Fructose-induced Insulin Resistance Research Articles

Inhibition of ketohexokinase prevents fructose-induced insulin resistance and endothelial dysfunction in high fat and sucrose-fed mice via enhancing energy expenditure

Abstract Introduction Cardiovascular disease linked to fatty liver poses a significant threat to health. Consumption of high-fat diets (HFD) is known to trigger a cascade of health issues including obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). These conditions are exacerbated, with the addition of dietary sugar to high-fat diets (HFSD), resulting in non-alcoholic steatohepatitis (NASH). Studies have shown that fructokinase (ketohexokinase or KHK) knockdown protects mice from HFSD-induced NASH. Purpose This study focused on examining the temporal changes of metabolic perturbations, triggered by sugar consumption, particularly in the transition from fatty liver to cardiovascular disease. Methods C57/BL6 wild type (WT) and KHK-knockout mice were fed with HFD or HFSD for different durations between 6 to 20 weeks, to induce NAFLD and NASH. Western blotting and quantitative-PCR were carried out on tissues and isolated endothelial cells for protein and mRNA expressions, respectively. Glucose and insulin tolerance tests and whole-body energy measurements were performed at different time-points. Combined Laboratory Animal Monitoring System was used to monitor various parameters of energy expenditure. Functional interactions between endothelial cells and adipose tissues were carried out using an in-house Organ-On-a-chip technology. Endothelial function was studied by measuring isometric tensions in organ bath. Results KHK-deficient mice had significantly lower weight compared to WT littermates. Wild-type mice fed HFD and HFSD exhibited significant glucose intolerance, insulin resistance, and endothelial dysfunction compared to KHK-knockout mice. However, HFSD led to more severe outcomes compared to HFD, demonstrating differing temporal effects on glucose intolerance and insulin resistance. Interestingly, KHK-knockout mice were significantly protected from the effects induced by HFSD, as well as, such as increased body weight, fasting hyperglycemia, hyperinsulinemia and endothelial function. KHK-knockout mice exhibited significant increase in oxygen consumption and energy expenditure, both in HFD and HFSD-fed conditions. These data suggest that high energy-expenditure is one of the primary mechanisms, in reducing adiposity and body weight in HFSD-fed knockout mice. Notably, KHK-deficient mice were protected against sugar-induced fat accumulation, random hyperinsulinemia and significant impairment of endothelial function. Conclusions A novel finding in this study is that KHK ablation protects not only against HFSD-induced, but also HFD-induced pathologies via significantly enhancing energy expenditure. The results suggest that targeting KHK could potentially mitigate the development of fatty liver and cardiovascular diseases, induced by high calorie diets.

Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats

In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro &invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.

Quercetin decreases fructose drinking in model of fructose-induced insulin resistance. Unexpected uric acid and TBARS lowering effect of methyl cellulose vehicle and fructose combination.

The aim of this study was to improve insulin sensitivity in fructose-treated animals by ingestion of flavonoid quercetin. Several signs of insulin resistance have been developed in rats by drinking 10% fructose solution for 9 weeks. The effect of 6-week-gavage-administrated quercetin (20 mg/kg/day in 1% methyl cellulose solution) was monitored. Rats of the control groups received methyl cellulose vehicle as well. The most striking result of the quercetin treatment was the normalization of the fructose solution drinking to the level of drinking water intake. In addition, quercetin supplementation considerably decreased the plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index in rats consuming fructose. Surprisingly, fructose ingestion did not elevate plasma uric acid, thiobarbituric acid reactive substances, nitrotyrosine, or advanced glycation end products fluorescence. Instead, a reduction of the above parameters was observed. In summary, these results indicate that quercetin supplementation reduces fructose drinking and decreases plasma glucose and the HOMA-IR index. Furthermore, methyl cellulose, in combination with fructose, causes uric acid - lowering, antioxidant and anti-glycation effects. Thus, methyl cellulose possibly shifts fructose metabolism in favor of the utilization of antioxidant features of fructose. Our results call for using methyl cellulose in sweetened beverages and other sweetened food.

Liver ChREBP deficiency inhibits fructose-induced insulin resistance in pregnant mice and female offspring

High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.

Protective Effect of Hydroalcoholic Extract of Punica granatum Leaves on High Fructose Induced Insulin Resistance in Experimental Animals.

Insulin resistance (IR) is a condition characterized by reduced sensitivity of body tissues to insulin, leading to impaired regulation of downstream metabolic pathways and elevated blood glucose levels. Diets rich in fructose have been proven to cause insulin resistance in test rats, resulting in decreased insulin sensitivity, particularly in the liver, and compromised disposal of glucose from the body. In the search for effective treatments, Plant-derived formulations have gained popularity because to their ability for treating a variety of ailments. One such plant is Punica granatum Linn. from the Punicaceae family, which has long been used in the treatment of diabetes and its consequences. This study investigates the insulin-resistant activity of an extract from Punica granatum leaves. The study goal is to assess the possible protective role of Punica granatum against insulin resistance through various analyses, including serum glucose and insulin levels, lipid profile assessment, measurement of liver enzymes (ALP, SGOT, SGPT), and histopathological examination of liver sections. The study involves several key methods to evaluate the insulin-resistant activity of Punica granatum extract in high fructose diet induced insulin resistance animal model. The extract was administered orally to the experimental animals. These methods include the measurement of serum glucose and serum insulin levels, analysis of the lipid profile, quantification of liver enzymes such as ALP, SGOT, and SGPT, and a detailed histopathological examination of liver tissue sections. These analyses collectively provide insights into the impact of Punica granatum extract on insulin resistance and related metabolic parameters. Findings of this study provide insight on the possible benefits of Punica granatum extract on insulin resistance. Through the assessment of serum glucose and insulin levels, lipid profile analysis, and measurement of liver enzymes, the study elucidates the impact of the extract on key metabolic indicators. Additionally, the histopathological examination of liver sections provides visual insights into the structural changes that may occur as a result of the treatment. In conclusion, this study highlights the ability of Punica granatum extract as a candidate for addressing insulin resistance. The findings suggest that the extract may have a protective role against insulin resistance, as evidenced by improvements in serum glucose and insulin levels, lipid profile, liver enzyme levels, and histopathological characteristics. Further research and investigations are warranted to fully understand the mechanisms underlying these observed effects and to validate the potential of Punica granatum extract as a therapeutic option for managing insulin resistance and its associated complications.

High fructose-induced skeletal muscle insulin resistance could be alleviated by berberine via AMPD1 and ADSL.

AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that is activated in response to an elevated intracellular AMP/ATP ratio. Although many studies have shown berberine is an AMPK activator widely used in metabolic syndrome, how to properly control AMPK activity remains obscure. Our present study aimed to examine the protective effect of berberine against fructose-induced insulin resistance in rats and L6 cells, as well as its potential activation mechanism on AMPK. The results showed that berberine effectively reversed body weight gain, Lee's index, dyslipidemia and insulin intolerance. Moreover, berberine alleviated inflammatory response, antioxidant capacity and promoted glucose uptake in vivo and in vitro. The beneficial effect was associated with upregulation of both Nrf2 and AKT/GLUT4 pathways, which were regulated by AMPK. Notably, berberine could increase the level of AMP and the ratio of AMP/ATP, then further activate AMPK. Mechanistic experiments revealed that berberine suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and promoted the expression of adenylosuccinate synthetase (ADSL). Taken together, berberine exerted excellent therapeutic effect on insulin resistance. And its mode of action may be related to the AMP-AMPK pathway by regulating AMPD1 and ADSL.

Quercetin decreases fructose drinking in model of fructose-induced insulin resistance. Antioxidant effects of fructose - methyl cellulose combination

Quercetin decreases fructose drinking in model of fructose-induced insulin resistance. Antioxidant effects of fructose - methyl cellulose combination

A Fructose-Rich Diet Decreases Insulin-Stimulated Glucose Incorporation into Lipids but Not Glucose Transport in Adipocytes of Normal and Diabetic Rats

To study the cellular mechanisms underlying fructose-induced insulin resistance in rats, the effects of fructose feeding on insulin-stimulated glucose transport, oxidation and incorporation into lipids in epididymal adipocytes were evaluated in 27 normal and 27 noninsulin-dependent diabetic male Sprague-Dawley rats. Diabetes was induced by streptozotocin injection 2 d after birth. At 5 wk of age, both normal and diabetic rats were fed a diet containing 62% carbohydrate as fructose, dextrose or cornstarch. Fructose feeding for 6 wk induced glucose intolerance in normal rats (P < 0.05) and aggravated that of diabetic rats (P < 0.05). Plasma triacylglycerol concentration was higher in fructose-fed than in starch-fed or dextrose-fed rats (P < 0.05). Adipocytes of fructose-fed rats had significantly lower maximum insulin-stimulated glucose incorporation into total lipids than those of rats fed starch, and tended (P = 0.22) to have lower production of CO2 from glucose than adipocytes of the other dietary groups. Glucose transport in adipocytes of dextrose-, starch- and fructose-fed rats did not differ. We conclude that in both normal and diabetic rats, a chronic fructose-rich diet induced hypertriacylglycerolemia, glucose intolerance and insulin resistance of adipocytes.

Effect of chronic administration of 17β-estradiol on the vasopressor responses induced by the sympathetic nervous system in insulin resistance rats

Several studies have demonstrated that the underlying mechanism of insulin resistance (IR) is linked with developing diseases like diabetes mellitus, hypertension, metabolic syndrome, and polycystic ovary syndrome. In turn, the dysfunction of female gonadal hormones (especially 17β-estradiol) may be related to the development of IR complications since different studies have shown that 17β-estradiol has a cardioprotector and vasorelaxant effect. This study aimed was to determine the effect of the 17β-estradiol administration in insulin-resistant rats and its effects on cardiovascular responses in pithed rats. Thus, the vasopressor responses are induced by sympathetic stimulation or i.v. bolus injections of noradrenaline (α1/2), methoxamine (α1), and UK 14,304 (α2) adrenergic agonist were determined in female pithed rats with fructose-induced insulin resistance or control rats treated with: 1) 17β-estradiol or 2) its vehicle (oil) for 5 weeks. Thus, 17β-estradiol decreased heart rate, prevented the increase of blood pressure induced by ovariectomy, but with the opposite effect on sham-operated rats; and decreased vasopressor responses induced by i.v. bolus injections of noradrenaline on sham-operated (control and fructose group) and ovariectomized (control) rats, and those induced by i.v. bolus injections of methoxamine (α1 adrenergic agonist). Overall, these results suggest 17β-estradiol has a cardioprotective effect, and its effect on vasopressor responses could be mediated mainly by the α1 adrenergic receptor. In contrast, IR with ovariectomy 17β-estradiol decreases or loses its cardioprotector effect, this could suggest a possible link between the adrenergic receptors and the insulin pathway.

Tert-butylhydroquinone abrogates fructose-induced insulin resistance in rats via mitigation of oxidant stress, NFkB-mediated inflammation in the liver but not the skeletal muscle of high fructose drinking rats.

The effect of 21% fructose drinking water (FDW) (w/v) on some parameters of metabolic syndrome, hepatic, and skeletal muscular histology of rats was studied using standard techniques. Twenty male albino rats were divided into four groups of 5 rats each in this in vivo study. Group I received distilled water, group 2 received FDW, group 3 received FDW and metformin (300 mg/kg body weight daily, orally), group 4 received FDW and 1% tert-butylhydroquinone feed. FDW changed the serum leptin, triacylglycerol, very low-density lipoprotein, and C-reactive protein levels of the rats, inducing hypertriglyceridemia, oxidative stress, and inflammation in their liver (but not the skeletal muscle) and insulin resistance which were modulated with metformin and tBHQ as corroborated by liver and muscle histology. The study reveals the potentials of metformin and tBHQ in mitigating hepatic and skeletal muscular morphological changes arising from exposure to high fructose drinks. PRACTICAL APPLICATIONS: There has been an increase in the global consumption of fructose (either as a sweetner in beverages or soft and carbonated drinks) in the last few decades and this has been positively correlated with the global increase in metabolic complications. Regular intake of fructose contributes to the pathogenesis of lipid disorders, oxidant stress, and chronic inflammation, which are linked with the metabolic syndrome components (MetS) (obesity, insulin resistance, and cardiovascular diseases) as well as increased morbidity and mortality. Given that the approaches that have been applied to treat the MetS have not been able to totally arrest it, currenty study which showed that tBHQ abrogated fructose-induced insulin resistance, dyslipidemia, hepatic, and skeletal muscular pathology in the rats places tBHQ in the spotlight as a nutraceutical that could be of relevance in mitigating high dietary fructose-induced hepatic and skeletal muscular pathology.

Metformin alleviates long-term high-fructose diet-induced skeletal muscle insulin resistance in rats by regulating purine nucleotide cycle

Nutrient excess caused by excessive fructose intake can lead to insulin resistance and dyslipidemia, which further causes the development of metabolic syndrome. Metformin is a well-known AMPK activator widely used for the treatment of metabolic syndrome, while the mechanism of AMPK activation remains unclear. The present study aimed to investigate the pharmacological effects of metformin on fructose-induced insulin resistance rat, and the potential mechanism underlying AMPK activation in skeletal muscle tissue. Results indicated that metformin significantly ameliorated features of insulin resistance, including body weight, Lee's index, hyperinsulinemia, dyslipidemia, insulin intolerance and pancreatic damage. Moreover, treatment with metformin attenuated the inflammatory response in serum and enhanced the antioxidant capacity in skeletal muscle tissue. The therapeutic effects of metformin on fructose-induced insulin resistance may be related to the activation of AMPK to regulate Nrf2 pathway and mitochondrial abnormality. Additionally, metformin suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and up-regulated the expression of adenylosuccinate synthetase (ADSS) in the purine nucleotide cycle (PNC), which facilitated the increase of AMP level and the ratio of AMP/ATP. Therefore, we proposed a novel mechanism that metformin activated AMPK via increasing AMP by regulating the expression of AMPD1 and ADSS in PNC pathway.

Fructose-Induced Insulin Resistance: Prospective Biochemical Mechanisms

Increased intake of dietary fructose is markedly associated with multiple negative health outcomes and burdens. Insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are the most common complications that present with conjugated cellular-biochemical abnormalities. This article explains the involvement of increased dietary fructose intake in the occurrence of IR and T2DM and addresses basic metabolic mechanisms. PubMed, Medline, Science Direct, ADI, and WHO databases were searched through June 2021. Current research predicts that over 350 million people may have diabetes by 2030. IR acts as an influencer promoter of T2DM development. IR can occur as a result of high fructose intake. Fructose metabolism results in de novo lipogenesis, while its decreasing effect of peroxisome proliferator-activated receptor (PPAR) activity elevates the levels of inflammatory cytokines, resulting in down-regulation of insulin receptor substrate-1 phosphorylation. Fructose stimulates oxidative stress by activating nicotinamide adenine dinucleotide phosphate oxidase and synthesis of advanced glycation end-products. Fructose also stimulates purine-induced uric acid synthesis and leptin resistance, which contributes to abnormal insulin action. It is crucial to understand the mechanisms of fructose-induced IR via induction of oxidative stress, inflammation, leptin resistance, and uric acid production. This helps prevent and control variable diseases, T2DM being the most.

Reversal of insulin resistance by Ficus benghalensis bark in fructose-induced insulin-resistant rats

Ethnopharmacological relevanceBark of Ficus benghalensis L. (family: Moraceae), commonly known as Banyan is recorded as Nyagrodha in Ayurvedic Pharmacopeia of India to manage burning sensation, obesity, diabetes, bleeding disorders, thirst, skin diseases, wounds, and dysmenorrhoea. However, the effect of F. benghalensis bark over glycolysis, gluconeogenesis, and appetite regulation in insulin-resistant pathogenesis has not been reported yet. Aim of the studyThe present study aimed to investigate the effect of hydroalcoholic extract of F. benghalensis bark in gluconeogenesis, glycolysis, and appetite regulation in fructose-induced insulin resistance in experimental rats. Materials and methodsMale Wister rats were supplemented with fructose in drinking water (10% w/v for 42 days and 20% w/v for next 12 days; a total of 54 days); insulin resistance was confirmed via the elevated area under the curve of the glucose during oral glucose tolerance test after 54 days and was subjected with extract treatment for next 30 days. After 30 days of treatment, animals were fasted to perform oral glucose and insulin tolerance test to estimate glucose and insulin levels. The blood sample was collected for biochemical estimation and the liver homogenate was prepared to estimate hepatic enzymes and enzymatic and non-enzymatic anti-oxidant biomarkers followed by histopathological evaluation. Also, glycogen content was quantified in gastrocnemius muscle and liver homogenates. Further, reported bioactives from the F. benghalensis were retrieved from the ChEBI database and docked against hexokinase, phosphofructokinase, glucose-6-phosphatase, lactate dehydrogenase, and fructose-1,6-biphosphatase to identify the probable lead hits against the enzymes involved in gluconeogenesis. ResultsTreatment with the F. benghalensis bark extract significantly increased the body weight and food intake and significantly decreased fructose supplemented water intake. Further, treatment with extract significantly increased the exogenous glucose clearance and well responded to the exogenous insulin. Further, extract treatment improved lipid metabolism, ameliorated plasma leptin, and multiple enzymatic and non-enzymatic antioxidant biomarkers. Likewise, it also improved gluconeogenesis mediated pathogenesis of non-alcoholic fatty liver injury. Additionally, molecular docking also identified mucusisoflavone A and B as lead hits in downregulating gluconeogenesis. ConclusionHydroalcoholic extract of F. benghalensis bark may prevent insulin resistance by downregulating gluconeogenesis and improving the appetite in fructose-induced insulin-resistant rats.

Sodium acetate ameliorated systemic and renal oxidative stress in high-fructose insulin-resistant pregnant Wistar rats.

Pregnancy is an insulin-resistant condition especially at near term predisposing maternal kidneys to hyperinsulinemia-induced oxidative stress. The impact of fructose on renal metabolic dysregulation and oxidative stress in pregnancy requires elucidation. Short-chain fatty acids (SCFAs) are known for protective roles in oxidative stress conditions. Therefore, the study aimed at investigating fructose-induced glucose dysregulation and renal oxidative stress in pregnant and non-pregnant rats and the possible preventive role of SCFA, acetate. Thirty female Wistar rats were grouped (n = 5/group). Three groups were made pregnant (P); the other three remained non-pregnant (NP). Both pregnant and non-pregnant rats received drinking water (control), 10% fructose (w/v) (NP+F or P+F), and 10% (w/v) fructose plus sodium acetate (200 mg/kg) (NP+F+A or P+F+A) for 3 weeks. Renal and plasma glutathione antioxidant index (GSH/GSSG), G6PDH, and adenosine were significantly lower in NP+F and P+F groups compared with control while renal and plasma adenosine deaminase (ADA), xanthine oxidase (XO), uric acid (UA), lactate dehydrogenase (LDH), and malonaldehyde (MDA) were significantly elevated in NP+F and P+F groups compared with controls. HOMA-IR showed marked impairment in both NP+F and P+F groups. The P+F group revealed greater suppression in plasma and renal G6PDH-dependent antioxidant index, adenosine, and aggravation of LDH, MDA compared with the NP+F group (p < 0.05). Sodium acetate reduces plasma and renal surrogate oxidative stress markers, improved G6PD-dependent antioxidant index, and HOMA-IR in NP+F and P+F groups. Pregnancy exacerbates fructose-induced insulin resistance and renal oxidative stress whereas acetate ameliorated fructose-induced redox and glucose dysregulation in pregnant and non-pregnant rats.

Apple pomace and rosemary extract ameliorates hepatic steatosis in fructose-fed rats: Association with enhancing fatty acid oxidation and suppressing inflammation.

Apple pomace and rosemary (AR) have been reported to contain rich bioactive molecules, which have numerous metabolic effects. Our preliminary work revealed that AR ameliorated fructose-induced insulin resistance in rats by modulating sarcolemmal CD36 and glucose transporter-4. The present study aimed to further examine how AR improves metabolic disorders by investigating the effect of AR on hepatic steatosis induced by fructose overconsumption. The results demonstrated that AR (100 mg/kg daily by gavage for 5 weeks) attenuated chronic liquid fructose consumption-induced increases in liver triglyceride content in rats. Mechanistically, reverse transcription-quantitative PCR and western blot analysis results indicated that AR reversed fructose-induced suppression of hepatic peroxisome proliferator-activated receptor α, carnitine palmitoyl-transferase 1α, sirtuin 1 and peroxisome proliferator-activated receptor-γ coactivator 1α, which were associated with the fatty acid oxidative (FAO) pathway. In addition, AR treatment decreased the expression levels of the pro-inflammatory proteins NF-κB and tumor necrosis factor-α. However, AR had no effect on the genes related to lipogenesis and the very low-density lipoprotein-export pathway in rat liver. Thus, the present results suggested that AR treatment diminished long-term fructose overconsumption-induced fatty liver, which was associated with enhanced FAO and suppressed inflammation.

ER Stress Amelioration by Saxagliptin Protects the Liver Against Fructose-induced Insulin Resistance

The study is aimed to demonstrate whether saxagliptin treatment may reduce endoplasmic reticulum (ER) stress, oxidative damage, and inflammation in the liver of fructose-induced insulin resistance (IR) rats. Twenty-eight rats were divided as control, IR, saxagliptin treatment (ST) and IR+ST groups. IR caused by fructose (10%) administration for 10weeks and, ST was administered for 15d. The liver tissues were obtained from rats. ER stress markers were analyzed using Real-Time PCR. Oxidative stress was measured. The inflammation in the liver was detected by the streptavidin-biotin immunostaining method. The values of total oxidant/antioxidant status were the same between control and IR rats. The numbers of IL-6, NF-κB and PPARγ immune+ cells showed significant changes in the liver among four groups. The increased mRNA expression levels of ER stress and apoptosis markers as GRP78, PERK, IRE1α, ATF-4 and -6, CHOP, Caspase-3, -8, -9 and -12 in IR reduced with ST. These findings indicate that saxagliptin treatment may ameliorate IR by reducing ER stress rather than inflammation and oxidative stress in the liver.

Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.

Correlation between brain neurotransmitters and insulin sensitivity: Neuro-preservative role of resveratrol against high fat, high fructose-induced insulin resistance

The development of obesity and prediabetes under conditions of long-term consumption of fructose solution in ratsVictoria Konopelnyuk, Alona Yurchenko, Taras Karpovets, Ludmila Ostapchenko

Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance

Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA "a sodium-glucose co-transporter 2 inhibitor") and infliximab [IFX "a tumor necrosis factor-α (TNF-α) antibody"] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30mg/kg), IFX (1 dose 5mg/kg), or EMPA + IFX for 4weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-β1 (TGF-β1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.

Berberine attenuates fructose-induced insulin resistance by stimulating the hepatic LKB1/AMPK/PGC1α pathway in mice

Context Berberine is an alkaloid that possesses various pharmacologic effects. Objective To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice. Materials and methods Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting. Results Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3β (GSK3β; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82). Conclusion The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance.