Adipose Insulin Resistance Research Articles

Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients With Type 2 Diabetes and NAFLD.

Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD. Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR. University ambulatory care practice. A total of 483 participants with T2D. Screening for steatosis and fibrosis with elastography. Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis. These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD.

ODP424 Postprandial Adipose Insulin Resistance in Adolescent Girls with PCOS and Obesity

Abstract Background Polycystic ovary syndrome (PCOS) is common and associated with metabolic disease, in particular glucose abnormalities and insulin resistance (IR). Fat metabolism is linked with IR, manifesting as decreased suppression of lipolysis following meals, inflammation, and ectopic fat accumulation. Our previous work demonstrated adipose IR during a hyperinsulinemic-euglycemic clamp and increased hepatic fat in adolescents with PCOS. We hypothesized that postprandial fat metabolism would be altered compared to controls with obesity. Design/Methodology Data from 133 girls aged 13-21 years with obesity (BMI &amp;gt;90th%ile) enrolled in 1 of 4 cross-sectional metabolic studies were included in this secondary analysis. PCOS was determined per NIH diagnostic standards. Controls had regular menses and were &amp;gt;1-year post-menarche. Metabolic assessments were identical across studies and included fasting labs (lipid panel, inflammatory markers, androgens, insulin sensitivity indices), 4-hour oral sugar tolerance test (OSTT, 75 grams glucose, 25 grams fructose), liver fat by MRI, and body composition by DXA. Glycerol production (Ra) D5 glycerol infusion to measure lipolysis was evaluated in a subset. Metrics of glucose, insulin, glycerol, free fatty acid (FFA), and glucagon during the OSTT were calculated including AUC, fasting, nadir, and peak. Adipo IR (fasting FAA x fasting insulin) was determined. Data between controls and girls with PCOS were compared by Student's t-tests with Welch correction. Spearman's correlations were used within groups to evaluate associations. Results Participants included 110 girls with PCOS (age 16.4±1.6 years; BMI 35.9±5.8 kg/m2) and 23 without PCOS (15.9±1.6; 34.6±6.7). Per design, markers of androgen excess including total testosterone (p&amp;lt;0.001), free testosterone (p&amp;lt;0.001), degree of hirsutism (p=0.004), and severity of acne (p&amp;lt;0.001) were worse in girls with PCOS. Consistent with previous work, girls with PCOS had worse markers of glycemia including higher HbA1c (p&amp;lt;0.001), fasting glucose (p=0.027), 2-hour glucose (p=0.008), glucose AUC (p=0.033), and insulin AUC (p=0.034). They also had higher liver (p&amp;lt;0.001) and visceral fat (p=0.007), total (p=0.007) and LDL cholesterol (p=0.006), and triglycerides (p=0.005). Regarding adipose IR, fasting FFA (699±175 µmol/L vs. 593±163, p=0.007), FFA nadir (68±26 vs. 51±16, p=0.003), FFA AUC (114210 vs. 92518, p = 0.018), glycerol AUC (13815 vs. 8393, p&amp;lt;0.0001), and Adipo IR (p=0.034) were significantly higher while fasting glycerol Ra (p=0.571) did not differ. There were no differences between groups in markers of inflammation. Within the PCOS group, higher glycerol AUC correlated with higher HbA1c (p=0.001) and highly-sensitive C-reactive protein (hsCRP) (p=0.029), while increased FFA AUC correlated with increased hsCRP (p=0.043) and AST (p=0.037), but not markers of insulin resistance or dysglycemia. Conclusions Adolescents with PCOS and obesity have increased adipose IR. Future focus and treatment of adipose IR may be a promising avenue to delay onset of metabolic syndrome complications in girls with PCOS and obesity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON244 Alterations in Nonesterified Free Fatty Acids (NEFA) Trafficking Rather Than Hyperandrogenism Contribute to Variations in Insulin Sensitivity Among Obese Women with Polycystic Ovary Syndrome

Abstract Objectives To compare the metabolic and hormonal features of metabolically unhealthy obese PCOS women (MU-PCOS) vs. metabolically healthy obese PCOS women (MH-PCOS) and determine whether alterations in non-esterified free fatty acids (NEFA) response to hyperinsulinemia contribute to variations in insulin sensitivity between MU-PCOS and MH-PCOS. Design Prospective cross-sectional study. Setting Tertiary-care academic center. Methods Insulin resistance (IR) in the basal state was assessed by HOMA-IR in 125 consecutive obese oligo-ovulatory PCOS women (BMI≥ 30 kg/m2; NIH 1990 or Rotterdam 2003 Phenotype A/B) undergoing an oral glucose tolerance test (oGTT); and IR in the dynamic state assessed by the modified frequently sampled intravenous glucose tolerance test (mFSIVGTT) in a subgroup of 16 non-diabetic obese PCOS women. Main Outcome Measures: Primary outcome measures were: 1) IR in AT was assessed in the basal state by the Adipose Insulin Resistance Index [Adipo-IR]) and dynamically by the mFSIVGTT-derived indices of insulin-mediated NEFA suppression [NEFAnadir, TIMEnadir, and %NEFAsupp]); 2) peak lipolysis rate [SNEFA]; and 3) peak NEFA uptake rate [KNEFA]. Secondary outcome measures were levels of insulin and glucose during oGTT, HOMA-β%, and degree of hyperandrogenism (i.e. mF-G score, free testosterone [T], total T, DHEAS). Results Eighty-five obese PCOS participants undergoing oGTT had a HOMA-IR index of ≥2.5 (MU-PCOS) and 40 had a HOMA-IR of &amp;lt;2.5 (MH-PCOS). MU-PCOS had higher mean HOMA-β%, levels of fasting, 1-hr and 2-hr. glucose and insulin, and peak insulin during the oGTT, and higher prevalence of prediabetes and elevated 1-hr. glucose and a trend towards higher prevalence of type 2 diabetes mellitus (T2DM), than MH-PCOS. Alternatively, measures of HA were similar between the groups. Assessing IR dynamically, subjects were subdivided into MU-PCOS by an insulin sensitivity index [Si] ≤1.7 [mU/L]−1·min−1 (n=8) or MH-PCOS by an Si ≥5.6 [mU/L]−1·min−1 (n=8), matched for age and BMI. MU-PCOS had lower Si and KNEFA, smaller %NEFAsupp, longer TIMEnidar, and higher NEFAnidar and Adipo-IR than MH-PCOS, although fasting plasma NEFA levels and SNEFA were similar. In bivalent analysis, Si correlated strongly and negatively with NEFAnadir, weakly and negatively with TIMEnadir, and positively and strongly with KNEFA and NEFAsupp, in MUO-PCOS only. Conclusion Independent of age and BMI, metabolically unhealthy obese PCOS women, compared with metabolically healthy obese PCOS women, had lower rates of NEFA uptake and altered insulin-mediated plasma NEFA suppression in response to mFSIVGTT-determined endogenous insulin secretion, rather than disparities in HA and rate of lipolysis, mechanism that may contribute to variations in insulin sensitivity among obese PCOS women. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Light Physical Activity Relates To Insulin Sensitivity And Earlier Time Of Day In Metabolic Syndrome

PURPOSE: Low insulin sensitivity is linked to metabolic syndrome (MetS). However, whether the time of day when light physical activity (LPA) occurs affects insulin sensitivity is unclear. We tested the relationship between LPA time of day and insulin sensitivity in MetS. METHODS: Thirty adults with MetS were classified as morning (MOR, n = 11, 9F), midday (MID, n = 9, 6F), or afternoon (AFT, n = 10, 6F) by active LPA time using 7-d tri-axial hip-worn accelerometry (Actigraph). Time of day was defined by which part of the day had the highest percentage (>50%) of LPA. Peripheral insulin sensitivity (M-value between 90-120 min) was measured using a 2-hr hyperinsulinemic-euglycemic clamp (40 mU/m2/min, 90 mg/dl), while hepatic (HOMA-IR), and adipose (Adipose-IR) insulin resistance were estimated from fasting glucose, FFA, and insulin, respectively. Aerobic fitness (VO2max), anthropometrics (BMI, waist circumference), and inflammation (TNF-α, CRP and IL-8 at 0 and 120 min) were also examined. RESULTS: There were no differences amongst groups in age (P = 0.60), ATP III criteria (P = 0.91), or VO2max (P = 0.76). While time in sedentary (P = 0.44) and moderate-to-vigorous activity (P = 0.66) were similar amongst groups, MOR (21.3 ± 1.7%, P = 0.03) and MID (21.1 ± 1.3%, P = 0.01) had increased time in LPA compared to AFT (16.5 ± 1.2%). Further, MOR had a lower BMI (33.1 ± 1 vs. 38.6 ± 1.8 vs. 41 ± 2 kg/m2, P = 0.004) and waist circumference (107.9 ± 1.8 vs. 115.3 ± 3.8 vs. 123.1 ± 5.4 cm, P = 0.02). Although clamp-derived insulin sensitivity (P = 0.43), HOMA-IR (P = 0.30), and adipose-IR (P = 0.81) were similar across groups, higher LPA (%) related to increased peripheral insulin sensitivity (r = 0.33, P = 0.04) and lower adipose-IR (r = -0.36, P = 0.02). There were no group differences in fasting or change (i.e. 120-0 min) in TNF-α (P = 0.55), CRP (P = 0.41) or IL-8 (P = 0.07). However, higher LPA (%) related to insulin stimulated reductions in IL-8 (r = -0.42, P = 0.01). These changes in IL-8 also correlated with a higher adipose-IR (r = 0.37, P = 0.03). CONCLUSION: Time spent in LPA relates to insulin sensitivity and earlier times of day. Future work should look at whether time of day influences body weight regulation and cardiovascular health to optimize disease prevention/treatment. Funding: NIH RO1-HL130296

Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency.

This study aims to investigate the metabolic phenotype and mechanism of 40% calorie restriction (CR) in mice. CR mice exhibit super-stable blood glucose, as evidenced by increased fasting blood glucose (FBG), decreased postprandial blood glucose, and reduced glucose fluctuations. Additionally, both fasting plasma insulin and the homeostasis model assessment of insulin resistance increase significantly in CR mice. Compared with control, the phosphorylation of insulin receptor substrates-1 and serine/threonine kinase decreases in liver and fat but increases in muscle of CR mice after insulin administration, indicating hepatic and adipose insulin resistance, and muscle insulin sensitization. CR reduces visceral fat much more than subcutaneous fat. The elevated FBG is negatively correlated with low-level fasting β-hydroxybutyrate, which may result from insufficient free fatty acids and diminishes ketogenic ability in CR mice. Furthermore, liver glycogen increases dramatically in CR mice. Analysis of glycogen metabolism related proteins indicates active glycogen synthesis and decomposition. Additionally, CR elevates plasma corticosterone and hypothalamic orexigenic gene expression. CR induces lipid insufficiency and stress, resulting in global physiological insulin resistance except muscle and enhances glycogen metabolism, culminating in the stability of blood glucose manifests in increased FBG, which compensates for insufficient blood ketones.

Adipose tissue insulin resistance predicts the incidence of hypertension: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases

We investigated the association of adipose tissue insulin resistance with blood pressure and hypertension incidence, comparing it with hepatic and skeletal muscle insulin resistance. The cross-sectional analysis included 6892 general health checkup examinees (mean age: 69.3 years; 51.3% women and 48.7% men) who had no cardiovascular disease. Of those, 3948 normotensive participants (mean age: 68.4 years; 54.8% women and 45.2% men) were enrolled in the retrospective cohort analysis. The adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and free fatty acid levels. A high adipo-IR, high homeostasis model assessment of insulin resistance (HOMA-IR), and low Matsuda index were indicated based on the optimal cutoff values in a receiver operating characteristic curve analysis. Adipo-IR (β = 0.096, P < 0.001), HOMA-IR (β = 0.052, P < 0.001), and Matsuda index (β = -0.055, P < 0.001) were associated with systolic blood pressure in the cross-sectional analysis. Over a mean 5.3-year follow-up period, 1310 participants developed hypertension. A high adipo-IR (adjusted OR, 1.29; 95% CI, 1.11-1.51), but not HOMA-IR or Matsuda index, was significantly associated with the incidence of hypertension. Moreover, the combination of high adipo-IR with high HOMA-IR or low Matsuda index showed no higher odds of hypertension than a high adipo-IR alone. These results suggest that insulin resistance is associated with blood pressure control regardless of the tissue in which it occurs; however, the risk of hypertension is determined by insulin resistance in adipose tissue rather than in liver or muscle tissue.

390-P: Adipose Insulin Resistance Relates to Perturbed Renal Hemodynamics in Obese Youth with and without Type 2 Diabetes

Our objective was to compare renal hemodynamic function between obese youth with and without type 2 diabetes (T2D) and relate these measures to adipose insulin resistance (IR) . We assessed insulin sensitivity and kidney function in obese youth with (n=31, 15.8 ± 1.8 years, BMI 35.6 ± 6.6 kg/m2) , and without (n=20, 15.3 ± 2.1 years, BMI 38.2 ± 7.4 kg/m2) T2D. A hyperglycemic clamp was performed with 20% dextrose to maintain mild hyperglycemia for 240 minutes. Free fatty acids (FFA) were measured at baseline and every minutes during the steady state. FFA suppression (baseline FFA subtracted from steady state FFA) was used to estimate adipose IR. Iohexol and p-aminohippurate clearances were used to measure GFR and renal plasma flow, respectively. Renal hemodynamic parameters were calculated using Gomez equations. FFA suppression was attenuated in youth with T2D compared to obese controls (55.6% vs. 92.1%, p&amp;lt;0.0001) . Impaired FFA suppression was associated with higher intraglomerular pressure (r= -0.49, p=0.005) , higher efferent arteriolar resistance, (r= -0.53, p=0.002) and higher renal vascular resistance (r= -0.59, p=0.0005) . Youth with T2D had impaired FFA suppression compared to obese controls, indicating adipose IR. Impaired FFA suppression was associated with perturbed renal hemodynamics, indicating a potential role for adipose IR in the development of early diabetic kidney disease. Disclosure C.Platnick: None. P.V.Prasad: None. L.Li: None. L.Pyle: None. R.G.Nelson: None. D.Van raalte: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Sanofi. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

The long noncoding RNA ADIPINT regulates human adipocyte metabolism via pyruvate carboxylase

The pleiotropic function of long noncoding RNAs is well recognized, but their direct role in governing metabolic homeostasis is less understood. Here, we describe a human adipocyte-specific lncRNA, ADIPINT, that regulates pyruvate carboxylase, a pivotal enzyme in energy metabolism. We developed an approach, Targeted RNA-protein identification using Orthogonal Organic Phase Separation, which identifies that ADIPINT binds to pyruvate carboxylase and validated the interaction with electron microscopy. ADIPINT knockdown alters the interactome and decreases the abundance and enzymatic activity of pyruvate carboxylase in the mitochondria. Reduced ADIPINT or pyruvate carboxylase expression lowers adipocyte lipid synthesis, breakdown, and lipid content. In human white adipose tissue, ADIPINT expression is increased in obesity and linked to fat cell size, adipose insulin resistance, and pyruvate carboxylase activity. Thus, we identify ADIPINT as a regulator of lipid metabolism in human white adipocytes, which at least in part is mediated through its interaction with pyruvate carboxylase.

Insulin Sensitivity and Metabolic Flexibility Parallel Plasma TCA Levels in Early Chronotype With Metabolic Syndrome.

People characterized as late chronotype have elevated type 2 diabetes and cardiovascular disease risk compared to early chronotype. It is unclear how chronotype is associated with insulin sensitivity, metabolic flexibility, or plasma TCA cycle intermediates concentration, amino acids (AA), and/or beta-oxidation. This study examined these metabolic associations with chronotype. The Morningness-Eveningness Questionnaire (MEQ) was used to classify adults with metabolic syndrome (ATP III criteria) as either early (n = 15 [13F], MEQ = 64.7 ± 1.4) or late (n = 19 [16F], MEQ = 45.5 ± 1.3) chronotype. Fasting bloods determined hepatic (HOMA-IR) and adipose insulin resistance (Adipose-IR) while a 120-minute euglycemic clamp (40 mU/m2/min, 5 mmoL/L) was performed to test peripheral insulin sensitivity (glucose infusion rate). Carbohydrate (CHOOX) and fat oxidation (FOX), as well as nonoxidative glucose disposal (NOGD), were also estimated (indirect calorimetry). Plasma tricarboxylic acid cycle (TCA) intermediates, AA, and acyl-carnitines were measured along with VO2max and body composition (DXA). There were no statistical differences in age, BMI, fat-free mass, VO2max, or ATP III criteria between groups. Early chronotype, however, had higher peripheral insulin sensitivity (P = 0.009) and lower HOMA-IR (P = 0.02) and Adipose-IR (P = 0.05) compared with late chronotype. Further, early chronotype had higher NOGD (P = 0.008) and greater insulin-stimulated CHOOX (P = 0.02). While fasting lactate (P = 0.01), TCA intermediates (isocitrate, α-ketoglutarate, succinate, fumarate, malate; all P ≤ 0.04) and some AA (proline, isoleucine; P = 0.003-0.05) were lower in early chronotype, other AA (threonine, histidine, arginine; all P ≤ 0.05) and most acyl-carnitines were higher (P ≤ 0.05) compared with late chronotype. Greater insulin sensitivity and metabolic flexibility relates to plasma TCA concentration in early chronotype.

Abstract P167: Soluble CD14 Level And Incident Diabetes Mellitus Risk: The Reasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Introduction: CD14 is a pattern recognition receptor that plays important roles in the inflammatory response. Circulating soluble CD14 (sCD14) is generated by hepatocyte secretion during the acute phase response and by cleavage from immune cell surfaces, and levels are higher in White than Black individuals. CD14 is implicated in adipose tissue-mediated inflammation and insulin resistance in experimental animal models and in some cross-sectional cohort studies. Prospective studies of sCD14 and incidence of diabetes mellitus (DM) are limited. We evaluated the prospective association of sCD14 with incident DM risk in participants of the REGARDS study. Methods: At the baseline study examination in 2003-07, REGARDS recruited 30,239 Black and White participants aged 45-years and older from across the contiguous U.S. A second in-home visit occurred in 2013-16. sCD14 was measured by ELISA in baseline serum samples among participants of the REGARDS Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study, a nested race- and sex-stratified random sample of 4400 participants who completed the first and second REGARDS visits. Poisson regression models estimated risk ratios (RR) of incident DM per 1-SD increment higher sCD14, with tiered adjustment for risk factors. We tested a priori for a sCD14-by-race interaction (p interaction significance threshold &lt;0.10). Results: Among REGARDS BioMedioR participants there were 475 cases of incident DM over a mean follow-up of 9.5 years. Adjusting for age, sex, and body mass index, the sCD14-by-race interaction term was statistically significant (p-interaction=0.05). In analyses stratified by race, higher sCD14 was associated with incident DM in White (RR: 1.18; 95% CI: 1.04, 1.35) but not Black participants (RR: 0.97; 95% CI: 0.86, 1.09). In models additionally adjusted for education, income, lipids, hypertension, and physical activity, the association of higher sCD14 with DM risk was attenuated among White participants (RR: 1.10; 95% CI: 0.95, 1.27) and slightly accentuated among Black participants (RR: 0.89; 95% CI: 0.80, 1.00), although these associations were not statistically significant. Conclusions: sCD14 is differentially associated with risk of DM by race with higher levels associated with increased risk among White but not Black adults. Observed associations were explained by other risk factors, providing clues as to potentially novel mechanisms of their association with DM.

Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans.

The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

Association of obesity with serum free fatty acid levels in individuals at different stages of prediabetes

We investigated the associations of prediabetes categories and obesity with serum free fatty acid (FFA) levels and adipose tissue insulin resistance. This study included 5006 male participants (1779, 1025, 629, 874, and 699 with normal fasting glucose/normal glucose tolerance, isolated impaired fasting glucose [IFG], isolated impaired glucose tolerance [IGT], IFG plus IGT, and diabetes, respectively). Serum FFA levels were assessed before and 30, 60, and 120 min after glucose ingestion, and the total area under the FFA curve (AUCFFA ) was calculated. Adipose insulin resistance index (adipo-IR) was assessed based on fasting FFA and insulin concentrations. Isolated IFG was associated with high fasting FFA levels (OR, 1.35; p < 0.001) and high adipo-IR (OR, 1.82; p < 0.001) only in the nonobesity group. Isolated IGT, IFG plus IGT, and diabetes were associated with high fasting FFA levels, regardless of obesity. Obesity was significantly associated with AUCFFA , and the duration of obesity-related impairment in lipolysis inhibition after glucose ingestion was prolonged in IFG plus IGT and diabetes. These results suggest that IFG and obesity may overlap in their effects on FFA metabolism whereas IGT has significant effects on FFA independent of obesity. Obesity impact on lipolysis may be involved in worsening glucose metabolism.

High-Fat Diets-Induced Metabolic Disorders to Study Molecular Mechanism of Hyperlipidemia in Rats

Hyperlipidemia is a lipid metabolism disorder occurring due to consumption of a high-fat diet (HFD), which contributes to atherosclerosis and cardiovascular disease development. HFD causes metabolic problems in Rodentia animals like human metabolic abnormalities, making it a popular model for studying the signaling systems involved. Hyperlipidemia is a condition in which the body's cholesterol levels elevate. In recent years, several studies have investigated the relationship between HFD feeding and hyperlipidemia and signaling pathways involved in cholesterol homeostasis. However, this signaling mechanism in lipid metabolism has not been fully explained, so additional analysis is needed. The present study aimed to investigate the mechanism that occurs from hyperlipidemia due to HFD feeding. The method used is a literature review approach following the PRISMA scheme for selecting the primary literature, including identification, screening, eligibility test, and inclusion. Eleven articles included primary literature with credibility (H-index) of 20, 33, 71, 92, 93, 162, 180, 192, and 332 (six articles from Q1 journals and five from Q2 journals). Long-term administration of HFD directly affects lipid metabolism, including an increase in the concentration of total cholesterol, triglycerides, LDL, and a decrease in HDL concentration, followed by an increase in body weight. In addition, HFD also disrupts adipose tissue and insulin resistance. The conclusion of this study is that HFD can cause hyperlipidemia either directly or indirectly by inducing insulin resistance, which contributes to lipid metabolism disorders.

Ursolic acid ameliorates adipose tissue insulin resistance in aged rats via activating the Akt-glucose transporter 4 signaling pathway and inhibiting inflammation.

Ageing often results in insulin resistance (IR) and chronic inflammation, and adipose is one of the tissues in which inflammation and IR occur earliest during this process. The present study investigated the effect and underlying mechanisms of ursolic acid (UA) on adipose IR and inflammation in ageing rats. Specific pathogen-free male Sprague-Dawley rats were randomly divided into 4 groups: i) Young normal (young); ii) untreated ageing (aged); and groups supplemented with UA either iii) low-UA 10 mg/kg (UA-L) or iv) high-50 mg/kg (UA-H). Animals in the UA-treated groups received 10 or 50 mg/kg UA (suspended in 5% Gum Arabic solution). The rats in the corresponding aged group and young groups received vehicle (5% Gum Arabic) alone. All rats were intragastrically treated once daily by oral gavage for 7 weeks. The day before the experiment terminated, overnight fasting blood (~700 µl) was collected and plasma was prepared to measure biochemical indicators; western blotting was performed to analyze the expression of insulin signaling proteins [(insulin receptor substrate 1 (IRS-1), phosphorylated (p)-IRS-1, PI3K, glucose transporter 4 (GLUT4), Akt and p-Akt)] and inflammatory factors (NF-κB, IL-6 and IL-1β) in the epididymis white adipose tissue (eWAT). The results revealed that treatment with UA-H decreased eWAT weight, the ratio of eWAT weight/body weight, fasted insulin and triglyceride levels, the homeostasis model assessment of insulin resistance and adipose tissue insulin resistance index in ageing rats, indicating the amelioration of systemic and adipose tissue IR, compared with the aged group. Mechanistically, UA-H administration upregulated p-protein kinase B, the ratio of p-Akt to protein kinase B and total and cellular membrane GLUT4 protein levels in eWAT of ageing rats. Conversely, UA inhibited the increase in NF-κB expression and proinflammatory cytokines IL-6 and IL-1β. However, these alterations were not observed in the rats of the aged group. Taken together, the findings of the present study indicated that UA may ameliorate adipose IR, which is associated with activation of the Akt-GLUT4 signaling pathway and inhibition of inflammation in ageing rats. These data provide a basis for the development of effective and safe drugs or functional substances, such as UA, for the prevention and treatment of metabolic diseases.

Association of adipose tissue insulin resistance and serum free fatty acid levels with the incidence of type 2 diabetes: a retrospective cohort study

Abstract Background Insulin resistance in adipose tissue attenuates the suppression of lipolysis, leading to increased free fatty acid (FFA) release. The excess FFA may be involved in the development of type 2 diabetes. Purpose In this study, we investigated the association of adipose tissue insulin resistance and serum free fatty acid levels with the incidence of type 2 diabetes. Methods This is an observational study involving 6800 participants (3451 women, mean age 69.2 years) without diabetes who underwent 75-g oral glucose tolerance test (OGTT) at baseline. The participants were divided into the obesity and nonobesity groups on the basis of body mass index of ≥25 and &amp;lt;25 kg/m2, respectively. Serum FFA levels were assessed before and 30, 60, and 120 min after glucose ingestion, and the total area under the FFA curve (AUCFFA) was calculated. Adipose tissue insulin resistance was assessed using adipose insulin resistance index (adipo-IR) calculated based on fasting FFA and insulin concentrations. The homeostasis model assessment of insulin resistance (HOMA-IR), and the Matsuda index were evaluated as measures of insulin resistance in the liver and whole-body, respectively. High adipo-IR, high fasting FFA, great AUCFFA high HOMA-IR, and low Matsuda index were determined based on the optimal cutoff values from ROC curve analysis. Results Over a mean 5.3-year follow-up period, 485 participants developed type 2 diabetes. Multivariate logistic regression analyses showed that high adipo-IR was a significant predicator for incident type 2 diabetes in the obesity group, but not in nonobesity group. AUCFFA, HOMA-IR, and Matsuda index were significantly associated with incident type 2 diabetes in both the two groups (Table). Conclusion Serum FFA levels after glucose loading predict the incidence of type 2 diabetes. Adipose tissue insulin resistance was associated with the risk of type 2 diabetes in individuals with obesity, but not in individuals without obesity. Funding Acknowledgement Type of funding sources: None.

The role of Akkermansia muciniphila in obesity, diabetes and atherosclerosis.

Alteration in the composition of the gut microbiota can lead to a number of chronic clinical diseases. Akkermansia muciniphila is an anaerobic bacteria constituting 3-5% of the gut microbial community in healthy adults. This bacterium is responsible for degenerating mucin in the gut; its scarcity leads to diverse clinical disorders. In this review, we focus on the role of A. muciniphila in diabetes, obesity and atherosclerosis, as well as the use of this bacterium as a next-generation probiotic. In regard to obesity and diabetes, human and animal trials have shown that A. muciniphila controls the essential regulatory system of glucose and energy metabolism. However, the underlying mechanisms by which A. muciniphila alleviates the complications of obesity, diabetes and atherosclerosis are unclear. At the same time, its abundance suggests improved metabolic disorders, such as metabolic endotoxemia, adiposity insulin resistance and glucose tolerance. The role of A. muciniphila is implicated in declining aortic lesions and atherosclerosis. Well-characterized virulence factors, antigens and cell wall extracts of A. muciniphila may act as effector molecules in these diseases. These molecules may provide novel mechanisms and strategies by which this bacterium could be used as a probiotic for the treatment of obesity, diabetes and atherosclerosis.

Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women.

ContextIncreased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women.ObjectiveThis work examines whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women.MethodsThis prospective cohort study took place in an academic center and comprised 19 normal-weight PCOS women and 21 age- and body mass index–matched controls. Interventions included circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. Serum T/A4 ratios, hormone/metabolic measures, and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si).ResultsIncreased serum T/A4 ratios (P = .040) and log adipose-IR values (P = .002) in PCOS women vs controls were accompanied by AKR1C3 messenger RNA overexpression of PCOS adipocytes matured in vitro (P = .016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TGs: R = –0.65, P = .002) and the TG index (R = –0.57, P = .011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R = –0.57, P = .013) and TG index (R = –0.50, P = .036), respectively, without significant relationships with other metabolic measures.ConclusionAn elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.

437-P: MicroRNA-223 Expression Is Upregulated in Type 2 Diabetes and Associated with Diabetic Retinopathy in Cohort of Qatar Biobank: Functional Validation in Zebrafish Model

MicroRNAs (miRNAs/miRs) are implicated in the pathogenesis of type 2 diabetes (T2D) and its long-term complications such as retinopathy. miRNAs circulating levels have explored as possible biomarkers for the advancement of T2D. We examined the expression of customized set of miRNAs in T2D Qatari nationals with and without diabetic retinopathy (DR) from Qatar Biobank 1000 Qatar omics cohort. MiR-223 appeared to be significantly upregulated in T2D in comparison to the healthy controls. MiR-223 previously found to play a role in insulin resistant human adipose tissues, human and murine obesity and potential regulators of optic nerve regeneration. To further investigate the potential role of miR-223 in the development of DR, we established a zebrafish (ZF) model to functionally validate this potential correlation. Our aim is to investigate the miR-223 with hyperglycemia on the developing retina in the ZF as a vertebrate model. Mimic miR-223 was injected into single cell ZF embryos and incubated in normal and induced hyperglycemia conditions. We have examined the glucose ratios, eye morphology and vasculature structure in the developing model in comparison to the control groups. To understand the cellular mechanisms involved in DR; histological examination, cell apoptosis and proliferation have been performed and to be evaluated. miR-223 over expression resulted in an alteration of the glucose metabolism within the ZF model. Glucose ratio was significantly increased in ZF embryos injected with mimic miR-223. Increased miR-223 in the developing ZF larvae together with hyperglycemia affected the retinal development. The eye size was significantly reduced with degenerated vasculature and altered eye morphology. In conclusion, we have identified a novel correlation between DR development and miR-223. Targeting miR-223 in T2D patients may serve as promising therapeutic strategy to control DR in at risk T2D patients. Disclosure A. S. Akil: None. S. Da’as: None. L. A. Jerman: None. D. Abdelrahman: None. W. Hasan: None. K. Fakhro: None. Funding Qatar National Research Fund (NPRP9-229-3-041)

Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.

Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. We will study 40 adults aged 20-55years with Type 1 diabetes (HbA1c 80mmol/mol [9.5%], fasting C-peptide <0.3nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500mg daily or matched placebo for 26weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. ACTRN12619001440112.

Photobiomodulation therapy ameliorates hyperglycemia and insulin resistance by activating cytochrome c oxidase-mediated protein kinase B in muscle.

Ameliorating hyperglycemia and insulin resistance are major therapeutic strategies for type 2 diabetes. Previous studies have indicated that photobiomodulation therapy (PBMT) attenuates metabolic abnormalities in insulin-resistant adipose cells and tissues. However, it remains unclear whether PBMT ameliorates glucose metabolism in skeletal muscle in type 2 diabetes models. Here we showed that PBMT reduced blood glucose and insulin resistance, and reversed metabolic abnormalities in skeletal muscle in two diabetic mouse models. PBMT accelerated adenosine triphosphate (ATP) and reactive oxygen species (ROS) generation by elevating cytochrome c oxidase (CcO) activity. ROS-induced activation of phosphatase and tensin homolog (PTEN)/ protein kinase B (AKT) signaling after PBMT promoted glucose transporter GLUT4 translocation and glycogen synthase (GS) activation, accelerating glucose uptake and glycogen synthesis in skeletal muscle. CcO subunit III deficiency, ROS elimination, and AKT inhibition suppressed the PBMT effects of glucose metabolism in skeletal muscle. This study indicated amelioration of glucose metabolism after PBMT in diabetic mouse models and revealed the metabolic regulatory effects and mechanisms of PBMT on skeletal muscle.