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Background: Second-generation antipsychotics (SGAs) is thought responsible for the metabolic abnormalities of schizophrenic patients, however, some untreated schizophrenic patients had already developed problems with glucose metabolism. The present study examined the hypothesis that schizophrenia itself but not risperidone, an extensively employed SGA, is accountable for metabolic abnormalities., Methods: A 56-day risperidone regimen (1 mg/kg/day) was employed for rats of social isolation rearing (SIR) beginning at different developmental stage (28 or 56 days after weaning, i.e., adolescent and young adulthood, respectively). Metabolic parameters including body weight, systolic blood pressure (SBP), triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and plasma glucose were measured at baseline, 28, and 56 days of the regimen. Oral glucose tolerance test (OGTT) was performed at the end of the regimen. Insulin function was evaluated by area under the curve (AUC) of OGTT, homeostasis model assessment-insulin resistance (HOMA-ir), and Matsuda index., Results: Our results demonstrated that: (i) SIR rats presented higher body weight, plasma triglyceride, and HOMA-ir than social controls. (ii) Higher insulin resistance was specifically presented in young adult rather than adolescent SIR rats. (iii) Adolescent drugged rats showed a lower level of LDL in day 28 of the regimen than young adult. Risperidone led to a lower LDL level in only young adult IR rats in day 56 than undrugged rats. (iv) SIR-induced dysregulation of insulin can be reversed by chronic risperidone treatment beginning at adolescence but not young adulthood., Conclusions: Our findings support the primary role of schizophrenia in metabolic abnormalities and risperidone appear beneficial when administered earlier., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Obesity is closely linked with type 2 diabetes and the effective therapies on obesity-associated diabetes are under development. The aim of this study was undertaken to investigate whether the inhibition of the augmented CCR5-mediated signaling could be a common target for treatment of obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high-fat diet (HFD) fed rats and CCR5 knockout mice and also in isolated islets and RIN-m5F cells. Conducted with SD rats, HFD-induced body weight gain was significantly decreased in those combined with Maraviroc treatment, but food intake remained similar compared to control. Maraviroc also significantly improved the impaired oral glucose tolerance test (OGTT). As compared with wild-type mice, CCR5 deletion significantly attenuated the HFD-induced increases in glucose area under curve of OGTT and the value of HOMA-IR as well as plasma lipid profile. It also reversed the HFD-suppressed gene expressions of GLUT4 and IRS-1 in adipose tissue. On the other hand, the HFD-associated islet macrophage and T-cell infiltration were significantly decreased in CCR5 KO mice. H 2 O 2 significantly suppressed glucose-stimulated insulin secretion (GSIS) is isolated islets, which were significantly reversed in those cotreated with CCR5 mAb. H 2 O 2 failed to change GSIS in those of CCR5 KO mice. The palmitate-induced reactive oxygen species production was significantly decreased in those cotreated with CCR5 antagonist in RIN-m5F cells. Collectively, it is suggested that targeting inhibition of the CCR5 mediated inflammatory pathway could not only improve obesity-associated insulin resistance but also directly alleviate pancreatic β-cell dysfunction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (-0.003 × GE - 212.6 × SPIS - 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.

Obesity and insulin resistance are two major risk factors for the development of metabolic syndrome, type 2 diabetes and associated cardiovascular diseases (CVDs). Cyclooxygenase (COX), a rate-limiting enzyme responsible for the biosynthesis of prostaglandins (PGs), exists in two isoforms: COX-1, the constitutive form, and COX-2, mainly the inducible form. COX-2 is the key enzyme in eicosanoid metabolism that converts eicosanoids into a number of PGs, including PGD 2 , PGE 2 , PGF 2α , and prostacyclin (PGI 2 ), all of which exert diverse hormone-like effects via autocrine or paracrine mechanisms. The COX-2 gene and immunoreactive proteins have been documented to be highly expressed and elevated in adipose tissue (AT) under morbid obesity conditions. On the other hand, the environmental stress-induced expression and constitutive over-expression of COX-2 have been reported to play distinctive roles under different pathological and physiological conditions; i.e., over-expression of the COX-2 gene in white AT (WAT) has been shown to induce de novo brown AT (BAT) recruitment in WAT and then facilitate systemic energy expenditure to protect mice against high-fat diet-induced obesity. Hepatic COX-2 expression was found to protect against diet-induced steatosis, obesity, and insulin resistance. However, COX-2 activation in the epidydimal AT is strongly correlated with the development of AT inflammation, insulin resistance, and fatty liver in high-fat-diet-induced obese rats. This review will provide updated information regarding the role of COX-2-derived signals in the regulation of energy metabolism and the pathogenesis of obesity and MS.

Background: The aim of the present study was to compare insulin resistance and metabolic changes using a global lipidomic approach., Methods: Rats were fed a high-fat diet (HFD) or a high-fructose diet (HFrD) for 12 weeks to induce insulin resistance (IR) syndrome. After 12 weeks feeding, physiological and biochemical parameters were examined. Insulin sensitivity and plasma metabolites were evaluated using a euglycemic-hyperinsulinemic clamp and mass spectrometry, respectively. Pearson's correlation coefficient was used to investigate the strength of correlations., Results: Rats on both diets developed IR syndrome, characterized by hypertension, hyperlipidemia, hyperinsulinemia, impaired fasting glucose, and IR. Compared with HFrD-fed rats, non-esterified fatty acids were lower and body weight and plasma insulin levels were markedly higher in HFD-fed rats. Adiposity and plasma leptin levels were increased in both groups. However, the size of adipocytes was greater in HFD- than HFrD-fed rats. Notably, the lipidomic heat map revealed metabolites exhibiting greater differences in HFD- and HFrD-fed rats compared with controls. Plasma adrenic acid levels were higher in HFD- than HFrD-fed rats. Nevertheless, linoleic and arachidonic acid levels decreased in HFrD-fed rats compared with controls. Plasma concentrations of docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were significantly reduced after feeding of both diets, particularly the HFrD. There was a strong positive correlation between these two fatty acids and the insulin sensitivity index., Conclusions: The systemic lipidomic analysis indicated that a reduction in DHA and DPA was strongly correlated with IR in rats under long-term overnutrition. These results provide a potential therapeutic target for IR and metabolic syndrome., (© 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

We investigated the effects of metformin and celecoxib on obesity-induced adipose tissue inflammation, insulin resistance (IR), fatty liver, and high blood pressure in high-fat (HF) fed rats. Male Sprague-Dawley rats were fed with either regular or HF diet for 8 weeks. Rats fed with regular diet were treated with vehicle for further 4 weeks. HF fed rats were divided into 6 groups, namely, vehicle, celecoxib (30mg/kg/day), metformin (300mg/kg/day), metformin (150mg/kg/day), metformin (300mg/kg/day) with celecoxib (30mg/kg/day), and metformin (150mg/kg/day) with celecoxib (15mg/kg/day) for additional 4 weeks. Increased body weight in HF fed rats was significantly reduced by metformin alone and metformin combined with celecoxib. The increases in the HOMA-IR value and the area under the curve of glucose following an oral glucose tolerance test, systolic blood pressure, and adipocyte size were significantly diminished in treated rats, especially rats undergoing combined treatment. Treatments with either celecoxib or in combination with metformin resulted in a reduction in AT macrophage infiltration and decreases in levels of adipose tissue TNF-α, MCP-1, and leptin levels in high-fat (HF) fed rats. Furthermore, the elevated hepatic triglycerides content was significantly decreased in the combined treatment group compared to that of groups of celecoxib or metformin alone. Celecoxib exerts a synergistic beneficial effect with metformin on and obesity-associated metabolic and cardiovascular disorders in high-fat fed rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) ≈ 0.04 µM] and EP3 (L-798106 100 µg/kg, IC50 ≈ 0.5 µM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-α and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-κB and hypoxia-inducible factor-1α transcription activation. These findings suggest that adipocyte COX-2 PGE2-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.-Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance., (© FASEB.)

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.

Context: Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Preclinical studies indicate that Gas6 and its receptors of the TAM (Tyro-3, Axl, Mer) family may be involved in the pathogenesis of obesity and its complications, including systemic inflammation and insulin resistance. Until now, little has been known about the clinical significance of the Gas6/TAM system in childhood obesity., Objectives: This study aimed to determine whether circulating Gas6 and soluble Axl (sAxl) levels are associated with adiposity, inflammation, and insulin resistance status among Taiwanese adolescents., Methods: Cross-sectional analyses using the data from the Taipei Children Heart Study-III were performed. A total of 832 adolescents (average age, 13.3 years) were included; they were divided into 3 groups: lean, overweight, and obese. Circulating Gas6 and sAxl levels, adiposity, inflammatory markers, and insulin resistance status were examined., Results: Levels of circulating Gas6 and sAxl were significantly higher in overweight and obese adolescents than in the lean group (both P < .05). Circulating Gas6 levels were significantly positively correlated with body mass index Z-score (P = .045), waist circumference (P < .001), waist to hip circumference ratio (P < .001), body fat mass (P = .02), serum high-sensitivity C-reactive protein (P = .005), and tumor necrosis factor-α levels (P = .039) among overweight and obese adolescents. The correlations remained significant after adjusting for age, gender, Tanner stage, smoking status, and drinking status. In addition, every 1 ng/mL increase in circulating Gas6 concentration corresponded to a 15% to 19% increase in the risk of developing insulin resistance among overweight and obese adolescents., Conclusions: Circulating Gas6 levels are strongly associated with adiposity, inflammation, and insulin resistance status among overweight and obese adolescents. The potential role of the Gas6/TAM system in the initiation of childhood obesity and obesity-associated complications deserves further attention.

Aim: This study was undertaken to examine the effect of cyclooxygenase (COX) 2 inhibition on the development of muscular insulin resistance in high-fat-induced obese rats., Main Methods: The rats were on a regular chow diet (C) or high-fat enriched diet (HFD) energy-restrictedly (HFr), or ad libitum (HFa) for 12weeks. The rats fed HFD ad libitum were further divided into 3 groups: oral gavage with vehicle (HFa), selective COX-2 inhibitors-celecoxib (HFa+C) or nimesulid (HFa+N), 30mg/kg/day, respectively., Key Findings: Increased fasting plasma insulin, triglyceride and 8-isoprostane levels in HFa were significantly suppressed in those of HFa+C and HFa+N. The whole body insulin resistance of HFa indicated by the increased fasting plasma insulin levels and the elevated area under curve of insulin obtained from the oral glucose tolerance test were significantly reversed in those combined with celecoxib and nimesulid administration compared with those in HFr. The gene expression of COX-2 was significantly increased in epididymal fat but not in soleus muscle in HFa and the enhanced adipose COX-2 expression in high-fat fed rats was suppressed by those with drug treatment. Both selective COX-2 inhibitors reversed the diminished insulin-stimulated glucose uptake and GLUT4 translocation in skeletal muscles of HFa. Obesity-induced oxidative stress indicated by the elevated plasma 8-isoprostane,the decreased ratio of GSH/GSSG and increased TBARS in soleus muscle were significantly reversed by COX-2 inhibition., Significance: The results suggest that COX-2 inhibition might suppress the muscular insulin resistance indirectly through decreasing the COX-2-mediated systemic oxidative stress in this diet-induced obese model., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Weight status and abnormal liver function are the two factors that influence whole-body insulin sensitivity. The main goal of the study was to compare insulin sensitivity in athletes (n=757) and physically active controls (n=670) in relation to the two factors., Methods: Homeostatic metabolic assessment for insulin resistance (HOMA-IR), weight status, and abnormal liver function (alanine aminotransferase and aspartate aminotransferase) were determined from 33 sports disciplines under morning fasted condition. This study was initiated in autumn 2006 and repeated in autumn 2007 (n=1508) to ensure consistency of all observations., Results: In general, HOMA-IR and blood pressure levels in athletes were significantly greater than those in physically active controls but varied widely with sport disciplines. Rowing and short-distance track athletes had significantly lower HOMA-IR values and archery and field-throwing athletes had significantly higher values than the control group. Intriguingly, athletes from 22 sports disciplines displayed significantly greater body mass index values above control values. Multiple regression analysis showed that, for non-athlete controls, body mass index was the only factor that contributed to the variations in HOMA-IR. For athletes, body mass index and alanine aminotransferase independently contributed to the variation of HOMA-IR., Conclusion: This is the first report documenting HOMA-IR values in athletes from a broad range of sport disciplines. Weight status and abnormal liver function levels appear to be the major contributors predicting insulin sensitivity for the physically active population.

The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.

This study was designed to examine the role of cyclooxygenase (COX) 2-mediated low-grade inflammation in the development of fructose-induced whole body and muscular insulin resistance in rats. The rats were on regular or fructose-enriched diets for 8 weeks. Fructose-fed rats were further divided into 3 groups (n = 8 per group). There were fructose-fed rats, fructose-fed rats with nimesulide (a selective COX2 inhibitor, 30 mg/kg/day, gavage) and fructose-fed rats with celecoxib (a selective COX2 inhibitor, 30 mg/kg/day, gavage). The present result showed that fructose-induced time-dependent increases in systolic blood pressure and fasting plasma insulin and triglyceride levels were significantly suppressed in rats treated with nimesulide or cerecoxib. The ratio of area under glucose curve divided by area under insulin curve obtained during the oral glucose tolerance test was significantly decreased in fructose-fed rats, which were markedly reversed in those co-treated with nimesulide or celecoxib. Accordingly, fructose-induced decrease in insulin-stimulated glucose uptake in soleus muscle was significantly reversed in those combined with nimesulide or celecoxib. Fructose-induced time-dependent increases in plasma 8-isoprostane and PGE metabolites were concomitantly suppressed by nimesulide or celecoxib co-treatment. The present study demonstrates that the COX2-mediated low-grade inflammation, especially mediated by increase in oxidative stress was important in the development of insulin resistance in fructose-fed rats.

Background: The effects of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) inhibition on insulin resistance in subjects with the metabolic syndrome remain elusive. Aims of this study were to examine the effects of COX1 and COX2 inhibitors on whole body and muscular insulin resistance in fructose-fed rats, an animal model of the metabolic syndrome., Materials and Methods: The rats on regular or 60% fructose-enriched diets for 6 weeks were further divided into rats combined with or without piroxicam (a selective COX1 inhibitor) or celecoxib (a selective COX2 inhibitor) treatment for an additional 2 weeks. Euglycaemic hyperinsulinaemic clamp (EHC) with a tracer dilution method was performed at the end of the study., Results: The present result showed that fructose-induced increases in systolic blood pressure and fasting plasma insulin levels were significantly suppressed in rats treated with celecoxib but not piroxicam. In the EHC period, celecoxib significantly reversed fructose-induced decreases in whole body glucose uptake, mainly by glucose storage. Hepatic glucose production and whole body glycolysis were not significantly changed among groups. Celecoxib but not piroxicam significantly reversed fructose-induced decreases in glycogen synthase activities in red and white quadriceps muscles and insulin-stimulated membrane GLUT4 recruitment in soleus muscles. Celecoxib and piroxicam both significantly diminished fructose-induced increases in plasma thromboxane B2 and 6-keto prostaglandin (PG) F1alpha; but only celecoxib treatment significantly attenuated a fructose-induced increase in 8-isoprostane levels. Plasma PGE metabolites were not different among groups., Conclusions: This study demonstrates that a therapeutic dose of celecoxib, but not piroxicam, could significantly attenuate fructose-induced whole body and muscular insulin resistance in rats.

This study aimed to evaluate the effect of hyperinsulinemia on hypertriglyceridemia-induced pressor response in normal and fructose-induced insulin resistant rats. The rats were divided into six groups of eight rats and were fed a fructose-enriched diet (FINs, F(INS+TG)) or a regular chow diet (C, C(TG), C(INS), C(INS+TG)) for 8 wks. The acute experiment was conducted at the end of wk 8 and consisted of a 30-min basal period and followed by a 120-min test period. After the basal period, somatostatin (1.3 microg/kg/ min) combined with regular insulin (0.6 or 4 mU/kg/min) and variable glucose infusion were given to clamp euglycemia and euinsulinemia in C and C(TG) or euglycemia and hyperinsulinemia in CINs, C(INS+TG), F(INS) and F(INS+TG). During test period, lipofundin (a triglyceride emulsion) was infused into CTG, C(INS+TG), F(INS+TG) and saline instead was infused into C, C(INS), FINS. Plasma insulin and triglyceride levels were significantly higher in fructose-fed rats than in normal rats. During the test period, the lipofundin infusion (1.2 ml/kg/hr) increased plasma triglyceride levels by 368 +/- 39, 351 +/- 71 and 489 +/- 38 mg/dl compared with their baseline levels in lipid-infused groups. During the test period, low-dose insulin infusion kept plasma insulin at basal levels in C and C(TG) and high-dose insulin infusion increased plasma insulin levels about 6 times the baseline insulin level in C. Glucose infusion rate (GIR) was significantly higher in rats with high insulin infusion than those with low insulin infusion. The increase in GIR was lower in fructose-fed groups than in control groups under similar hyperinsulinemia. Rats with or without lipofundin infusion did not alter GIR during the test period. The present results demonstrated that hypertriglyceridemia-induced pressor response was diminished under hyperinsulinemic condition in both normal and fructose-induced insulin resistant rats.

Background: The present study was undertaken to compare the effects of chronic hyperinsulinemia with or without insulin resistance on the autonomic control of heart rate (HR) in rats., Methods: Male Sprague-Dawley rats were implanted subcutaneously with insulin (3 mU/kg x min) or vehicle-filled osmotic minipumps for 8 weeks. Insulin-infused rats were further divided into insulin resistant (IR) and insulin sensitive (IS) groups according to the results of the homeostasis model assessment method and euglycemic hyperinsulinemic clamp study. Autonomic function in HR control was indicated by arterial baroreflex sensitivity (BRS) after a bolus injection of phenylephrine or sodium nitroprusside., Results: Compared with those in control group, plasma insulin levels were elevated about threefold and 1.5-fold in the IR and IS groups at the end of week 8, respectively. Blood glucose level remained basal in the IR group, but was significantly lower in the IS group. The elevated mean arterial pressure (MAP) observed in IR was not exhibited in IS. The HR and BRS in reflex tachycardia were significantly increased in the IR and IS groups, but the BRS in reflex bradycardia was not different among all rats. Propranolol eliminated the tachycardia and enhanced BRS responses in both groups. Methylatropine further accelerated tachycardia and diminished the enhanced BRS in the IR group. However, in IS, the enhanced BRS remained after methylatropine was given. The intrinsic HR was similar among all groups. The baseline MAP, HR, and BRS in reflex tachycardia were significantly correlated to plasma insulin levels but not to the Si value, an index of insulin sensitivity., Conclusions: The present results demonstrate that hyperinsulinemia but not insulin resistance is a dominant contributing factor to the development of arterial baroreflex abnormalities in this chronic hyperinsulinemic model, which may simultaneously enhance sympathetic nerve activity and possibly vagal withdrawal if insulin resistance coexisted.

This study was designed to compare the pressor response to hypertriglyceridemia under basal glucose and insulin condition as well as the decay pattern of this lipid-induced pressor effect in normal (NRs) and fructose-induced insulin resistant rats (FIRs). The rats were on a fructose-enriched or a regular chow diet for 8 wks and then were further divided into two subgroups (n = 8/group) with lipofundin (a 20% triglyceride emulsion) or saline infusion during the following clamp study. The acute clamp experiment contained a 30-min basal period, followed by a 120-min test period and a 90-min off period. After the basal period, somatostatin (1.3 microg/kg/min) combined with regular insulin (0.6 mU/kg/min) and variable glucose infusion were given to keep insulin and glucose levels basal throughout the experiment. The baseline triglyceride levels were about 6 folds higher in FIRs than those in NRs. During the test period, the lipofundin infusion (1.2 ml/kg/hr) increased plasma triglyceride levels by 368 +/- 39 and 489 +/- 38 mg/dL from baseline in NRs and FIRs, respectively. The elevated triglyceride level was dropped promptly while the lipofundin infusion was discontinued in the following off period. FIRs have higher mean arterial blood pressure (MAP) levels than those in NRs. During the test period, the hypertriglyceridemia-induced press responses were markedly delayed and attenuated in FIRs compared with those in NRs. Accordingly, the value of deltaMAP/deltaTG served as an index of the hypertriglyceridemia-induced increase in BP was significantly lower in FIRs than in NRs. This hypertriglyceridemia-induced pressor effect was sustained to the end of study even after removal of the lipid infusion for 60 min in NRs and FIRs. In rats without lipofundin infusion, MAP and plasma triglyceride levels failed to change throughout the study. The present results suggest that the prolonged pressor response induced by acute hypertriglyceridemia is attenuated in rats with fructose-induced insulin resistance.

The present study was performed to evaluate the potential role and functional interaction of angiotensin II AT1 and AT2 receptors (AT1R and AT2R) in the regulation of blood pressure and glucose homeostasis in fructose-induced insulin-resistant, hypertensive rats. Male Sprague-Dawley rats on fructose-enriched or regular diets for 4 weeks were subjected to 2-step euglycemic euinsulinemic (EEI) and euglycemic hyperinsulinemic (EHI) clamp studies with [3-3H]glucose infusion. After a 40-minute basal period, selective AT1R and AT2R antagonists, losartan (LOS, 10 mg/kg IV bolus) and PD123319 (PD, 50 microg/kg/min), alone or in combination were separately given to control and fructose-fed groups in the 2 clamp periods. The results showed that during the EEI period, LOS significantly reduced the elevated blood pressure in fructose-fed rats, whereas PD further increased fructose-induced high blood pressure. Coadministration of LOS and PD did not alter the elevated blood pressure in fructose-fed rats. Administration of LOS and/or PD failed to change the blood pressure in control rats. During the EHI period, blockade of both AT1R and AT2R eliminated the insulin-induced blood pressure elevation in control and fructose-fed rats. Hepatic glucose production (HGP) did not alter among groups in the basal and EEI periods. Insulin infusion (EHI period) markedly suppressed HGP in control rats, but this suppressive effect was significantly attenuated in fructose-fed rats. LOS administration further reduced the insulin-induced suppression of HGP in fructose-fed rats. The whole-body glucose uptakes (rates of glucose disappearance, Rd) during the basal and EEI periods were similar among groups. During the EHI period, Rd was markedly increased in all groups and the magnitude of increase was significantly greater in control rats than in fructose-fed rats except those with LOS treatment. LOS treatment also redirected Rd in favor of glycolysis in fructose rats, but not in control rats, during the EEI and EHI periods. The effects of LOS on glycolysis during the 2 clamp periods and on HGP during the EHI period were reversed when PD was concomitantly administered, but PD alone did not alter glucose metabolism throughout the experiment in fructose-fed rats. Administration of LOS and/or PD did not change the glucose metabolism in control rats. Our data suggest that AT2R can counterbalance the AT1R-mediated effects on blood pressure and glucose metabolism in fructose-induced insulin-resistant, hypertensive rats. Furthermore, AT1R- and AT2R-mediated effects on blood pressure are disassociated with their actions on glucose metabolism in this hypertensive model.

Hyperinsulinemia and insulin resistance frequently coexist and have been implicated in the pathogenesis of hypertension. This study aimed to identify the specific effect of hyperinsulinemia on blood pressure and nitric oxide (NO) release in fructose-induced hyperinsulinemic, insulin-resistant rats. Male Sprague-Dawley rats were fed either standard chow or a 60% fructose-enriched diet for 8 weeks before acute study. After basal period, somatostatin (1.3 microg/kg/min) and a variable glucose infusion (to maintain euglycemia) were given intravenously to all groups of rats. In control rats (C) and fructose-fed rats (F) with insulin infusion, insulin (4 mU/kg/min) was given to create a similar hyperinsulinemic condition. In C and F without insulin infusion, a vehicle instead of insulin was infused to produce a hypoinsulinemic state. In C, somatostatin reduced plasma insulin level but did not alter mean arterial pressure (MAP) and heart rate. Insulin infusion significantly increased MAP and NOx (sum of nitrate and nitrite) levels after 90 min and thereafter the elevated MAP and NOx responses were sustained throughout the study. In the basal period, F exhibited significantly higher MAP and plasma insulin levels than C. The index of insulin sensitivity (M) was significantly lower in F than in C with insulin infusion. Somatostatin significantly reduced plasma insulin level but did not affect MAP and NOx level in F. The stimulatory effects of insulin on MAP and NO levels were significantly smaller in F than in C. In conclusion, acute insulin-induced pressor response and NO release were attenuated in rats with fructose-treated insulin resistance, suggesting that hyperinsulinemia-associated attenuation of NO production contributes, at least partly, to the development of fructose-induced hypertension in rats., (Copyright 2004 American Journal of Hypertension, Ltd.)