Insulin Resistance-related Disorders Research Articles

Compromised cardiac autonomic function in non-diabetic subjects with 1 h post-load hyperglycemia: a cross-sectional study

BackgroundA compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction.MethodsPresence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT.ResultsAs compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN.ConclusionSubjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

The role of high fat diet on serum uric acid level among healthy male first degree relatives of type 2 diabetes mellitus

First-degree relatives (FDR) of type 2 diabetes mellitus have increased risk of developing insulin resistance-related disorders including hyperuricemia. We investigated metabolic profile and serum uric acid (SUA) metabolism in response to high-fat diet among healthy male FDR in comparison to those without family history of diabetes. A total of 30 FDR and 30 non-FDR subjects completed a 5-days-hypercaloric diet with fat added to regular daily intake. Despite similar insulin response, FDR displayed different changes in SUA compared to non-FDR subjects (0.26 ± 0.83 mg/dL vs − 0.21 ± 0.78 mg/dL, p = 0.028). In subgroup analyses stratified by body mass index and waist circumference, significant different SUA changes between FDR and non-FDR subjects were only found in obese (0.48 ± 0.87 mg/dL vs − 0.70 ± 0.71 mg/dL, p = 0.001) and centrally obese (0.59 ± 0.83 mg/dL vs − 0.55 ± 0.82 mg/dL, p = 0.011) subgroups. In multivariate analysis, visceral adiposity seemed mediating the different response in SUA metabolism between FDR and non-FDR subjects induced by short-term obesogenic diet.

Myo-inositol supplementation improves cardiometabolic factors, anthropometric measures, and liver function in obese patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of metabolic syndrome is closely associated with type 2 diabetes mellitus. Myo-inositol (MI)-a 6-C sugar alcohol-with insulin-mimetic, anti-diabetic, lipid-lowering, and anti-inflammatory properties has exerted favorable effects on insulin resistance-related disorders and metabolic disease, while recent animal studies revealed its positive effects on liver function. This study aimed to investigate the effects of MI supplementation on cardiometabolic factors, anthropometric measures, and liver function in obese patients with NAFLD. This double-blinded placebo-controlled randomized clinical trial was carried out on 48 obese patients with NAFLD who were randomly assigned to either MI (4g/day) or placebo (maltodextrin 4g/day) along with dietary recommendations for 8 weeks. Glycemic indices, lipid profile, liver enzymes anthropometric measures, and blood pressure were evaluated pre- and post-intervention. Dietary intakes were assessed using a 3-day 24 h recall and analyzed by Nutritionist IV software. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), and beta-cell function (HOMA-B) was also estimated. Anthropometric measures decreased significantly in both groups, while the reduction in weight (p = 0.049) and systolic blood pressure (p = 0.006) in the MI group was significantly greater than in the placebo group after adjusting for baseline values and energy intake. Although energy and macronutrient intakes decreased significantly in both groups, between-group differences were not significant after adjusting for the potential confounders. MI supplementation led to a significant reduction in serum fasting insulin (p = 0.008) and HOMA-IR (p = 0.046). There were significant improvements in lipid profile, liver enzymes, and aspartate aminotransferase/alanine aminotransferase ratio as well as serum ferritin level in the MI group, compared to the placebo group at the endpoint. By MI supplementation for eight weeks, 1 in 3 patients reduced one- grade in the severity of NAFLD. MI supplementation could significantly improve IR, lipid profile, and liver function in patients with NAFLD. Further clinical trials with larger sample sizes, longer duration, different MI doses, and other inositol derivatives are recommended.

Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state.

Empagliflozin is a SGLT2 inhibitor that has shown remarkable cardiovascular and renal activities in patients with type 2 diabetes (T2D). Preclinical and clinical studies of empagliflozin in T2D population have demonstrated significant improvements in body weight, waist circumference, insulin sensitivity, and blood pressure – effects beyond its antihyperglycaemic control. Moreover, several studies suggested that this drug possesses significant anti-inflammatory and antioxidative stress properties. This paper explores extensively the main preclinical and clinical evidence of empagliflozin administration in insulin resistance-related disorders beyond a diabetic state. It also discusses its future perspectives, as a therapeutic approach, in this high cardiovascular-risk population.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

Oral L-glutamine restores adenosine and glutathione content in the skeletal muscle and adipose tissue of insulin-resistant pregnant rats.

Mishandling of lipid and glycogen has been documented as a feature of metabolic tissues in insulin resistance-related disorders. However, reports exist detailing that L-glutamine (GLN) protects non-adipose tissue against the deleterious effects of metabolic disorders. Therefore, we hypothesized that GLN would protect skeletal muscle and adipose tissue against the deleterious effects of lipid and glycogen mishandlings by increasing adenosine and glutathione levels in pregnant rats exposed to fructose (FRU)-enriched drinks. Pregnant Wistar rats weighing 150 to 180 g were randomly assigned to control, GLN, FRU, and FRU + GLN groups (six rats/group). The groups received vehicle (P.o.), glutamine (1 g/kg), FRU (10%; w/v), and FRU + GLN, respectively, for 19 d. Data show that FRU caused insulin resistance with corresponding increased blood glucose, circulating and pancreatic insulin levels, and lipid accumulation and glycogen depletion in skeletal muscle, but glycogen accumulation and a decreased lipid profile in adipose tissue. Adenosine and glutathione content decreased, whereas adenosine deaminase, xanthine oxidase, uric acid, and malondialdehyde concentrations increased in both tissues. In addition, glucose-6-phosphate dehydrogenase activity decreased in skeletal muscle but remained unaltered in adipose tissue. However, supplementation with GLN improved perturbed lipid and glycogen with a corresponding increase in adenosine and glutathione. The present results collectively indicate that lipid and glycogen mishandlings caused by high gestational FRU intake result in the depletion of adenosine and glutathione in skeletal muscle and adipose tissue. These findings also suggest that L-glutamine protects against skeletal muscle and adipose tissue dysmetabolism by enhancing adenosine and glutathione.

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study.

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.

BMP7 improves insulin signal transduction in the liver via inhibition of mitogen-activated protein kinases.

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.

Endothelial adenosine kinase deficiency ameliorates diet-induced insulin resistance.

Insulin resistance-related disorders are associated with endothelial dysfunction. Accumulating evidence has suggested a role for adenosine signaling in the regulation of endothelial function. Here, we identified a crucial role of endothelial adenosine kinase (ADK) in the regulation of insulin resistance. Feeding mice with a high-fat diet (HFD) markedly enhanced the expression of endothelial Adk. Ablation of endothelial Adk in HFD-fed mice improved glucose tolerance and insulin sensitivity and decreased hepatic steatosis, adipose inflammation and adiposity, which were associated with improved arteriole vasodilation, decreased inflammation and increased adipose angiogenesis. Mechanistically, ADK inhibition or knockdown in human umbilical vein endothelial cells (HUVECs) elevated intracellular adenosine level and increased endothelial nitric oxide synthase (NOS3) activity, resulting in an increase in nitric oxide (NO) production. Antagonism of adenosine receptor A2b abolished ADK-knockdown-enhanced NOS3 expression in HUVECs. Additionally, increased phosphorylation of NOS3 in ADK-knockdown HUVECs was regulated by an adenosine receptor-independent mechanism. These data suggest that Adk-deficiency-elevated intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders, and this is associated with an enhancement of NO production caused by increased NOS3 expression and activation. Therefore, ADK is a potential target for the prevention and treatment of metabolic disorders associated with insulin resistance.

Elevated plasma copeptin levels identify the presence and severity of non-alcoholic fatty liver disease in obesity

IntroductionCopeptin is the stable surrogate marker of vasopressin (VP), which is released in response to elevated plasma osmolality or low blood pressure. Elevated plasma copeptin levels are associated with higher risk of insulin resistance-related disorders, such as type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease, and experimental reduction of circulating VP levels is shown to significantly decrease hepatic fat content in obese rats, independently from body adiposity. However, the association between copeptin and non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) in humans has not been explored yet. The aim of this study was to explore the relationship between plasma copeptin and the presence/severity of NAFLD/NASH.MethodsFor this study, we recruited 60 obese patients candidate to bariatric surgery for clinical purposes in which intraoperative liver biopsies were performed for diagnosing NAFLD/NASH. Circulating copeptin levels were also assessed in 60 age- and sex-comparable non-obese individuals without NAFLD at liver ultrasonography. Plasma copeptin was measured by sandwich immunoluminometric assay (Thermo Fisher Scientific).ResultsObese patients with biopsy-proven NAFLD (53%) had significantly higher copeptin levels than both obese individuals without NAFLD and non-obese subjects (ob/NAFLD+ 9.5 ± 4.9; ob/NAFLD− 6.4 ± 2.6; and non-ob/NAFLD− 7.4 ± 5.1 pmol/L; p = 0.004 and p = 0.01 respectively). Plasma copeptin concentration positively correlated with hepatic macro- and micro-vesicular steatosis (r = 0.36, p = 0.026; r = 0.31, p = 0.05), lobular inflammation (r = 0.37, p = 0.024) and significantly increased throughout degrees of NASH severity, as expressed as absence, borderline, and overt NASH at the liver biopsy (r = 0.35, p = 0.01). Greater circulating copeptin predicted the presence of NASH with OR = 1.73 (95% CI = 1.02–2.93) after multivariate adjustment for age, sex, renal function and presence of T2DM and MS components.ConclusionsIncreased plasma copeptin is independently associated with the presence and severity of NAFLD and NASH, pointing to a novel mechanism behind human fatty liver disease potentially modifiable by pharmacological treatment and lifestyle intervention.

Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improving effects on insulin resistance-associated metabolic abnormalities, including obesity and type 2 diabetes mellitus. However, the related molecular mechanisms are still unclear. In this research, we investigated the protective effects of theaflavins against insulin resistance in HepG2 cells induced by palmitic acid. Theaflavins significantly increased glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the total and membrane bound glucose transporter 4 protein expressions, increasing the phosphor-Akt (Ser473) level, and decreasing the phosphorylation of IRS-1 at Ser307. Moreover, theaflavins were found to enhance the mitochondrial DNA copy number, down-regulate the PGC-1β mRNA level and increase the PRC mRNA expression. Mdivi-1, a selective mitochondrial division inhibitor, could attenuate TFs-induced promotion of glucose uptake in insulin-resistant HepG2 cells. Taken together, these results suggested that theaflavins could improve hepatocellular insulin resistance induced by free fatty acids, at least partly through promoting mitochondrial biogenesis. Theaflavins are promising functional food ingredients and medicines for improving insulin resistance-related disorders.

Higher serum levels of uric acid are associated with a reduced insulin clearance in non-diabetic individuals.

Decreased insulin clearance has been reported to be associated with insulin resistance-related disorders and incident type 2 diabetes. The aim of this study was to evaluate whether higher levels of uric acid (UA), a known risk factor of type 2 diabetes, are associated with a reduced insulin clearance. 440 non-diabetic individuals were stratified in tertiles according to serum UA levels. Insulin clearance and skeletal muscle insulin sensitivity were assessed by euglycemic hyperinsulinemic clamp. Hepatic insulin resistance was estimated by the liver IR index. Subjects with higher levels of UA displayed an unfavorable metabolic phenotype with a worse lipid profile, increased levels of 2-h post-load glucose levels, fasting, and 2-h post-load insulin levels, hsCRP, liver IR index, and lower levels of eGFR and skeletal muscle insulin sensitivity, in comparison to individuals with lower UA levels. Moreover, subjects with higher UA concentrations exhibited decreased levels of insulin clearance even after adjustment for age, gender, BMI, eGFR, and skeletal muscle insulin sensitivity. In a multivariate regression analysis model including several confounding factors, UA concentration was an independent predictor of insulin clearance (β = - 0.145; P = 0.03). However, when liver IR index was included in the model, the independent association between UA levels and insulin clearance was not retained. Accordingly, in a mediation analysis, liver IR index was a mediator of the negative effects of UA levels on insulin clearance (t = - 2.55, P = 0.01). Higher serum levels of UA may affect insulin clearance by impairing hepatic insulin sensitivity.

Acknowledgement to reviewers

The Journal of Insulin Resistance is a peer-reviewed, clinically oriented journal covering advances in disorders of insulin resistance. Articles focus on clinical care and advancing therapy for patients with insulin resistance-related disorders. Insulin resistance includes pathophysiology, management, patient education, and treatment considerations for different patient populations.

Lipid profile and insulin sensitivity in rats fed with high-fat or high-fructose diets

The occurrence and severity of obesity- and insulin resistance-related disorders vary according to the diet. The aim of the present longitudinal study was to examine the effects of a high-fat or a high-fructose diet on body weight (BW), body fat mass, insulin sensitivity (IS) and lipid profiles in a rat model of dietary-induced obesity and low IS. A total of eighteen, 12-week-old male Wistar rats were divided into three groups, and were fed with a control, a high-fat (65 % lipid energy) or a high-fructose diet (65 % fructose energy) for 10 weeks. BW, body fat mass ((2)H2O dilution method), IS (euglycaemic-hyperinsulinaemic clamp technique), plasma glucose, insulin, NEFA, TAG and total cholesterol were assessed before and at the end of 10-week period. Cholesterol was measured in plasma lipoproteins separated from pooled samples of each group and each time period by using fast-protein liquid chromatography. All rats had similar BW at the end of the 10-week period. Body fat mass was higher in the high-fat group compared to the control group. There was no change in basal glycaemia and insulinaemia. The IS was lower in the high-fat group and was unchanged in the high-fructose group, compared to the control group. Plasma TAG concentration and cholesterol distribution in lipoproteins did not change over time in any group. Plasma NEFA concentration decreased, whereas plasma TAG concentration increased over time, regardless of the diet in both cases. The 10-week high-fat diet led to obesity and low IS, whereas rats fed with the high-fructose diet exhibited no change in IS and lipidaemia. The high-fat diet had more deleterious response than high-fructose diet to induce obesity and low IS in rats.

Vaspin,obesity,and type 2 diabetes

Vaspin,a serine protease inhibitor derived from visceral adipose tissue,has been identified as an adipokine with insulin-sensitizing effects in a rat model of type 2 diabetes.Recent studies showed that the administration of recombinant human vaspin significantly improved insulin sensitivity and glucose tolerance,and reversed the expression of genes that may promote insulin resistance in diet-induced obese mice.However,the regulation of serum vaspin concentration in individuals with insulin resistance,and the association of vaspin with obesity,type 2 diabetes,and insulin resistance related disorders remain unclear. Key words: Adipokine; Vaspin; Obesity; Diabetes mellitus,type 2; Insulin resistance

Genetics of serum resistin: a paradigm of population-specific regulation?

Keywords Insulinresistance.Population-specificeffect.Resistincirculatinglevels.RETNAdipocytes release a number of peptide hormones, collec-tively known as adipokines, which are essential inregulation of intermediate metabolism, and which maycontribute to the pathogenesis of insulin resistance andrelated disorders [1].Among these is resistin, a 12.5 kDa cysteine-rich proteinthat is secreted also by macrophages [2–4]. Several piecesof evidence suggest that this molecule antagonises insulinaction and fosters inflammation [2–4]. In humans, mostcross-sectional studies have reported that elevated resistinlevels are associated with insulin resistance [5–7] and type2 diabetes [8]. In most [9–11], although not all [12],prospective studies, resistin turned out to be a predictor oftype 2 diabetes and cardiovascular disease. Taken together,these findings highlight the role of serum resistin as anemerging pathogenic factor and a potential therapeutictarget for insulin resistance-related disorders. This latterpossibility is reinforced by the observation that resistinexpression in human adipose tissue is inhibited bythiazolidinediones [13], insulin-sensitising molecules thatare used as oral hypoglycaemic agents in the treatment ofpatients with type 2 diabetes.The mechanisms regulating resistin expression, secretionand circulating levels are still poorly understood. Recentdata clearly indicate that resistin serum levels are undergenetic control [6, 14]. Several single-nucleotide poly-morphisms (SNPs) in the RETN gene coding for resistin,have been associated with serum resistin levels and insulinresistance traits [6 ,8 14–18].Among others, rs1862513 at position g.−420 in theRETN 5′ flanking region has attracted much attention. ThisSNP has been associated with high resistin levels [8, 16],insulin resistance [ 17], obesity [15 , 18] and type 2diabetes [8, 19]. A recent meta-analysis, including morethan 3,500 individuals, has shown that those homozygousfor the G allele at rs1862513 have a 30% increase in theodds of being affected by type 2 diabetes [8]. Along thesame lines, the G allele was predictive of glycaemicdeterioration in a Chinese population followed for 5 years[20]. These associations are supported by functional datademonstrating a stronger activation of the RETN promoterby Sp1 and Sp3 transcription factors in the presence of theG allele [8]. In agreement with these data, the same allelehas been reported to be associated with higher abdominal-fat resistin mRNA levels [21]. Thus, so far, so good forSNP rs1862513.Recently, a fine-mapping analysis of the RETN gene hasbeen carried out in a sample of more than 2,500 individualsof European ancestry [14]. The authors found that alleles at

Associaton of Insulin Resistance Linked Diseases and Hair Loss in Elderly Men. Finnish Population-based Study

Previous investigations have shown an association of androgenetic alopecia (AGA) with insulin resistance related disorders such as ischemic heart disease. An association between AGA and anthropometric abnormalities linked with insulin resistance and heredity in women aged 63 years has also been shown. We therefore compared 63-year-old men with AGA and ones with normal hair status for insulin resistance linked parameters. A population of 245 men aged 63 years, who were participants in a population-based cross-sectional study in the City of Oulu, underwent a medical check-up including assessment of hair status on the Hamilton-Norwood scale and determination of anthropometric measures, blood pressure, fasting glucose and serum lipids. Fifty eight per cent of the men reported extensive hair loss (grade III-VII). Hypertension and the use of antihypertensive drugs were common among men with AGA (61% vs. 45% and 50% vs. 26%, respectively). The rates of diabetes and hyperinsulinemia (21% vs. 12% and 61% vs. 49%) were higher among men with AGA compared to those with normal hair status but no difference was seen in other factors. Our findings show that AGA is common among Finnish men aged 63 years but that it is also associated with insulin linked disturbances, such as hypertension and diabetes. Such men developing AGA might benefit from attention in medical check-up.