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Objectives: The aim of this study was to explore, on an additive scale, the combined effect of the association between insulin resistance (IR), chronic low-grade inflammation (CLGI) and vitamin D deficiency (VDD) on the risk of type 2 Diabetes Mellitus (T2DM). Methods: This is a cohort study, including 1484 non-diabetic subjects, followed for a period of four years. 25 hydroxy-vitamin D (25OHD), hypersensitive C-reactive protein (HsCRP) and triglyceride-glucose index were assessed. Based on VDD and CLGI, the population was subdivided into 4 exposure groups. Analysis was performed both in the case of IR and without IR. Cox proportional regression and additive interaction were applied to explore cumulative effects of exposure. Results: At follow-up, 162 newly diagnosed cases of T2DM were identified. TYG index (RR = 4.0[2.8–5.6]), HsCRP (RR = 1.6 [1.4–1.7]) and 25OHD (RR = 0.96 [0.39–0.98]) were all significantly associated with the risk of T2DM (p < 0.01). The highest excess risk was recorded in patients cumulating simultaneously IR, CLGI and VDD (RR= 8.4[3.6–19.8], p < 0.0001). The additive interaction was significant, the excess risk linked to the interaction RERI = 10.5[1.43–19.7], the proportion attributable to the combined effect: AP = 0.61[0.37–0.85], and the interaction was synergistic: synergy index: 2.8[1.42–5.69]. Conclusion: Baseline levels of TYG index, 25OHD and HsCRP are strongly predictive of future T2DM, and their joint effects are additive and synergistic. Interventional studies are therefore warranted in order to evaluate whether vitamin D supplementation, combined with appropriate anti-inflammatory therapies, is effective as a preventive strategy to reduce the risk of T2DM. [ABSTRACT FROM AUTHOR]

Aims: To utilize the estimated glucose disposal rate (eGDR) index of insulin sensitivity, which is based on readily available clinical variables, namely, waist circumference, hypertension and glycated haemoglobin, to discriminate between metabolically healthy and unhealthy phenotypes, and to determine the prevalence of prediabetic conditions. Methods: Non‐diabetic individuals (n = 2201) were stratified into quartiles of insulin sensitivity based on eGDR index. Individuals in the upper quartiles of eGDR were defined as having metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW) or metabolically healthy obesity (MHO) according to their body mass index, while those in the lower quartiles were classified as having metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW) and metabolically unhealthy obesity (MUO), respectively. Results: The frequency of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG + IGT status was comparable among the MHNW, MHOW and MHO groups, while it increased from those with MUNW status towards those with MUOW and MUO status. As compared with participants with MHNW, the odds ratio of having IFG, IGT, or IFG + IGT was significantly higher in participants with MUOW and MUO but not in those with MUNW, MHOW and MHO, respectively. Conclusions: A metabolically healthy phenotype is associated with lower frequency of IFG, IGT, and IFG + IGT status across all body weight categories. [ABSTRACT FROM AUTHOR]

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity. [ABSTRACT FROM AUTHOR]

Abstract Background Rare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications. Objective We aimed to evaluate the patients’ age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care. Patients and methods We analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares). Results A cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes (n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31–60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8–42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3–19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4–27.8] with a diagnostic delay of 10.5 years [IQR: 1.8–27.0]. Conclusion The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.

Thiazolidinedione (TZD) plays a crucial role in activating PPAR-γ receptor, which helps to inhibit insulin-resistant diabetes mellitus through binding with DNA by forming a complex with retinoid receptors. TZD derivatives are the sulphur and nitrogen containing heterocyclic compounds that have a massive impact in synthetic chemistry for their plethora of pharmacological activities. TZD helps to improve insulin resistance and lowering the blood glucose level through oxidation of carbohydrate in case of type II diabetes mellitus. TZD scaffold is a pentacyclic sulphur-containing compound with two carbonyl groups and an alpha hydrogen offering a huge possibility in structural modification of this biologically active molecule, here N-3 & C-5 positions are the most versatile site for structural modification in TZD nucleus. In this review, we focus on a brief description of its antidiabetic activity with its mechanism of action, structure activity relationship and various synthetic approach of the main pharmacophore TZD and hope it will help to develop idea about this moiety for future researchers.

Despite the advancement and benefits of antiretroviral therapy in recent years since its introduction, it has also resulted in complications such as metabolic syndrome like insulin resistance. This study is aimed at determining the prevalence and risk factors of metabolic syndrome in people living with HIV/AIDS (on Highly Active Antiretroviral Therapy (HAART) and HAART-naïve) at the Bamenda Regional Hospital. 273 participants were consecutively recruited; 191 were HAART-exposed, and 82 were HAART-naïve. Anthropometric and blood pressure measurements were conducted under standard conditions. Fasting blood sugar, triglyceride, and High-density-lipoprotein cholesterol (HDLc), were determined spectrophotometrically. Chi-square (χ2) and odd ratios were used to compare the prevalence of the metabolic syndromes between cases and controls at a 99% confidence interval. The study recorded a prevalence of 24.2%, 3.66%, 38.1% and 39.56% for insulin resistance, hyperglycemia, hypertension, and central obesity, respectively. HAART-naïve were significantly about twice at risk of developing decreased HDL compared to the HAART-exposed group [OR 2.04; 95% CI 1.14-3.66; P=0.015]. However, HAART-treatment duration ≥10 years was significantly associated with hyperglycemia. The type of HAART regimen also showed a significant association with increased central obesity. It is evident from this study that the following risk factors of metabolic syndrome are common among HIV/AIDS patients: lower HDL, central obesity, alcohol consumption, smoking habits, and age≥50 years. This, therefore, highlights the importance of these patients regulating their lifestyle since there is a rising risk of developing metabolic syndromes among them.

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition. [ABSTRACT FROM AUTHOR]

Ecological theories suggest that environmental factors significantly influence obesity risk and related syndemic morbidities, including metabolically abnormal obesity associated with nonalcoholic fatty liver disease (MASLD). These factors encompass anthropogenic influences and endocrine-disrupting chemicals (EDCs), synergistically interacting to induce metabolic discrepancies, notably in early life, and disrupt metabolic processes in adulthood. This review focuses on endocrine disruptors affecting a child's MASLD risk, independent of their role as obesogens and thus regardless of their impact on adipogenesis. The liver plays a pivotal role in metabolic and detoxification processes, where various lipophilic endocrine-disrupting molecules accumulate in fatty liver parenchyma, exacerbating inflammation and functioning as new anthropogenics that perpetuate chronic low-grade inflammation, especially insulin resistance, crucial in the pathogenesis of MASLD. [ABSTRACT FROM AUTHOR]

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder that affects a large proportion of women. Due to its heterogeneity, the best diagnostic strategy has been a matter of contention. Since 1990 scientific societies in the field of human reproduction have tried to define the pivotal criteria for the diagnosis of PCOS. The consensus Rotterdam diagnostic criteria included the presence of hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology (PCOM), and have now been updated to evidence based diagnostic criteria in the 2018 and 2023 International Guideline diagnostic criteria endorsed by 39 societies internationally. Within the Rotterdam Criteria, at least two out of three of the above-mentioned features are required to be present to diagnose PCOS, resulting in four phenotypes being identified: phenotype A, characterized by the presence of all the features, phenotype B, exhibiting hyperandrogenism and oligo-anovulation, phenotype C, presenting as hyperandrogenism and PCOM and finally the phenotype D that is characterized by oligo-anovulation and PCOM, lacking the hyperandrogenic component. However, it is the hypothesis of the EGOI group that the Rotterdam phenotypes A, B, and C have a different underlying causality to phenotype D. Recent studies have highlighted the strong correlation between insulin resistance and hyperandrogenism, and the pivotal role of these factors in driving ovarian alterations, such as oligo-anovulation and follicular functional cyst formation. This new understanding of PCOS pathogenesis has led the authors to hypothesis that phenotypes A, B, and C are endocrine-metabolic syndromes with a metabolic clinical onset. Conversely, the absence of hyperandrogenism and metabolic disturbances in phenotype D suggests a different origin of this condition, and point towards novel pathophysiological mechanisms; however, these are still not fully understood. Further questions have been raised regarding the suitability of the “phenotypes” described by the Rotterdam Criteria by the publication by recent GWAS studies, which demonstrated that these phenotypes should be considered clinical subtypes as they are not reflected in the genetic picture. Hence, by capturing the heterogeneity of this complex disorder, current diagnostic criteria may benefit from a reassessment and the evaluation of additional parameters such as insulin resistance and endometrial thickness, with the purpose of not only improving their diagnostic accuracy but also of assigning an appropriate and personalized treatment. In this framework, the present overview aims to analyze the diagnostic criteria currently recognized by the scientific community and assess the suitability of their application in clinical practice in light of the newly emerging evidence.

Insulin resistance (IR) is associated with reductions in neuronal proteins often observed with Alzheimer's disease (AD), however, the mechanisms through which IR promotes neurodegeneration/AD pathogenesis are poorly understood. Metformin (MET), a potent activator of the metabolic regulator AMPK is used to treat IR but its effectiveness for AD is unclear. We have previously shown that chronic AMPK activation impairs neurite growth and protein synthesis in SH‐SY5Y neurons, however, AMPK activation in IR was not explored. Therefore, we examined the effects of MET‐driven AMPK activation with and without IR. Retinoic acid‐differentiated SH‐SY5Y neurons were treated with: (1) Ctl: 24 h vehicle followed by 24 h Vehicle; (2) HI: 100 nM insulin (24 h HI followed by 24 h HI); or (3) MET: 24 h vehicle followed by 24 h 2 mM metformin; (4) HI/MET: 24 h 100 nM insulin followed by 24 h 100 nM INS+2 mM MET. INS and INS/MET groups saw impairments in markers of insulin signaling (Akt S473, mTOR S2448, p70s6k T389, and IRS‐1S636) demonstrating IR was not recovered with MET treatment. All treatment groups showed reductions in neuronal markers (post‐synaptic marker HOMER1 mRNA content and synapse marker synaptophysin protein content). INS and MET treatments showed a reduction in the content of the mature neuronal marker NeuN that was prevented by INS/MET. Similarly, increases in cell size/area, neurite length/area observed with INS and MET, were prevented with INS/MET. These findings indicate that IR and MET impair neuronal markers through distinct pathways and suggest that MET is ineffective in treating IR‐driven impairments in neurons. [ABSTRACT FROM AUTHOR]

Parkinsons disease (PD) is a predominantly idiopathic pathological condition characterized by protein aggregation phenomena, whose main component is alpha-synuclein. Although the main risk factor is ageing, numerous evidence points to the role of type 2 diabetes mellitus (T2DM) as an etiological factor. Systemic alterations classically associated with T2DM like insulin resistance and hyperglycemia modify biological processes such as autophagy and mitochondrial homeostasis. High glucose levels also compromise protein stability through the formation of advanced glycation end products, promoting protein aggregation processes. The ability of antidiabetic drugs to act on pathways impaired in both T2DM and PD suggests that they may represent a useful tool to counteract the neurodegeneration process. Several clinical studies now in advanced stages are looking for confirmation in this regard. [ABSTRACT FROM AUTHOR]

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disorder characterized by generalized lipoatrophy, acanthosis nigricans, diabetes mellitus, and hypertriglyceridemia. Aggressive control of diabetes is necessary and challenging in these patients due to the associated severe insulin resistance. We report a case of 5-year-old girl who presented with acromegaloid facies, acanthosis nigricans and diabetes mellitus in consideration of its rarity. [ABSTRACT FROM AUTHOR]

Aim: This retrospective cohort study aimed to identify the cardiometabolic characteristics, cross‐sectionally and longitudinally, associated with clinical stage in youth accessing early intervention mental health services. Methods: Cardiometabolic data we collected in 511 young people (aged 12–25 years at entry) receiving mental health care at the early intervention services in Sydney, Australia. Results: The majority of young people (N = 448, 87.67%) were classified in stage 1a or 1b at entry. At entry to care, there was no cross‐sectional relationship between clinical stage and age, gender, fasting insulin, fasting glucose, updated homeostatic model assessment for insulin resistance (HOMA2‐IR) score, BMI or waist circumference. Of the 111 (21.7%) young people initially classified at stage 1a ('non‐specific symptoms') and the 337 (65.9%) classified in stage 1b ('attenuated syndromes'), 40 individuals transitioned to stage 2+ (7.8%) ("full‐threshold disorders") longitudinally. No cardiometabolic factors predicted clinical stage transitions. However, those with an increase in BMI over the course of care (n = 54) were 1.46 (OR; 95% CI: 1.02–2.17) times more likely to progress to stage 2+ at follow up. Conclusions: Whilst no relationships were found between demographic or cardiometabolic variables and clinical stage at entry to care, an increased BMI over time was associated with clinical stage transition longitudinally. Further longitudinal research is needed to understand the demographic, clinical, illness progression or treatment factors associated with changes in cardiometabolic status. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a predominantly idiopathic pathological condition characterized by protein aggregation phenomena, whose main component is alpha-synuclein. Although the main risk factor is ageing, numerous evidence points to the role of type 2 diabetes mellitus (T2DM) as an etiological factor. Systemic alterations classically associated with T2DM like insulin resistance and hyperglycemia modify biological processes such as autophagy and mitochondrial homeostasis. High glucose levels also compromise protein stability through the formation of advanced glycation end products, promoting protein aggregation processes. The ability of antidiabetic drugs to act on pathways impaired in both T2DM and PD suggests that they may represent a useful tool to counteract the neurodegeneration process. Several clinical studies now in advanced stages are looking for confirmation in this regard.

Abstract Insulin resistance (IR) is associated with reductions in neuronal proteins often observed with Alzheimer's disease (AD), however, the mechanisms through which IR promotes neurodegeneration/AD pathogenesis are poorly understood. Metformin (MET), a potent activator of the metabolic regulator AMPK is used to treat IR but its effectiveness for AD is unclear. We have previously shown that chronic AMPK activation impairs neurite growth and protein synthesis in SH‐SY5Y neurons, however, AMPK activation in IR was not explored. Therefore, we examined the effects of MET‐driven AMPK activation with and without IR. Retinoic acid‐differentiated SH‐SY5Y neurons were treated with: (1) Ctl: 24 h vehicle followed by 24 h Vehicle; (2) HI: 100 nM insulin (24 h HI followed by 24 h HI); or (3) MET: 24 h vehicle followed by 24 h 2 mM metformin; (4) HI/MET: 24 h 100 nM insulin followed by 24 h 100 nM INS+2 mM MET. INS and INS/MET groups saw impairments in markers of insulin signaling (Akt S473, mTOR S2448, p70s6k T389, and IRS‐1S636) demonstrating IR was not recovered with MET treatment. All treatment groups showed reductions in neuronal markers (post‐synaptic marker HOMER1 mRNA content and synapse marker synaptophysin protein content). INS and MET treatments showed a reduction in the content of the mature neuronal marker NeuN that was prevented by INS/MET. Similarly, increases in cell size/area, neurite length/area observed with INS and MET, were prevented with INS/MET. These findings indicate that IR and MET impair neuronal markers through distinct pathways and suggest that MET is ineffective in treating IR‐driven impairments in neurons.

Male hypogonadism is a result of low testosterone levels, but patients could be insulin-sensitive (IS) or insulin-resistant (IR), showing different impaired metabolic pathways. Thus, testosterone coadministration, which is commonly used to reestablish testosterone levels in hypogonadism, must take into account whether or not insulin is still active. By comparing metabolic cycles recorded in IS and IR plasma before and after testosterone therapy (TRT), it is possible to know what metabolic pathways can be reactivated in the two different groups upon testosterone recovery, and it is possible to understand if antagonism or synergy exists between these two hormones. IS hypogonadism uses glycolysis, while IR hypogonadism activates gluconeogenesis through the degradation of branched-chain amino acids (BCAAs). Upon administration of testosterone, acceptable improvements are observed in IS patients, wherein many metabolic pathways are restored, while in IR patients, a reprogramming of metabolic cycles is observed. However, in both subgroups, lactate and acetyl-CoA increases significantly. In IS patients, lactate is used through the glucose–lactate cycle to produce energy, while in IR patients, both lactate and acetyl-CoA are metabolized into ketone bodies, which are used to produce energy. Thus, in IR patients, an ancestral molecular mechanism is activated to produce energy, mimicking insulin effects. Regarding lipids, in both groups, the utilization of fatty acids for energy (β-oxidation) is blocked, even after TRT; free fatty acids (FFAs) increase in the blood in IS patients, while they are incorporated into triglycerides in those with IR. In both subgroups of hypogonadism, supplementation of useful chemicals is recommended during and after TRT when metabolites are not restored; they are listed in this review. [ABSTRACT FROM AUTHOR]

Ecological theories suggest that environmental factors significantly influence obesity risk and related syndemic morbidities, including metabolically abnormal obesity associated with nonalcoholic fatty liver disease (MASLD). These factors encompass anthropogenic influences and endocrine-disrupting chemicals (EDCs), synergistically interacting to induce metabolic discrepancies, notably in early life, and disrupt metabolic processes in adulthood. This review focuses on endocrine disruptors affecting a child’s MASLD risk, independent of their role as obesogens and thus regardless of their impact on adipogenesis. The liver plays a pivotal role in metabolic and detoxification processes, where various lipophilic endocrine-disrupting molecules accumulate in fatty liver parenchyma, exacerbating inflammation and functioning as new anthropogenics that perpetuate chronic low-grade inflammation, especially insulin resistance, crucial in the pathogenesis of MASLD.

Abstract Background Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition. Results Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from − 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from − 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p

Neuronal insulin resistance is a major risk for development of Alzheimer's Disease (AD). Studies already reported few kinases participating in neuronal insulin signaling connected with progression of AD pathogenesis, yet complete information is missing. α isoform of Protein Phosphatase-2C (PP2C) is a Ser/Thr phosphatase, only known in 3T3-L1 adipocytes as a positive regulator of insulin signaling. However, many aspects of its function in neuronal insulin signaling and insulin resistance are unidentified. Recently, we reported that PP2Cα positively regulates neuronal glucose uptake possibly by a mechanism of dephosphorylation of IRS-1 at Ser522 and by inactivating AMPK, exacerbating hyperinsulinemia mediated neuronal insulin resistance. Since PP2Cα affected neuronal insulin signaling and AD is connected to neuronal insulin resistance, in the present study, we studied the role of PP2Cα in regulating activities of both isoforms of GSK3α and GSK3β (one of the leading kinases for AD progression). The results led us to test the role of PP2Cα on AD hallmarks. Silencing of PP2Cα caused hyperphosphorylation of a potential kinase Tau, leading to NFT formation and increased Aβ deposition. Our study thereby demonstrates escalation of hyperinsulinemia mediated neuronal insulin resistance leading to AD-like pathogenesis by PP2Cα in vitro and hints a novel molecule, PP2Cα, linking AD pathogenesis. [Display omitted] • PP2Cα is involved in AD pathogenesis. • PP2Cα positively promotes neuronal insulin signaling and prevents AD pathogenesis. • PP2Cα absence exacerbates insulin resistance leading to progression of AD hallmarks. [ABSTRACT FROM AUTHOR]

The definition of metabolic syndrome (MetS) in childhood is controversial. Recently, a modified version of the International Diabetes Federation (IDF) definition was proposed using reference data from an international population for high waist circumference (WC) and blood pressure (BP), while the fixed cutoffs for lipids and glucose were not changed. We analyzed MetS prevalence using this modified definition (MetS-IDFm) and its association with non-alcoholic fatty liver disease (NAFLD) in 1057 youths (age 6–17 years) with overweight/obesity (OW/OB). A comparison with another modified definition of MetS according to the Adult Treatment Panel III (MetS-ATPIIIm) was performed. The prevalence of MetS-IDFm was 27.8% and 28.9% by MetS-ATPIIIm. The Odds (95% Confidence Intervals) of NAFLD was 2.70 (1.30–5.60) (p = 0.008) for high WC, 1.68 (1.25–2.26)(p = 0.001) for MetS, 1.54 (1.12–2.11)(p = 0.007) for low HDL-Cholesterol, 1.49 (1.04–2.13)(p = 0.032) for high triglycerides and 1.37 (1.03–1.82)(p = 0.033) for high BP. No substantial difference was found in the prevalence of MetS-IDFm and frequency of NAFLD compared to Mets-ATPIIIm definition. Our data demonstrate that one third of youths with OW/OB have MetS, whichever was the criterion. Neither definition was superior to some of their components in identifying youths with OW/OB at risk for NAFLD. [ABSTRACT FROM AUTHOR]

PP2Cα is one of the newly identified isoforms of metal‐dependent protein phosphatases (PPM). The role of this phosphatase in neuronal insulin signalling is completely unknown. In the present study, we show insulin‐mediated rapid upregulation of a protein of the insulin signalling cascade, PP2Cα, in mouse N2a cells and human SH‐SY5Y cells. By contrast, such PP2Cα upregulation is not observed in insulin‐resistant conditions despite insulin stimulation. Here, we report that, under insulin‐sensitive and insulin‐resistant conditions, the translation of PP2Cα was regulated by insulin through c‐Jun N‐terminal kinase. PP2Cα in turn dephosphorylated a novel inhibitory site of insulin receptor substrate‐1 at Ser522 and AMP‐activated protein kinase, hence positively regulating neuronal insulin signalling and insulin resistance. [ABSTRACT FROM AUTHOR]

Objective: Youth with early-onset mood or psychotic disorders are occasionally prescribed metformin to manage cardiometabolic risk. This retrospective study explores the demographic, clinical and metabolic factors associated with metformin prescription youth with mood or psychotic disorders. Method: Participants included 72 youth with mood or psychotic disorders from a young adult mental health inpatient unit, of which 18 (33%) were newly prescribed metformin, and 54 (66%) were not prescribed metformin. Demographic and clinical information were extracted from the patients' medical files along with body mass index (BMI), fasting serum bloods and calculated updated homeostatic model of insulin resistance assessment (HOMA2-IR) scores to compare profiles between groups. Results: Of those prescribed metformin, 83% were overweight or obese and 72% had elevated HOMA2-IR scores. Of those not receiving metformin treatment, 41% were overweight or obese and 22% had elevated HOMA2-IR scores. Youth prescribed metformin had significantly higher BMI, and elevated markers of insulin resistance, but did not differ to those not prescribed metformin on other demographic, clinical or metabolic factors. Conclusions: While metformin is prescribed to some youth with mood or psychotic disorders displaying markers of cardiometabolic disturbance, there is a need to develop clearer treatment guidelines for metformin in these youth. [ABSTRACT FROM AUTHOR]

IntroductionDLK1 gene is considered a molecular gatekeeper of adipogenesis. DLK1 mutations have been reported as a cause of central precocious puberty associated with obesity and metabolic syndrome with undetectable DLK1 serum levels. We investigated the association between DLK1 circulating levels with clinical and biochemical parameters in obese adolescents and healthy controls.MethodsSixty-five obese adolescents and 40 controls were enrolled and underwent a complete clinical examination and biochemical assessment for glucose homeostasis and DLK1 plasma levels.ResultsWe observed lower DLK1 levels in cases compared to controls. Moreover, we found a negative correlation between DLK1 and HOMA-IR and a direct correlation with insulin-sensitivity index.DiscussionOur findings suggest that DLK1 might be involved in metabolic derangement in obese children.

Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves proanthocyanidins (BLPs) were natural bioactive compounds in the treatment of obesity and diabetes with a unique structural characteristic. This study aimed to investigate the effect of BLPs on hepatic glucose metabolism in insulin-resistant HepG2 cells and elucidate the underlying mechanism. With the supplementation of BLPs, the glucose consumption and glucose uptake in IR-HepG2 cells were increased. BLPs promoted glycogen synthesis via up-regulating p-GSK3β and GYS2 expression, and attenuated gluconeogenesis by down-regulating PEPCK and G6Pase expression. It was attributed to the activation of PI3K/AKT signal pathway by BLPs, which was confirmed using the PI3K inhibitor LY294002. Moreover, BLPs remarkably reduced the expression of miR-29a, miR-423 and miR-122, which involved in hepatic glucose metabolism. Our results provide an insight of the hypoglycemic potential of BLPs on the hepatic glucose metabolism, suggesting that BLPs can be further used as a novel ingredient in functional food.

Background and Aims: Impaired myocardial mechano-energetic efficiency (MEE) has been associated with cardiac insulin resistance measured by dynamic positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) combined with euglycemic-hyperinsulinemic clamp. Estimate glucose disposal rate (eGDR) index has a good correlation with whole-body insulin sensitivity. It remains unsettled whether eGDR index is a suitable proxy of cardiac insulin sensitivity as well as its association with myocardial MEE. The aims of this study were: 1) to compare eGDR index with HOMA-IR, QUICKI and FIRI indexes for association with myocardial glucose metabolic rate (MrGlu); and 2) to determine the association of eGDR index with myocardial MEE., Methods: We evaluated MrGlu using PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp in 50 individuals without history of coronary heart disease. Myocardial MEE per gram of left ventricular mass (MEEi) was measured in 1181 subjects by echocardiography. eGDR (mg kg -1 /min) was calculated as: 21.158 - (0.09 × waist circumference in cm) - (3.407 × hypertension, 1 = yes 0 = no) - (0.551 × HbA1c%)., Results: eGDR index was more strongly associated with myocardial MrGlu than HOMA-IR, QUICKI, and FIRI indexes (r = -0.662, r = -0.492, r = 0.570, and r = -0.492, respectively). Individuals in the lower tertiles of eGDR exhibited a significant reduction of MEEi as compared to those in the highest tertile (P < 0.001). In a stepwise multivariate linear regression analysis eGDR index was the major determinant of MEEi independently of well-established cardio-metabolic risk factors., Conclusions: These data suggest that the eGDR index may be a useful marker to identifying individuals at high cardiovascular risk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cognitive deficits are difficult to treat and negatively influence quality of life and functional outcomes of persons with schizophrenia. In the last twenty years, extensive literature demonstrated that persons with diabetes and insulin resistance (IR) also display cognitive deficits. Being type 2 diabetes (T2DM) and IR highly frequent in persons with schizophrenia, it is plausible to hypothesize that these conditions might play a role in determining dyscognition. If that is the case, acting on glucose dysmetabolism may eventually improve cognitive functioning. This review aims at: 1. evaluating the association between IR or T2DM and cognitive dysfunction in schizophrenia; 2. reviewing the evidence that pharmacological treatment of IR or T2DM may improve dyscognition in schizophrenia., Methods: Two systematic searches were conducted in PubMed, PsycInfo, and Scopus. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines., Results: From the first search we included 17 studies, 8 on the effects of T2DM and 9 on the effects of IR-other prediabetes measures on cognition in persons with schizophrenia. From the second search we included 12 studies investigating the effect on cognition of glucose (4 studies), insulin (2 studies), metformin (2 studies), PPAR-γ agonists (2 studies), GLP-1 agonist (1 study), bromocriptine (1 study)., Conclusions: T2DM was associated with worse cognitive function in persons with schizophrenia, while IR was less strongly associated with cognitive dysfunction. Evidence regarding the efficacy of glucose-lowering medications on cognition in schizophrenia is inconclusive, yet methodological issues likely contribute to explain conflicting results., Competing Interests: Declaration of competing interest The authors declare no conflict of interest for the present article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study evaluates the protective effect of spirulina against diet-induced obesity and metabolic disorders in Psammomys obesus, an animal model of metabolic syndrome. Psammomys obesus lives on a low-energy diet, in order to remain healthy. However, under a standard laboratory chow diet (SLCD), this animal exhibits insulin resistance, which occurs as a result of obesity. Psammomys obesus was maintained on SLCD, in order to evaluate the effect of spirulina on obesity development with a particular focus on glucose and lipid metabolism, as well as the mRNA expression of some pro-inflammatory cytokines. After 12 weeks of treatment with spirulina, there was a significant reduction in body weight gain, plasma glucose, insulin and triglyceride levels. There was also a significant reduction in the mRNA expression of genes involved in lipogenesis and inflammation. Spirulina improved insulin sensitivity, glucose and lipid metabolism. These findings highlight the positive effect of spirulina on weight maintenance. [ABSTRACT FROM AUTHOR]

Background: Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition.Results: Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from - 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from - 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p < 0.05). With respect to dietary intakes, protein intake (g/kg) and protein intake (g/kg)/RDA ratio directly correlated with the glucose/insulin ratio (p < 0.05) and inversely correlated with HOMA-IR (Homeostasis model assessment of insulin resistance, p < 0.05), BMI SDS (p < 0.05) and %ibw (ideal body weight percentage, p < 0.01).Conclusion: A prompt establishment of specific nutritional therapy allowed to preserve growth, improve glycemic control and prevent liver complication, during childhood. Remarkably, the administration of a high protein diet appeared to have a protective effect against overweight/obesity and insulin-resistance. [ABSTRACT FROM AUTHOR]

Childhood overweight and obesity are among the major health problems of modern times, especially in Western countries, due to their association with increased cardiovascular and cancer risk in adulthood. Neudesin, a recently discovered peptide secreted mainly in the brain and adipose tissue, is being investigated for its possible activity as a negative regulator of energy expenditure. We conducted a cross-sectional observational preliminary study with the aim of testing the hypothesis that plasma levels of neudesin can be modified in obese and overweight children and to evaluate any possible relationship between plasma neudesin levels and metabolic and anthropometric parameters. 34 Children (Tanner's stage 1) were included and divided in two groups according to Cole's criteria. Group A included obese and overweight children (23 patients, 17 females and 6 males, aged 4-10 years); Group B included healthy normal-weight children (11 subjects, 7 females and 4 males, aged 3-10 years). Metabolic (glucose and insulin, total, LDL- and HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters were evaluated. HOMA-IR and QUICKI index and the area under the curve (AUC) of glucose and insulin after oral glucose load were calculated in obese and overweight children. Neudesin was measured by ELISA. Neudesin levels were significantly higher in obese/overweight children than in controls. In obese and overweight children, plasma neudesin levels were significantly directly correlated with blood glucose and glucose AUC. Taken together, these results, although preliminary, may suggest a possible age-related role of neudesin in glucose homeostasis in obese/overweight children. [ABSTRACT FROM AUTHOR]

[Display omitted] • Methyglyoxal (MG) is a key pathogenic molecule in chronic metabolic disease, difficult to measure. • Its end metabolite D-lactate can be used as a surrogate marker of MG fluxes. • We present a modified, optimized and validated method to measure serum D-lactate using a commercial kit. • We increased the specificity and the sensitivity of the method to 2 orders of magnitude. • It is a cost-efficient resource for researchers to explore the D-lactate pathway in metabolic disorders. Plasma D-lactate levels can be considered a surrogate indicator of MG flux. There are commercial methods specifically designed to cover pathological ranges (mmol/l in sepsis or leaky gut) that are not suitable to encompass the metabolically relevant ranges. We modified and optimized the D-lactate Colorimetric Assay kit MAK058 from Sigma adding an ultracentrifugation step, kinetic reading and increasing reaction temperature. We present a modified, optimized and validated method to measure serum D-lactate using a commercial kit to increase the sensitivity of the method to 2 orders of magnitude lower as well as minimizing interferences so that it may be used by researchers to explore the D-lactate pathway in metabolic disorders at a low cost (colorimetric method and a plate reader) and with a much higher specificity. [ABSTRACT FROM AUTHOR]

Childhood overweight and obesity are among the major health problems of modern times, especially in Western countries, due to their association with increased cardiovascular and cancer risk in adulthood. Neudesin, a recently discovered peptide secreted mainly in the brain and adipose tissue, is being investigated for its possible activity as a negative regulator of energy expenditure. We conducted a cross-sectional observational preliminary study with the aim of testing the hypothesis that plasma levels of neudesin can be modified in obese and overweight children and to evaluate any possible relationship between plasma neudesin levels and metabolic and anthropometric parameters. 34 Children (Tanner’s stage 1) were included and divided in two groups according to Cole’s criteria. Group A included obese and overweight children (23 patients, 17 females and 6 males, aged 4-10 years); Group B included healthy normal-weight children (11 subjects, 7 females and 4 males, aged 3-10 years). Metabolic (glucose and insulin, total, LDL- and HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters were evaluated. HOMA-IR and QUICKI index and the area under the curve (AUC) of glucose and insulin after oral glucose load were calculated in obese and overweight children. Neudesin was measured by ELISA. Neudesin levels were significantly higher in obese/overweight children than in controls. In obese and overweight children, plasma neudesin levels were significantly directly correlated with blood glucose and glucose AUC. Taken together, these results, although preliminary, may suggest a possible age-related role of neudesin in glucose homeostasis in obese/overweight children.

Oana Albai,1 Mirela Frandes,2 Romulus Timar,1 Bogdan Timar,1 Teodora Anghel,3 Vlad Florian Avram,1 Alexandra Sima1 1Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 2Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 3Department of Neuroscience, “Victor Babes” University of Medicine and Pharmacy, Timisoara, RomaniaCorrespondence: Mirela FrandesDepartment of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu, Timisoara, 300041, RomaniaTel +40-731117020Fax +40-256462856Email mirela.frandes@umft.roBackground: Diabetes mellitus (DM) is one of the most serious public health problems, involving increasing costs worldwide. The mental state of a person with DM is varied and ever-changing, such as stress, the pressure to always do everything by the book, sadness, anger, and even denial of the disease, all these are feelings patients with DM will experience throughout their life.Aim: The aim of our study was to assess the presence of mental and psychiatric disorders (anxiety, depressive states, paranoid ideation, phobia, obsessive-compulsive disorder) in a group of patients with DM after hospitalization in the Clinic for Diabetes, Nutrition, and Metabolic Diseases, for various exacerbations of the underlying condition, looking for possible correlations with other cardiovascular risk factors.Patients and Methods: Clinical and biological parameters, the presence of acute and chronic complications of the diabetic patients have been evaluated. To assess mental health, the symptom checklist (SCL)-90 questionnaire was conducted for all admitted patients.Results: We observed that the number of patients with obsessive-compulsive disorders was relatively high (23.3%), while depression was present in 17.1% of the patients. Also, 10.6% of patients had hostility and 15.6% had delusional ideation. The presence of psychiatric disorders was associated with a higher age (62 vs. 46.5 years; p < 0.001), a longer diabetes duration (11 vs. 9 years; p < 0.001), higher fasting glycemia (188 vs. 132 mg/dL; p < 0.001) and postprandial glycemia (212 vs. 152 mg/dL; p < 0.001), and triglycerides (125 vs. 110 mg/dL; p < 0.001). Patients with altered mental status have shown statistically significantly more altered clinical and biological parameters compared to those without these mental disorders.Conclusion: Patients with DM represent a psychologically vulnerable population, which is why they should undergo early and regular screening for both psychological and psychiatric conditions, especially at admission.Keywords: mental disorders, cardiovascular risk, cardiovascular risk factors, insulin-resistance, compliance, adherence to treatment

Male hypogonadism is a result of low testosterone levels, but patients could be insulin-sensitive (IS) or insulin-resistant (IR), showing different impaired metabolic pathways. Thus, testosterone coadministration, which is commonly used to reestablish testosterone levels in hypogonadism, must take into account whether or not insulin is still active. By comparing metabolic cycles recorded in IS and IR plasma before and after testosterone therapy (TRT), it is possible to know what metabolic pathways can be reactivated in the two different groups upon testosterone recovery, and it is possible to understand if antagonism or synergy exists between these two hormones. IS hypogonadism uses glycolysis, while IR hypogonadism activates gluconeogenesis through the degradation of branched-chain amino acids (BCAAs). Upon administration of testosterone, acceptable improvements are observed in IS patients, wherein many metabolic pathways are restored, while in IR patients, a reprogramming of metabolic cycles is observed. However, in both subgroups, lactate and acetyl-CoA increases significantly. In IS patients, lactate is used through the glucose–lactate cycle to produce energy, while in IR patients, both lactate and acetyl-CoA are metabolized into ketone bodies, which are used to produce energy. Thus, in IR patients, an ancestral molecular mechanism is activated to produce energy, mimicking insulin effects. Regarding lipids, in both groups, the utilization of fatty acids for energy (β-oxidation) is blocked, even after TRT; free fatty acids (FFAs) increase in the blood in IS patients, while they are incorporated into triglycerides in those with IR. In both subgroups of hypogonadism, supplementation of useful chemicals is recommended during and after TRT when metabolites are not restored; they are listed in this review.

[Display omitted] • NH 2 @Pt with AgVO 3 /PG electrode was fabricated. • 3-Mercaptophenylboronic acid was used as a recognition molecule for glucose. • The reaction mechanism of boronate ester formation and glucose oxidation were scrutinized by DFT calculation. • Insulin-resistant macrophage phenotypes were studied by glucose analysis. • The linkage between insulin resistance and IL-1β release was studied. Glucose is a known energy source that gives insights into cellular metabolism by glycolysis, biosynthesis and glycogen for storage. Investigation of glucose uptake in immune cells requires highly expensive tags and imaging techniques, however, we developed an amine (NH 2) nobbled Platinum (Pt)-Silver vanadate (AgVO 3) sensor platform combined with 3-mercapto phenylboronic acid (MPBA) recognition element for an enzyme-free glucose sensor. Introducing the amine groups into the Pt surface protects the stability of the Pt and extends the longevity of the electrode. A slightly acidic pH-driven boronate ester formation between glucose and boronic acid mechanism and the glucose combined electronic structure of MPBA/NH 2 @Pt/AgVO 3 with its adsorption energy (−2.1 eV) has been scrutinized via density functional theory. Accelerated electron transfer (k s = 4.69 s−1) driven electrochemical oxidation of glucose sensor showed the higher detection limit (LOD) of 61.3 μM and the linear dynamic range from 0.05 to 22.0 mM. Glucose uptake assay of macrophage phenotypes between the healthy and insulin-resistant types provides an in-depth understanding of how glucose impairment affects the macrophage phenotypes. We also observed the M1-type macrophages have uptaken significantly larger amounts of glucose than the others (M0 and M2). [ABSTRACT FROM AUTHOR]

Background: The impact of the gut microbiome on the organism has become a growing research focus with the development of 16S rRNA sequencing. However, the effect of the gut microbiome in male reproduction has yet to be investigated. Objective: To overview on possible mechanisms by which the gut microbiome could affect male reproduction and therapeutic opportunities related to the gut microbiome Methods: Authors searched PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane Library for medical subject headings terms and free text words referred to "male infertility" "testis" "gut microbiome" "insulin resistance" "erectile dysfunction" "therapy" "sex hormones" and "genital diseases" until December 2, 2021. Results: Evidence suggests that immune system activation caused by the gut microbiome translocation not only leads to testicular and epididymal inflammation but can also induce insulin resistance together with gastrointestinal hormones such as leptin and ghrelin, which in turn affects the secretion of various sex hormones such as LH, FSH, and T to regulate spermatogenesis. In addition, the gut microbiome can influence spermatogenesis by controlling and metabolizing androgens as well as affecting the blood–testis barrier. It also promotes vascular inflammation by raising trimethylamine‐N‐oxide (TMAO) levels in the blood, which causes erectile dysfunction. The testicular microbiome and gut microbiome can interact to influence male reproductive function. This study discusses therapeutic options such as probiotics, prebiotics, and fecal microbiota transplantation, as well as the challenges and opportunities behind ongoing research, and emphasizes the need for additional research in the future to demonstrate the links and underlying mechanisms between the gut microbiome and male reproduction. Therapeutic options such as probiotics, prebiotics, and fecal microbiota transplantation are potential treatments for male infertility. Discussion and conclusion: Gut microbiota may have a causal role in male reproduction health, therapeutic strategies such as supplementation with appropriate probiotics could be undertaken as a complementary treatment. In the future, additional research is needed to demonstrate the links and underlying mechanisms between the gut microbiome and male reproduction. [ABSTRACT FROM AUTHOR]

• Metabolically unhealthy lean adolescents have dyslipoproteinemia. • ANGPTL-3 and ApoC-III are higher in lean adolescents with insulin resistance. • Resultant LPL inhibition impairs VLDL and chylomicron catabolism leading to atherogenic remnants. • Attention should be given to the early presence of these components for prevention. Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity. This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42). As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C c, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant. Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48). [ABSTRACT FROM AUTHOR]

Background & Aims: There is a close relationship between obesity and type 2 diabetes, so that the risk of developing type 2 diabetes in obese people is higher than people with normal weight (2, 3). Both type 2 diabetes and obesity are associated with changes in the body's metabolism, which is a determining factor in the development of insulin resistance (4, 5). Studies show that adipose tissue is a central metabolic organ in regulating energy homeostasis throughout the body and plays an important role in the development of insulin resistance and type 2 diabetes (6). It also secretes various hormones, cytokines, and metabolites that control systemic energy balance by regulating appetite signals from the central nervous system and metabolic activity in peripheral tissues (8). One of the peptide hormones expressed by various body tissues, including adipose tissue in animal and human samples, is adropin, which is involved in energy homeostasis, metabolic adaptation, and modulation of insulin sensitivity and obesity (9). Increased adropin levels have been reported following aerobic exercise (17). also, Abbasian et al. (2016) observed increase in serum adropin levels in overweight and obese men after 8 weeks of intense intermittent exercise (18). However, in the study of Alizadeh et al. (2015) following a session of aerobic exercise, no significant change in glucose and adropin factors was observed in overweight women (19). The effects of exercise training on changes of factors involved in energy metabolism in obese diabetic subjects have been less studied, therefore, the present study intends to investigate the question of whether six weeks of aerobic training affect the on adipose tissue energy homeostasis index in obese diabetic rats? Methods: This is an experimental study. This research was conducted on Wistar rats at Islamic Azad University, Marvdasht Branch. 32 obese male wistar rats (weight 320±20 gr) after induction of diabetes randomly were divided into 4 groups including obese control, shem (obese), obese diabetic, obese aerobic training - obese diabetic. Rats were exposed to a high-fat controlled diet in the form of pellets for 4 weeks to gain weight (20). In this study, the rats were type 2 diabetic using peritoneal injection nicotinamide-STZ (21). Aerobic training program was performed on treadmill 4 days a week with intensity of 70% VO2max for six weeks (22). Blood samples were used to measure fasting glucose by enzymatic colorimetric method with glucose oxidase technology by Pars Azmoun Tehran kit company. Insulin was measured by ELISA method using a laboratory kit (Demeditec insulin ELIZA DE2935, Germany). Insulin resistance index was measured after Calculated fasting glucose and fasting insulin concentrations using the homeostasis model (HOMA-IR) and according to the formula. Also, the amount of adropine in adipose tissue of rats was measured using a special kit (Phoenix Pharmaceuticals, Inc. USA) by ELISA method. Adropin level were measured using ELISA kit. Data were analyzed by One-way ANOVA and Tukey post hoc test at the P<0.05. Results: Mean and standard deviation of variables in adipose tissue of different research groups are presented in Table 2. The results showed that the adropin level in adipose tissue in the obese diabetic group was significantly lower than the obese control group (P=0.001). Also, insulin resistance was significantly higher in the obese diabetic group than the obese control groups (P=0.004). Aerobic training was associated with significant increase of adropin in adipose tissue and decrease of insulin resistance in obese diabetic rats (P=0.001). Conclusion: The findings of this study were consistent with the results of Previous research (17, 23, 24). Insulin resistance, fasting glucose and insulin have a negative correlation with adropin levels (29). In the present study, a negative relationship was observed between adropin levels of adipose tissue and insulin and insulin resistance index, which may be one of the effective factors in increasing adropin levels of adipose tissue after aerobic training in the obese-diabetic exercise group. The molecular mechanism by which fat causes insulin resistance is unclear. Inflammation due to lipid accumulation, inhibitory effect of fatty acid oxidation on glucose oxidation, and secretion of adipocytokines are all associated with the development of local and systemic insulin resistance (36). Improvements in insulin resistance following exercise may be due in part to the potential effect of adropine on vasodilation. This improvement can facilitate access to glucose and enhance glucose metabolism (9). There were some limitations in the present study, such as the lack of measurement of other indicators of associated with energy homeostasis and metabolic adaptation in adipose tissue. According to the results, it seems that Aerobic training may be able to help reduce the effects of obesity in diabetes by improving adropin levels in adipose tissue and insulin resistance. [ABSTRACT FROM AUTHOR]

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Adela Chirita-Emandi,1,2,* Costela Lacrimioara Serban,2,3,* Corina Paul,4,5,* Nicoleta Andreescu,1,2 Iulian Velea,4,5 Alexandra Mihailescu,1 Vlad Serafim,1,6 Diana-Andreea Tiugan,1 Paul Tutac,1 Cristian Zimbru,1,7 Maria Puiu,1,2 Mihai Dinu Niculescu1,8 1Department of Microscopic Morphology - Genetics, Center of Genomic Medicine, University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania; 2Regional Center of Medical Genetics Timis, Clinical Emergency Hospital for Children “Louis Turcanu”, Timisoara, Romania; 3Department of Functional Sciences, University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania; 4Pediatrics Department – Pediatrics Discipline II, University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania; 5Pediatrics, Endocrinology and Diabetes Department, Clinic II Pediatrics, “Pius Branzeu” Clinical Emergency County Hospital, Timisoara, Romania; 6The National Institute of Research and Development for Biological Sciences, Bucharest, Romania; 7Department of Automation and Applied Informatics, Politehnica University of Timisoara, Timisoara, Romania; 8Advanced Nutrigenomics, Cary, NC 27511, USA*These authors contributed equally to this workCorrespondence: Nicoleta AndreescuDepartment of Microscopic Morphology - Genetics, Center of Genomic Medicine, University of Medicine and Pharmacy “Victor Babes”, Timisoara, RomaniaEmail andreescu.nicoleta@umft.roIntroduction: Insulin resistance plays a major role in metabolic syndrome and is recognized as the most common risk factor for non-alcoholic fatty liver disease (NAFLD). Identifying predictors for insulin resistance could optimize screening and prevention.Purpose: To evaluate the contribution of multiple single nucleotide polymorphisms across genes related to NAFLD and choline metabolism, in predicting insulin resistance in children with obesity.Methods: One hundred fifty-three children with obesity (73 girls), aged 7– 18 years, were evaluated within the NutriGen Study (ClinicalTrials.gov-NCT02837367). Insulin resistance was defined by Homeostatic Model Assessment for insulin-resistance cut-offs that accommodated pubertal and gender differences. Anthropometric, metabolic, intake-related variables, and 55 single nucleotide polymorphisms related to NAFLD and choline metabolism were evaluated. Gene–gene interaction effects were assessed using Multiple Data Reduction Software.Results: Sixty percent (93/153) of participants showed insulin resistance (58.7% of boys, 63% of girls). Children with insulin resistance presented significantly higher values for standardized body mass index, triglycerides, transaminases and plasma choline when compared to those without insulin resistance. Out of 52 single nucleotide polymorphisms analysed, the interaction between genotypes CHDH(rs12676) and PNPLA3(rs738409) predicted insulin resistance. The model presented a 6/10 cross-validation consistency and 0.58 testing accuracy. Plasma choline levels and alanine aminotransferase modulated the gene interaction effect, significantly improving the model.Conclusion: The interaction between genotypes in CHDH and PNPLA3 genes, modulated by choline and alanine aminotransferase levels, predicted insulin-resistance status in children with obesity. If replicated in larger cohorts, these findings could help identify metabolic risk in children with obesity.Keywords: insulin-resistance, obesity, gene–gene interaction, CHDH-PNPLA3, choline, children

Introduction and objectives: Non-alcoholic fatty liver disease (NAFLD) is multistage with heterogeneous outcomes. We studied the influence of insulin resistance (IR) on the hepatic transcriptome of early NAFLD stages, to understand disease development. Materials and methods: In this cross-sectional study, possible clinicopathological risk factors were compared between mild-NAFL (N = 72) and non-alcoholic steatohepatitis (NASH; N = 51) patients. Liver tissue-transcriptome difference was studied between a subset of 25 mild-NAFL and 20 NASH biopsies and validated on another subset of 12 mild-NAFL and 13 NASH biopsies, using RT-PCR. The relationship between IR driven gene expression changes with fibrosis in NASH was investigated. Results: Significantly higher weight (p = 0.005) and elevated levels of HbA1c (p = 0.009), FBG (p = 0.03) and HOMA-IR (p = 0.009) were found in NASH patients. Five differentially expressed genes (DEGs, fold change > 1.5) were identified in NASH-FABP4, FABP5L2, CD24, PRAP1, and SPP1. The DEGs were positively associated with disease severity and HOMA-IR, and were found to be efficient classifiers of mild-NAFL and NASH. Additional 1218 genes identified related to IR (IrCGs), which can classify NASH-with-fibrosis patients separately from mild-NAFL and NASH patients. IrCGs can promote intra-hepatic fat accumulation, dysregulation of the lipid metabolism, lipotoxicity, and activation of cell survival pathways including activation of cell proliferation and differentiation pathways. Conclusions: Hepatic expression of genes associated with insulin resistance may drive NAFLD development and progression.

Abstract Background Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glucose 6-phosphate (G6P) availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients. Methods Seventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed. Results Baseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients. Conclusions The present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11βHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.

Background: Different benefits of various herbal medicines in decreasing blood sugar have been reported in different clinical trials so far. Considering the growing tendency toward these combinations and the booming market, inappropriate advice is growing accordingly. Hence, it is necessary to evaluate the effects and possible complications of such combinations on health status and blood glucose control. Methods: Two 38-subject groups were formed and a 12-week treatment program was administered for both groups. The inclusion criteria were failure to control blood glucose with two oral medicines, unwillingness to inject insulin. The medicine was prepared in capsules by Booali Company. Each capsule weighed 750 mg and contained nettle leaf 20% (w/w), berry leaf 10% (w/w), onion and garlic 20% (w/w), fenugreek seed 20% (w/w), walnut leaf 20% (w/w), and cinnamon bark 10% (w/w) all in powder. Results: At the beginning of the study, there was no significant difference between the subjects regarding the evaluated parameters, but after the intervention, the level of glucose was significantly lower in fasting (P=0.0001) and 2-hour postprandial(P=0.002) levels. The level of glycated hemoglobin A1c (HbA1c) (P=0.0001) also decreased from 0.33±9.72 % to 0.20±8.39 %. Finally, the level of insulin resistance reduced from 1.9±4.1 to 1.4±2.6 (P=0.001) after consuming herbal medicine. Conclusion: According to the results of the current study, the herbal combination was effective in controlling blood sugar, and considering the reduction of HbA1c by 1.31 %, it seems that the herbal combination is an effective medicine to treat diabetes.

The definition of metabolic syndrome (MetS) in childhood is controversial. Recently, a modified version of the International Diabetes Federation (IDF) definition was proposed using reference data from an international population for high waist circumference (WC) and blood pressure (BP), while the fixed cutoffs for lipids and glucose were not changed. We analyzed MetS prevalence using this modified definition (MetS-IDFm) and its association with non-alcoholic fatty liver disease (NAFLD) in 1057 youths (age 6–17 years) with overweight/obesity (OW/OB). A comparison with another modified definition of MetS according to the Adult Treatment Panel III (MetS-ATPIIIm) was performed. The prevalence of MetS-IDFm was 27.8% and 28.9% by MetS-ATPIIIm. The Odds (95% Confidence Intervals) of NAFLD was 2.70 (1.30–5.60) (p = 0.008) for high WC, 1.68 (1.25–2.26)(p = 0.001) for MetS, 1.54 (1.12–2.11)(p = 0.007) for low HDL-Cholesterol, 1.49 (1.04–2.13)(p = 0.032) for high triglycerides and 1.37 (1.03–1.82)(p = 0.033) for high BP. No substantial difference was found in the prevalence of MetS-IDFm and frequency of NAFLD compared to Mets-ATPIIIm definition. Our data demonstrate that one third of youths with OW/OB have MetS, whichever was the criterion. Neither definition was superior to some of their components in identifying youths with OW/OB at risk for NAFLD.