Antilipolytic Effect Of Insulin Research Articles

A new oral model of free fatty acid kinetics to assess lipolysis in subjects with and without type 2 diabetes.

Assessing free fatty acids (FFAs) kinetics and the role of insulin and glucose on FFA lipolysis and disposal may improve our understanding of the pathogenesis of type 2 diabetes (T2D). Some models have been proposed to describe FFA kinetics during an intravenous glucose tolerance test and only one during an oral glucose tolerance test. Here, we propose a model of FFA kinetics during a meal tolerance test and use it to assess possible differences in postprandial lipolysis in individuals with type 2 diabetes (T2D) and individuals with obesity without type 2 diabetes (ND). We studied 18 obese ND and 16 T2D undergoing three meal tolerance tests (MTT) on three occasions (breakfast, lunch, and dinner). We used plasma glucose, insulin, and FFA concentrations collected at breakfast to test a battery of models and selected the best one based on physiological plausibility, ability to fit the data, precision of parameter estimates, and the Akaike parsimony criterion. The best model assumes that the postprandial suppression of FFA lipolysis is proportional to the above basal insulin, while FFA disposal is proportional to FFA concentration. It was used to compare FFA kinetics in ND and T2D along the day. The maximum lipolysis suppression occurred significantly earlier in ND than T2D (39 ± 6 min vs. 102 ± 13 min, 36 ± 4 min vs. 78 ± 11 min, and 38 ± 6 min vs. 84 ± 13 min, P < 0.01, at breakfast, lunch, and dinner, respectively), making lipolysis significantly lower in ND than T2D. This is mainly attributable to the lower insulin concentration in the second group. This novel FFA model allows to assess lipolysis and insulin antilipolytic effect in postprandial conditions.NEW & NOTEWORTHY In this study, we propose a new mathematical model able to quantify postprandial FFA kinetics and adipose tissue insulin sensitivity in both subjects with obesity without type 2 diabetes (ND) and subjects with type 2 diabetes (T2D). Results show that the slower postprandial suppression of lipolysis in T2D contributes to the higher free fatty acid (FFA) concentration that, in turn, may contribute to hyperglycemia.

Effect of Exogenous Hydrogen Sulfide and Polysulfide Donors on Insulin Sensitivity of the Adipose Tissue.

Hydrogen sulfide (H2S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in adipose tissue. We examined the effect of H2S and polysulfides on insulin sensitivity of the adipose tissue in rats. Plasma glucose, insulin, non-esterified fatty acids, and glycerol were measured after administration of H2S and the polysulfide donors, Na2S and Na2S4, respectively. In addition, the effect of Na2S and Na2S4 on insulin-induced glucose uptake and inhibition of lipolysis was studied in adipose tissue explants ex vivo. Na2S and Na2S4 administered in vivo at a single dose of 100 μmol/kg had no effect on plasma glucose and insulin concentrations. In addition, Na2S and Na2S4 did not modify the effect of insulin on plasma glucose, fatty acids, and glycerol concentrations. Na2S and Na2S4had no effect on the antilipolytic effect of insulin in adipose tissue explants ex vivo. The effect of insulin on 2-deoxyglucose uptake by adipose tissue was impaired in obese rats which was accompanied by lower insulin-induced tyrosine phosphorylation of IRS-1 and Akt. Na2S4, but not Na2S, improved insulin signaling and increased insulin-stimulated 2-deoxyglucose uptake by adipose tissue of obese rats. The results suggest that polysulfides may normalize insulin sensitivity, at least in the adipose tissue, in obesity/metabolic syndrome.

A longitudinal study of the antilipolytic effect of insulin in women following bariatric surgery

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.

230-OR: Exercise Training Improved Antilipolytic Sensitivity to Insulin in Obese Adults with Low Sensitivity to Insulin before Training

Low sensitivity to the antilipolytic effects of insulin in adipose tissue has been linked with impaired insulin-mediated glucose uptake in skeletal muscle. The aims of this study were: 1) to compare adipose tissue morphology in obese adults with high- (HIGH) vs. low-sensitivity (LOW) to the antilipolytic effects of insulin, and 2) compare the effects of exercise training on adipose tissue from HIGH vs. LOW subjects. Using isotopic dilution methods before and during a hyperinsulinemic-euglycemic clamp, we measured the antilipolytic response to insulin in a total of 36 obese adults - and we identified sub-cohorts of 13 LOW (64±7% lipolytic suppression by insulin; BMI: 34±4kg/m2) and 13 HIGH (82±3% lipolytic suppression by insulin; BMI:33±3kg/m2). Abdominal subcutaneous adipose tissue (aSAT) samples were collected before the clamp (non-insulin stimulated). Measurements were made before and after a 12-week endurance exercise training program (4 days/week). Before training, capillary density (# of capillaries/mm2) in aSAT samples for LOW was significantly lower than HIGH (p=0.004). Collagen abundance in aSAT extracellular matrix (ECM) was lower in LOW (p=0.013). In response to training, the antilipolytic response to insulin was significantly improved in LOW (72±5% lipolytic suppression by insulin; p&amp;lt;0.001) but not HIGH. This was accompanied by an increased capillary density (p=0.03), and collagen abundance in ECM (p = 0.02), along with a slight reduction in fat mass (1±1kg; p=0.05). Adipocyte size was reduced in both groups (p=0.02). In summary, aSAT from obese adults with low antilipolytic sensitivity to insulin displayed lower capillarization and ECM collagen abundance compared with obese adults with high sensitivity to the antilipolytic effects of insulin. Importantly, morphological adaptations to exercise training accompanied an increased antilipolytic sensitivity to insulin in subjects with low antilipolytic sensitivity before training. Disclosure C. Ahn: None. M. W. Schleh: None. B. J. Ryan: None. A. Ludzki: None. P. Varshney: None. J. B. Gillen: None. S. Chen: None. J. F. Horowitz: None. Funding National Institutes of Health (R01DK077966, P30DK089503, T32DK007245, F32DK117522); Canadian Institutes of Health Research (DFS146190, 338735)

Insulin and β-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes.

Control of fatty acid storage and release in adipose tissue is fundamental in energy homeostasis and the development of obesity and type 2 diabetes. We here take the whole signalling network into account to identify how insulin and β-adrenergic stimulation in concert controls lipolysis in mature subcutaneous adipocytes obtained from non-diabetic and, in parallel, type 2 diabetic women. We report that, and show how, the anti-lipolytic effect of insulin can be fully explained by protein kinase B (PKB/Akt)-dependent activation of the phosphodiesterase PDE3B. Through the same PKB-dependent pathway β-adrenergic receptor signalling, via cAMP and PI3Kα, is anti-lipolytic and inhibits its own stimulation of lipolysis by 50%. Through this pathway both insulin and β-adrenergic signalling control phosphorylation of FOXO1. The dose–response of lipolysis is bell-shaped, such that insulin is anti-lipolytic at low concentrations, but at higher concentrations of insulin lipolysis was increasingly restored due to inhibition of PDE3B. The control of lipolysis was not altered in adipocytes from diabetic individuals. However, the release of fatty acids was increased by 50% in diabetes due to reduced reesterification of lipolytically liberated fatty acids. In conclusion, our results reveal mechanisms of control by insulin and β-adrenergic stimulation — in human adipocytes — that define a network of checks and balances ensuring robust control to secure uninterrupted supply of fatty acids without reaching concentrations that put cellular integrity at risk. Moreover, our results define how selective insulin resistance leave lipolytic control by insulin unaltered in diabetes, while the fatty acid release is substantially increased.

1215-P: Adipose Tissue Insulin Resistance Predicts Ketosis via an SGLT2 Inhibitor

Diabetic ketoacidosis characterized by lipolysis due to insulin deficiency is a side effect reported for SGLT2 inhibitors (SGLT2is). However, little is known about predictors of ketosis via SGLT2i. The antilipolytic effect of insulin in adipose tissue can be evaluated as adipose tissue insulin resistance (Adipo-IR). This study investigated predictors of ketosis via the SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D) focusing on Adipo-IR. Analyzed were 304 T2D patients who received TOFO as initial monotherapy in two TOFO phase 2 and 3 studies. Adipo-IR was calculated by the product of fasting insulin (IRI) and fasting free fatty acids (FFA). Baseline characteristics were: males (67%), age (mean: 58 y), HbA1c (8%), BMI (26kg/m2), β-hydroxybutyrate (BHB) (75µmol/L), eGFR (84mL/min/1.73m2) and Adipo-IR (33pmol/L mmol/L). Participants were grouped by tertiles of baseline Adipo-IR levels (T1-T3). Differences across tertiles were analyzed by ANOVA, Kruskal Wallis and ANCOVA. Multivariate analysis explored the predictors of ketosis. In the order of T3-T1, younger age, higher baseline HOMA-IR levels and higher baseline HOMA-β levels were observed, while baseline HbA1c and BHB levels were identical across tertiles. At 24 weeks after TOFO administration, reduced HbA1c and body weight and increased urinary glucose excretion were identical among tertiles. Percent changes in FFA were T1, mean +50.9%* (* p&amp;lt;0.001 vs. baseline); T2, +25.8*; and T3, +6.6 (p&amp;lt;0.001 across tertiles); and those for BHB were T1, median +117.9%*; T2, +126.9*; and T3, +62.0* (p&amp;lt;0.05). Conversely, percent changes in IRI were T1, mean -11.3%*; T2, -24.2* and T3, -28.3* and in Adipo-IR were T1, +31.1%*; T2, -2.9 and T3, -24.1* (p&amp;lt;0.001 across tertiles). Multivariate analysis indicated an independent association of T3 with a weaker increase in BHB than T1 and T2. In conclusion, high baseline Adipo-IR may attenuate ketosis via SGLT2i through improved Adipo-IR and the antilipolytic effect of insulin despite reduced IRI in T2D. Disclosure Y. Matsubayashi: None. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. T. Nojima: Employee; Self; Kowa Co., Ltd. H. Suganami: Employee; Self; Kowa Co., Ltd. K. Fujihara: None. K. Kaku: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

2101-P: Adipose Tissue Insulin Resistance in Overweight and Lean Patients with Impaired Glucose Tolerance or Type 2 Diabetes

Background: When adipose tissue shows insulin resistance, insulin is unable to suppress lipolysis. Several Western studies have revealed a relationship between obesity and the antilipolytic effect of insulin. However, it is unclear whether a distinctly different degree of obesity between Westerner and Japanese could lead to a different outcome of the insulin antilipolytic effect. Thus, we investigated the impact of adipose tissue insulin resistance in Japanese patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2D). Methods: Twenty Japanese patients with T2D and 20 participants without diabetes were recruited (January 2014 to March 2015). A 75-g oral glucose tolerance test (OGTT) was performed and plasma glucose, serum insulin, and free fatty acid (FFA) levels were measured during this test. Insulin resistance was estimated using the Matsuda index, HOMA-IR, and the adipocyte insulin resistance index (Adipo-IR). Glucose-stimulated insulin secretion was evaluated based on the insulinogenic index (II). The definition of overweight was BMI ≥ 25 kg/m2. Results: We included patients with IGT (n=19) and T2D (n=19). BMI in all patients was 26.0 ± 6.2 kg/m2. In T2D, HbA1c was higher and II was lower compared with those in IGT. No statistically significant difference in other parameters, such as BMI, FFA, insulin resistance, were observed between T2D and IGT. In overweight IGT, Adipo-IR was significantly higher (overweight IGT, 4.0 [2.0-9.4] vs, lean IGT, 1.0 [0.8-2.3], p&amp;lt;0.05), although there were no differences in the Matsuda index or HOMA-IR. However, there was no difference in Adipo-IR for overweight T2D (7.4 [2.6-10.9]) compared with lean T2D (1.9 [0.9-3.1], p=0.13). Conclusion: Overweight status in IGT, but not in T2D, could be related to worsening Adipo-IR. These findings suggest that encouraging weight loss to the ideal weight for IGT patients might reduce the risk of worsening adipose tissue insulin resistance, and progression of IGT to T2DM. Disclosure A. Miya: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. T. Atsumi: Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB, Inc.

1846-P: The Insulin-Sensitizing Effects of Palmitic Acid Esters of Hydroxy Stearic Acids Involve Intertissue Communication

Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with anti-inflammatory and antidiabetic effects, improve glucose tolerance and insulin sensitivity in insulin-resistant mice. We found that PAHSA treatment enhances insulin action to suppress endogenous glucose production (EGP) in chow and HFD mice and promotes glucose uptake in glycolytic muscle and heart in HFD-fed mice. We aimed to determine the mechanisms by which PAHSAs enhance hepatic insulin sensitivity. We examined both direct effects in hepatocytes and indirect effects resulting from augmentation of insulin-mediated suppression of WAT lipolysis. Here, we show that PAHSAs inhibit lipolysis in WAT explants to the same extent as insulin. PAHSAs also enhance the anti-lipolytic effect of insulin in vivo, as indicated by a 30% reduction in FFAs during the clamp in PAHSA-treated mice under conditions with no suppression in Vehicle treated mice. To determine whether lowering FFAs is necessary for PAHSA effects on insulin sensitivity, we infused intralipid during a hyperinsulinemic-euglycemic clamp. In chow-fed mice infused with intralipid, PAHSAs still have a partial effect to lower EGP (Intralipid: vehicle 12±0.8 vs. PAHSA 7±1.7 mg/kg/minute), whereas in HFD-fed mice, preventing PAHSA-induced FFA reduction blocks PAHSA effects on hepatic insulin sensitivity (EGP Intralipid: vehicle 13±0.6 vs. PAHSA 12±1.7 mg/kg/minute). Our mechanistic studies show that PAHSAs inhibit basal EGP and reduce glucagon stimulated EGP directly in isolated hepatocytes. This is mediated by a cAMP-dependent pathway involving Gα/i protein-coupled receptors. Hepatic phospho-CREB is also reduced by PAHSAs in vivo. Sum: PAHSAs enhance hepatic insulin sensitivity through direct and indirect actions involving inter-tissue communication between adipose tissue and liver. These data reveal new mechanisms underlying the beneficial effects of PAHSAs, which will clarify their roles in healthy and disease states. Disclosure P. Zhou: None. A. Santoro: None. O.D. Peroni: None. A.T. Nelson: None. A. Saghatelian: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Alterna Therapeutics, Inc., American Diabetes Association, Harrington Discovery Institute, Janssen Research &amp; Development. Consultant; Self; Ironwood Pharmaceuticals, Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Funding American Diabetes Association (1-18-PDF-134 to P.Z.); National Institutes of Health (R01DK43051 to B.K.), (R01DK106210 to B.K., A.S.); JPB Foundation (to B.K.); American Heart Association (to A.T.N.)

PID1 alters the antilipolytic action of insulin and increases lipolysis via inhibition of AKT/PKA pathway activation.

PurposeThe aim of this study was to investigate the effect of phosphotyrosine interaction domain containing 1 (PID1) on the insulin-induced activation of the AKT (protein kinase B)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) pathway and lipolysis.MethodsSprague–Dawley rats were fed either chow or a high-fat diet (HFD). The levels of insulin, glycerol, free fatty acids (FFAs) and PID1 mRNA expression were measured in the 2 groups. Furthermore, we examined the role of PID1 in the regulation of the AKT/PKA/HSL cascade and lipolysis in the 3T3-L1 cell line.ResultsAdipose tissue from HFD rats exhibited elevated PID1 expression, which showed a positive correlation with insulin levels and lipolysis. In 3T3-L1 adipocytes, we found that the antilipolytic effect of insulin is mediated by AKT and that phosphorylated AKT results in the promotion of PDE3B expression, the dephosphorylation of PKA and HSL and the suppression of glycerol release. However, overexpression of PID1 and treatment with 1 μM isoproterenol and 100 nM insulin for 24 h resulted in an increased release of glycerol and a noticeable inhibition of AKT phosphorylation, PDE3B expression and the phosphorylation of PKA/HSL in 3T3-L1 cells. In contrast, knockdown of PID1 and treatment with the above reagents inhibited lipolysis and activated the phosphorylation of AKT, which resulted in the dephosphorylation of PKA and HSL.ConclusionsOur findings indicate that PID1 in adipose tissue increases lipolysis by altering the antilipolytic action of insulin. This suggests that PID1 may represent a new therapeutic target to ameliorate adipocyte lipolysis and hence improve insulin sensitivity.

Effects of the amino acid derivatives, β-hydroxy-β-methylbutyrate, taurine, and N-methyltyramine, on triacylglycerol breakdown in fat cells.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1μM to 1mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1mM. However, 100μM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

Attenuation of Weight Loss Through Improved Antilipolytic Effect in Adipose Tissue Via the SGLT2 Inhibitor Tofogliflozin

Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known. To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue. An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs). Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m2; estimated glomerular filtration rate, 83.9 mL/min/1.73m2; 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (-3.6 mmol/L·pmol/L and -6.2 mmol/L·pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52. The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.

Relationship between insulin, glucose, non-esterified fatty acid and indices of insulin resistance in obese cows during the dry period and early lactation

The aim of this study was to determine to relationship between glucose, insulin, non-esterified fatty acid (NEFA) and indices of insulin resistance in the dry period (DP) and early lactation (EL). The importance of this study was in determining the relation between insulin sensitivity in DP and insulin resistance in EL. A total of 30 normally fed Holstein-Friesian cows with a high body condition score (&gt; 3.75) were included in the study. Blood samples were collected in DP (weeks 5-7 ante partum) and EL (weeks 1-2 post partum). Cows in EL showed higher insulin resistance in comparison to DP due to a lower concentration of glucose and insulin, higher concentration of NEFA, lower value of revised quantitative insulin sensitivity check index and higher values of glucose:insulin and NEFA:insulin ratios (lower pancreas responsivnes to glucose and antilipolytic effect of insulin). Higher concentrations of insulin and glucose in the DP lead to a decrease in their concentrations and an increase in glucose:insulin and NEFA:insulin ratios in the EL. The revised quantitative insulin sensitivity check index in DP negatively correlates with the same index in EL, while positively correlating with the NEFA and NEFA:insulin ratio in EL. The EL revised quantitative insulin sensitivity check index value was influenced by dynamic changes (DP minus EL) in the insulin, NEFA, and glucose concentrations. The relationship between the indicators shows that higher insulin sensitivity in the DP increases resistance in EL in normally fed obese dairy cows.

CB4211 Is a Potential Treatment for Metabolic Diseases with a Novel Mechanism of Action—Sensitization of the Insulin Receptor

Metabolic dysfunction and insulin resistance are common underlying factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and many age-related diseases, including obesity and type 2 diabetes. CB4211 is a novel peptide analog of MOTS-c, a mitochondrially encoded peptide with a potential role in metabolic homeostasis. CB4211 reduces free fatty acid release from cultured adipocytes, improves NAFLD activity score (NAS) in STAM® mice, and selectively decreases fat mass in DIO mice. We investigated the mechanism of action (MOA) of CB4211 in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. CB4211 potentiated insulin mediated inhibition of lipolysis in isoproterenol stimulated adipocyte cultures without changing maximal response, while CB4211 alone had no effect. Inhibitors of IR auto-phosphorylation (GSK183705A) or downstream PI3K/Akt signaling pathway components (wortmannin, Akti-1/2) abolished the antilipolytic effects of insulin alone and in combination with CB4211. Further supporting sensitization of insulin signaling, CB4211 enhanced insulin mediated phosphorylation of IR, IRS-1, and Akt, without affecting IGF mediated phosphorylation of IGF-1R. Consistent with activity through IR, CB4211 potentiated insulin induced reduction in glucose production in H4-IIE cells. The acute in vivo effect of CB4211 on insulin tolerance was determined in fasted DIO mice. Administration of CB4211 with insulin enhanced insulin sensitivity, prolonging the reduction in blood glucose levels compared to insulin alone. In conclusion, CB4211 potentiates insulin effects on fatty acid metabolism and glucose homeostasis by acting at the level of IR. The observed MOA of CB4211 therefore supports its potential utility for treatment of NASH, obesity, type 2 diabetes, and other metabolic disorders. Disclosure K. Grindstaff: Employee; Self; CohBar, Inc.. R. Magnan: None. R. Shang: Employee; Self; CohBar Inc. E. Stenger: Employee; Self; CohBar, Inc.. J.S. Holland: None. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. K.C. Cundy: Employee; Self; CohBar, Inc.. Stock/Shareholder; Self; CohBar, Inc..

Short-term effects of obestatin on hexose uptake and triacylglycerol breakdown in human subcutaneous adipocytes.

AIMTo study complete dose-dependent effects of obestatin on lipolytic and glucose transport activities in human adipocyte preparations highly responsive to insulin.METHODSAdipocytes were prepared by liberase digestion from subcutaneous abdominal adipose tissue obtained from overweight subjects undergoing plastic surgery. The index of lipolytic activity was the glycerol released in the incubation medium, while glucose transport was assessed by [3H]-2-deoxyglucose uptake assay.RESULTSWhen tested from 0.1 nmol/L to 1 μmol/L, obestatin did not stimulate glycerol release; it did not inhibit the lipolytic effect of isoprenaline and did not alter the insulin antilipolytic effect. Obestatin hardly activated glucose transport at 1 μmol/L only. Moreover, the obestatin stimulation effect was clearly lower than the threefold increase induced by insulin 100 nmol/L.CONCLUSIONLow doses of obestatin cannot directly influence lipolysis and glucose uptake in human fat cells.

Schisandrin B regulates lipid metabolism in subcutaneous adipocytes

Subcutaneous adipocytes in obese subjects have a lower sensitivity to catecholamine-induced lipolysis and a higher sensitivity to insulin anti-lipolytic effects compared to adipocytes in other adipose depots. Therefore, increasing lipolysis in subcutaneous adipocytes coupled with enhanced fatty acid oxidation may be an anti-obesity strategy. Schisandrin B (Sch B) is one of the most abundant active dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis which is a commonly prescribed Chinese medicinal herb. We found that Sch B reduced glycerolipid contents in 3T3-L1 adipocytes and subcutaneous adipocytes dissected from DIO mice. Sch B also activated hormone sensitive lipase (HSL) and increased lipolysis in these adipocyte in a protein kinase A-dependent manner. Interestingly, Sch B increased fatty acid oxidation gene expressions in these adipocytes, implying an increase in fatty acid oxidation after treatment. In in vivo model, we found that Sch B increased HSL phosphorylation, reduced glycerolipid levels and increased fatty acid oxidation gene expressions in the subcutaneous adipocytes in the DIO mice. More importantly, Sch B significantly reduced the subcutaneous adipocyte sizes, subcutaneous adipose tissue mass and body weight of the mice. Our study provides scientific evidence to suggest a potential therapeutic function of Sch B or Schisandra chinensis seed containing Sch B in reducing obesity.

Pterostilbene Inhibits Lipogenic Activity similar to Resveratrol or Caffeine but Differently Modulates Lipolysis in Adipocytes.

The anti-obesity effects of resveratrol shown in rodents are not transposed into an efficient therapy of human obesity. Consequently, the search for molecules mimicking or surpassing resveratrol actions is ongoing. The natural phenolic compound pterostilbene exhibits beneficial health effects and has the capacity to limit fat mass in animal models. In this study, we tested whether pterostilbene modulates triacylglycerol accumulation/breakdown. Prolonged exposure to pterostilbene or resveratrol inhibited adipocyte differentiation in 3T3-F442A preadipocytes. Acute effects on lipolysis, antilipolysis and lipogenesis were determined for pterostilbene in mouse adipocytes, and compared with resveratrol. Pterostilbene was also tested on glycerol release and glucose uptake in subcutaneous human adipocytes. Dose-response analyses did not reveal a clear lipolytic effect in both species. The antilipolytic effect of insulin was improved by pterostilbene at 1-10μM in mouse fat cells only, while at 1mM, the phenolic compound was antilipolytic in human fat cells in a manner not additive to insulin. Pterostilbene dose-dependently inhibited glucose incorporation into lipids similarly to resveratrol and caffeine. However, only the former did not inhibit insulin-stimulated glucose uptake. Indeed, pterostilbene abolished the insulin lipogenic effect without inhibiting its antilipolytic action and rapid activation of glucose uptake. Pterostilbene therefore exhibits a unique panel of direct interactions with adipocytes that relies on its reported anti-obesity and antidiabetic properties. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of niacin supplementation on the insulin resistance in Holstein cows during early lactation

Insulin resistance in early lactation includes low glucose concentration, low insulin release and responsiveness and high lipolysis. Niacin is important antilipolytic agent and leads to increase glucose and insulin concentration. The objectives of this study were to determine the influence of niacin on the insulin resistance in cows during early lactation using the difference of value and regression analysis between blood non-esterified fatty acid (NEFA), glucose and insulin concentrations, revised quantitative insulin sensitivity check index and glucose-to-insulin ratio. Niacin supplementation led to a decrease of NEFA concentration and an increase of glucose and insulin concentrations during the first three weeks after calving. Cows in the niacin group which were more resistant to insulin showed higher concentrations of non-esterified fatty acid in comparison with more sensitive cows from the same group, but still lower than the control. The regression analyses suggest the following characteristics of cows supplemented with niacin in comparison with the control group: the insulin response to glucose was more intense; the antilipolytic effect of insulin was lower; insulin efficiency expressed as glucose-to-insulin ratio increase with a decrease in NEFA. The metabolic changes due to niacin supplementation showed a dual influence on the insulin resistance in dairy cows during early lactation: decreased NEFA concentrations led to a decrease in the insulin resistance (due to an increase in insulin efficiency and insulin sensitivity index), but increased concentrations of insulin and glucose possibly caused an increase in the insulin resistance in dairy cows (due to lower insulin sensitivity index and possibly lower antilipolytic effects of insulin).

A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small‐animal PET/MRI and the novel radioligand [18F]‐AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP‐10 recruited BAT and potentiated thermogenesis in vivo. In diet‐induced obese mice, chronic administration of MP‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP‐10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes.

Placental, Lipid, and Glucidic Effects of Mammalian Target of Rapamycin Inhibitors: Impact on Fetal Growth and Metabolic Disorders During Pregnancy After Solid Organ Transplantation

BackgroundMammalian target of rapamycin inhibitors (mTORi) are a promising new family of immunosuppressive drugs. No teratogenic effects have been reported to date. Their lipid and glucidic effects should not be underestimated, however, especially during pregnancy. Moreover, mTORi may affect fetal growth by mTOR placental activity. ObjectiveOur purpose was to highlight mTORi placental impact and metabolic implications to detect possible maternal or fetal effects and define management guidelines in pregnant women after solid organ transplantation. MethodsA literature search was performed for articles from the Medline and Pubmed databases with the use of the following keywords: mTOR inhibitors, pregnancy, placental transport, lipid metabolism, glucose metabolism. ResultsmTOR works as a positive regulator of system A, system L, and taurine placental amino acid transporter activity, which are critical for the transport of amino acids to the fetus. Exposing trophoblast cells to rapamycin reduces system L activity; therefore, treatment with rapamycin in human pregnancies could alter fetal growth with intrauterine growth restriction (IUGR). Regarding the metabolic effects mTORi increase lipolysis, impair insulin's antilipolytic effect and reduce lipid storage, which may potentially contribute to dyslipidemia. Chronic rapamycin treatment reduces adipose tissue size and β-cell mass/function, causes hyperlipidemia, severe insulin resistance, and glucose intolerance, and promotes hepatic gluconeogenesis. ConclusionsThe studies on mTORi treatment in transplanted pregnant women have not focused to date on the potential metabolic and placental effects. Selection of women at high risk for metabolic disorders could be needed and consideration of switching to another immunosuppressive drug required if diabetes and abnormal blood lipids have been diagnosed in prepregnancy counseling. It seems to be mandatory to encourage prompt reporting of any additional cases of pregnancy during mTORi exposure to provide a better understanding of the placental effects and safety profile of these immunosuppressive drugs.

Adipocyte dysfunction in rats with streptozotocin-nicotinamide-induced diabetes.

Administration of streptozotocin (STZ) and nicotinamide (NA) to adult rats allows for the induction of mild diabetes. However, this experimental model has not been fully characterized. This study was undertaken to determine the metabolic and secretory activity of adipose tissue in rats with STZ-NA-induced diabetes. Experiments were performed using epididymal adipocytes isolated from control and mildly diabetic rats. Lipogenesis, glucose transport as well as glucose and alanine oxidation, lipolysis, anti-lipolysis, cAMP levels and adipokine secretion were compared in cells isolated from the control and diabetic rats. Lipogenesis, glucose transport and oxidation were diminished in the adipocytes of diabetic rats compared with the fat cells of control animals. However, alanine oxidation appeared to be similar in the cells of non-diabetic and diabetic animals. Lipolytic response to low epinephrine concentrations was slightly increased in the adipocytes of diabetic rats; however, at higher concentrations of the hormone, lipolysis was similar in both groups of cells. The epinephrine-induced rise in cAMP levels was higher in the adipocytes of STZ-NA-induced diabetic rats, even in the presence of insulin. Lipolysis stimulated by dibutyryl-cAMP did not significantly differ, whereas anti-lipolytic effects of insulin were mildly decreased in the cells of diabetic rats. Secretion of adiponectin and leptin was substantially diminished in the adipocytes of diabetic rats compared with the cells of control animals. Our studies demonstrated that the balance between lipogenesis and lipolysis in the adipose tissue of rats with mild diabetes induced by STZ and NA is slightly shifted towards reduced lipid accumulation. Simultaneously, adiponectin and leptin secretion is significantly impaired.