fat Diet–Induced Glucose Intolerance and ß-Cell Dysfunction

Islet failure in type 2 diabetes (T2DM) is characterised by loss of glucose-stimulated insulin secretion (GSIS) attributed in part to β-cell dedifferentiation (e.g., mis-expression of alpha cell-specific genes). Recent single cell transcriptomics studies identified SLC4A4 (a gene encoding an electrogenic Na+-nHCO3- cotransporter, NBCe1) as one of the mis-expressed genes in β-cells of patients with T2DM. Thus, we set out to test the hypothesis that mis-expression of SLC4A4 in β-cells contributes to loss of GSIS and impaired glucose homeostasis in T2DM. To address this hypothesis, we first confirmed induction of robust SLC4A4 protein expression in β-cells of patients with T2DM utilizing immunofluorescence staining of autopsy-derived human pancreas specimens. We next generated β-cell-specific slc4a4 knockout (β-slc4a4-/-) and corresponding control (β-slc4a4+/+) mice through crossing of slc4a4 loxP/loxP and Ins2-Cre mouse models. Adult (3 month old) β-slc4a4-/- mice displayed normal body weight, glycaemia, glucose tolerance and insulin sensitivity under standard chow fed conditions (p&amp;gt;0.vs. β-slc4a4+/+). In contrast, β-slc4a4-/- mice exhibited enhanced glucose tolerance and in vivo glucose-stimulated insulin response under conditions of metabolic stress induced by ad libitum intake of 60% high fat diet (HFD) for 8 weeks (p&amp;lt;0.vs. β-slc4a4+/+ HFD). Interestingly, improved glucose tolerance in β-slc4a4-/-mice was also associated with a tendency for expansion of β-cells mass (82%, p=0.09 vs. β-slc4a4+/+ HFD) and increased β-cells proliferation (26%, p=0.11 vs. β-slc4a4+/+ HFD). These results suggest that β-cell mis-expression of the Na+-nHCO3- cotransporter encoded by SLC4A4 contributes to induction of β-cell failure under conditions of metabolic stress and T2DM. Disclosure M. Brown: None. H.L. Holmes: None. K. Rakshit: None. M.F. Romero: None. A. Matveyenko: None.

High Iron Feeding Modulates Glucose Metabolism in Duodenal-Jejunal Bypass Surgery but Not in Vertical Sleeve Gastrectomy in Mice

High dietary iron intake is associated with impaired islet-cell function and increased risk of type 2 diabetes mellitus (T2DM) while iron chelation leads to improved glucose tolerance. Bariatric surgery has multiple metabolic benefits but iron-deficiency anemia is a common occurrence following surgery, presumably because of preferential iron absorption in the upper intestine. We hypothesized that a duodenal-jejunal bypass (DJB) procedure that bypasses the proximal small bowel and vertical sleeve gastrectomy (VSG) that eliminate 80% of the stomach without altering the intestine would have differential effects on iron metabolism and glucose homeostasis. C57BL6J mice were fed either high- (2000 ppm) or low-iron diet (4 ppm) for 16 weeks before DJB (n=6 per diet group), VSG (n=6/7 per diet group) or sham surgery (n = 11 per diet group). Intraperitoneal glucose, and insulin, tolerance tests were performed at Day 0, 10 and 20 after surgery. Compared to animals given a low-iron diet, 4 months of high-iron diet significantly impaired glucose tolerance (p&amp;lt;0.05) and decreased insulin and glucagon secretion, but had no effect on body weight or insulin sensitivity prior to surgery. Compared to sham controls neither VSG nor DJB affected glucose or insulin tolerance at day 10 after surgery. However, 20 days after surgery, VSG significantly improved glucose tolerance in both the high- and low-iron diet groups, with increased secretion of islet hormones in in vivo test. In contrast, DJB surgery only improved glucose tolerance in the low-iron-fed mice, this response was not present in the high-iron-fed animals. In sum, these findings indicate that high-iron intake modulates the benefits of DJB, but not VSG on glucose metabolism. This is consistent with an important contribution of GI tract handling of dietary iron to the metabolic effect of surgery to improve glucose tolerance. Disclosure J. Niu: None. J.D. Douros: None. J. Campbell: None. M. Capozzi: None. S.M. Gray: None. F. Lorenzo: None. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S. D. McClain: None. J. Tong: None.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&amp;lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&amp;lt;0.05). Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production. Disclosure D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men

Obesity is associated with nonalcoholic fatty liver disease (NAFLD) leading to increased hepatic glucose production. NAFLD is one of the most frequent liver diseases however, effective treatment is limited. Animal studies showed a reduction in hepatic steatosis with dietary alpha linoleic acid, which is highly enriched in rapeseed oil (RA). In this study we used a nutritional therapeutic approach and investigated the effect of an isocaloric diet supplemented with RA or olive oil (OL) on liver fat content, endogenous glucose production, total body insulin sensitivity and serum lipids in obese humans suffering from NAFLD. 27 obese men (BMI 30-35, age 18-65) consumed an isocaloric diet including 50 g of either RA (n=12) or OL (n=15) daily for eight weeks. Hepatic MRI, hyperinsulinemic-euglycemic clamp studies with isotope labelled glucose and blood tests were performed prior to and at the end of the study to assess liver fat content, endogenous glucose production and cholesterol and free fatty acid levels, respectively. Body fat content and BMI did not change over the time of intervention for RA and OL. At the end of the study a significant reduction in hepatic fat content (P=0.038) could be observed for RA (13.09±1.61 before vs. 11.14±1.58% after intervention) vs. OL (13.29±2.52 before vs. 15.73±2.74% after intervention). For RA, a 21% reduction (P&amp;lt;0.02) in serum free fatty acids was observed after eight weeks of oil consumption whereas no significant changes were seen for OL. Consuming RA resulted in a slight reduction in basal endogenous glucose production (1.71±0.15 before vs. 1.49±0.mg/kg/min after intervention, P=n.s.) compared to OL (1.66±0.before vs. 1.65±0.mg/kg/min after intervention, P=n.s.). There were no significant changes in total body insulin sensitivity and serum cholesterol levels in RA or OL. Our results demonstrate a beneficial effect of the fatty acid composition of RA on hepatic lipid production as shown by reduced hepatic fat content and free fatty acid levels. Disclosure M. Kruse: None. M. Kemper: None. S. Gancheva: None. D. Dannenberger: None. D.F. Markgraf: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. A.F. Pfeiffer: None.

The Fecal Microbiota in the Domestic Cat (Felis catus) Is Influenced by Interactions Between Age and Diet; A Five Year Longitudinal Study.

In humans, aging is associated with changes in the gastrointestinal microbiota; these changes may contribute to the age-related increase in incidence of many chronic diseases, including Type 2 diabetes. The life expectancies of cats are increasing, and they are also exhibiting the same types of diseases. While there are some studies investigating the impacts of diets on gastrointestinal microbiota in young cats, the impacts of aging in older cats has not been explored. We followed a cohort of related kittens, maintained on two commercial diets (kibbled and canned) from weaning (8 weeks) to 5 years of age (260 weeks). We hypothesized that the long-term feeding of specific diet formats would (a) lead to microbial composition changes due to aging, (b) impact body composition, and (c) affect insulin sensitivity in the aging cat. We observed that both diet and age affected fecal microbial composition, and while age correlated with changes in body composition, diet had no effect on body composition. Similarly insulin sensitivity was not affected by age nor diet. 16S rRNA sequencing found unclassified Peptostreptococcaceae were prominent across all ages averaging 21.3% of gene sequence reads and were higher in cats fed canned diets (average of 25.7% of gene sequence reads, vs. 17.0% for kibble-fed cats). Age-related effects on body composition and insulin sensitivity may become apparent as the cats grow older; this study will continue to assess these parameters.