Correction Of Insulin Resistance Research Articles

Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.

Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.

Correction of insulin resistance in patients with chronic obstructive pulmonary disease under the influence of recovery treatment

According to modern concepts chronic obstructive pulmonary disease (COPD) is accompanied by persistent respiratory symptoms, as well as extrapulmonary systemic manifestations. Insulin resistance and metabolic syndrome belong to the leading causes of comorbidity formation. The aim is to study the possibilities of insulin resistance correction in COPD patients, taking into account the previous COVID-19, under the influence of complex non-pharmacological treatment based on haloaero­soltherapy in connection with the applied treatment complex. Clinical and functional examinations and carbohydrate metabolism investigations were carried out in 115 patients with COPD (GOLD II-III) beyond the acute period before and after the course of recovery treatment. Among them 60 patients were convalescents after COVID-19. The average age of patients was 60,3±1,71 years and duration of COPD – 14,2±0,89 years. 12 practically healthy persons were also exa­mined as a control group. The presence of insulin resistance was diagnosed by evaluation of the glucose, insulin, HOMA-IR index and C-peptide levels. Treatment was carried out according to three treatment complexes. The main component of the treatment was the use of haloaerosoltherapy and its combination with singlet oxygen therapy or drinking and inhalation of mineral water. The duration of the course of treatment was 20-21 days. Before treatment the presence of insulin resistance was confirmed in both groups of patients with COPD (without COVID-19 and convalescents after COVID-19). Blood glucose levels were significantly higher in the latter group. After the course of recovery treatment a decrease in insulin resistance was noted, especially in patients who received complex treatment, although complete normalization of the studied indices was not achieved. Thus, insulin resistance is a characteristic, pathogenetically determined metabolic manifestation in COPD, which requires constant monitoring and development of long-term programs of complex clinical management of this contingent of patients, especially beyond the exacerbation period. The use of haloaerosoltherapy, which has a sanative and anti-inflammatory effect and promotes clinical stabilization of COPD, is accompanied by a decrease in the manifestations of insulin resistance. Expressiveness of these changes depend on the applied treatment complex. The most pronounced decrease in insulin resistance in COPD patients was noted under the influence of complex treatment based on haloaerosoltherapy with additional drinking and inhalation use of low-mineralized hydrocarbonate siliceous mineral water.

Peripheral insulin resistance is early, progressive, and correlated with cachexia in Walker-256 tumor-bearing rats.

Insulin (INS) resistance is often found in cancer-bearing, but its correlation with cachexia development is not completely established. This study investigated the temporal sequence of the development of INS resistance and cachexia to establish the relationship between these factors in Walker-256 tumor-bearing rats (TBrats). INS hepatic sensitivity and INS resistance-inducing factors, such as free fatty acids (FFA) and tumor necrosis factor-α (TNF-α), were also evaluated. Studies were carried out on Days 2, 5, 8, and/or 12 after inoculation of tumor cells in rats. The peripheral INS sensitivity was assessed by theINS tolerance testand the INS hepatic sensitivity in in situ liver perfusion. TBrats with 5, 8, and 12 days of tumor, but not 2 days, showed decreased peripheral INS sensitivity (INS resistance), retroperitoneal fat, and body weight, compared to healthy rats, which were more pronounced on Day 12. Gastrocnemius muscle wasting was observed only on Day 12 of tumor. The peripheral INS resistance was significantly correlated (r = -.81) with weight loss. Liver INS sensitivity of TBrats with 2 and 5 days of tumor was unchanged, compared to healthy rats. TBrats with 12 days of tumor showed increased plasma FFA and increased TNF-α in retroperitoneal fat and liver, but not in the gastrocnemius, compared to healthy rats. In conclusion, peripheral INS resistance is early, starts along with fat and weight loss and before muscle wasting, progressive, and correlated with cachexia, suggesting that it may play an important role in the pathogenesis of the cachectic process in TBrats. Therefore, early correction of INS resistance may be a therapeutic approach to prevent and treat cancer cachexia.

Alternative therapy of menopausal vegetative disorders in women taking the metabolic status into account

Research objectives: to study the clinical effectiveness of alternative complex therapy of vegetative syndrome in menopausal patients using L-arginine and xylitol drugs. Materials and methods. The clinical prospective study included 50 patients in the early postmenopausal period with natural menopause, neurovegetative and psychoemotional manifestations of the climacteric syndrome. According to the Life extension strategy, patients received intravenous L-arginine (Tivortin drug) and xylitol solution with electrolytes (Xylat drug) for endothelial protection and correction of insulin resistance in order to treat climacteric syndrome. Modified Kupperman menopausal index, serum triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein levels were determined in all women. Examinations were performed before the start of therapy and 3 months after the end of treatment.Results. The Life extension therapeutic strategy as an alternative comprehensive therapy of the vegetative syndrome in menopausal patients contributed to a reliable reduction of the manifestations of the climacteric syndrome. The advantage of combined therapy involving L-arginine and xylitol was manifested in a significant decrease in diastolic blood pressure (p = 0.043); reduction of the Kupperman index (p = 0.002) and the average score of vasomotor symptoms (p = 0.02). There was also a significant decrease in the serum level of insulin (p = 0.00007), HOMA index (p = 0.01), low-density lipoproteins (p = 0.04), and triglycerides (p = 0.03). The selected therapy was well tolerated during the observation period.Conclusions. The combined therapy involving L-arginine and xylitol in the early postmenopausal period with neurovegetative and psychoemotional manifestations of the climacteric syndrome had a pronounced clinical effect, which consisted in a significant reduction of vegetative disorders and stabilization of carbohydrate and lipid metabolism. The given therapeutic strategy can be considered as an alternative therapy in patients with climacteric disorders when phytotherapy is ineffective and when there are contraindications or limitations to menopausal hormone therapy. The results of this study showed the safety of the Life extension strategy.

Современные альфа1-адреноблокаторы: влияние длительного назначения на инсулинорезистентность.

Introduction. Alpha1-blockers previously have been considered as essential antihypertensive drugs with relatively good results in long-term administration. This effect on metabolism has been noted, in particular on the lipid spectrum and glycemic profile. However, at present, drugs of this group are not considered even in the reserve of basic metabolic therapy. The aim of our study was to study the effect of reducing insulin resistance in patients with long-term administration of a uroselective alpha1-blocker (Tamsulosin) in combination with vitamin-like drugs. Materials and methods. Under our supervision there was a group of patients of 63 people, which included 36 men and 27 women. The mean age in the observation group was 60 ± 1.56 years, ranging from 29 to 81 years. An original study design was developed, which involved combination therapy in combination with alpha-lipoic acid, L-carnitine and nootropics instead of monotherapy with one alpha1-blocker. Results. The study showed that with an average duration of therapy of 16 ± 2 months, an improvement in biochemical parameters of glucose metabolism was noted in 61% of patients. In the general observation group, there was a decrease in blood glucose (7.01 ± 0.29 → 6.32 ± 0.19, р = 0.004), plasma insulin (21.33 ± 1.75 → р=0.0007) and C-peptide (4.00 ±0.30 → 3.15 ±0.19, p=0.0003), glycated hemoglobin (5.99 ±0.17 → 5.90 ±0 .10, р=0.25). Similar changes are also observed in the subgroup of men and the subgroup of women. In patients under 60 years of age with a duration of therapy of 11 ± 3 months, deviations of the glycemic profile from the norm were less pronounced, while the correction of insulin resistance was carried out more effectively, in the subgroup of patients over 60 years of age, more therapy time was required (20 ± 3 months), but still , insulin resistance decreased less pronounced than in the subgroup younger than 60 years. Conclusions. The results of combined metabolic therapy support the hypothesis that alpha1-blockers have the properties of drugs with metabolic action in long-term administration, and in combination with vitamin-like drugs, such treatment can be considered as an alternative option to reduce insulin resistance and improve follow-up outcome.

Telomere biology and target-based approach in correction of insulin resistance in patients with prediabetes

Telomere biology and target-based approach in correction of insulin resistance in patients with prediabetes

Investigation of the effects of astaxanthin in experimental polycystic ovary syndrome (PCOS) in rats.

The aim of this study was to investigate the effect of Astaxanthin (ASX) on ovaries in letrozole-induced polycystic ovary syndrome (PCOS) model in female rats by histopathological, immunohistochemical and biochemical techniques. Seventy two Sprague-Dawley female rats with an average weight of 200-250 gr and 10-12 weeks old were randomly divided into 9 groups. PCOS model was applied to all groups except healthy group. In the study, low (10 mg / kg) moderate (20 mg / kg) and high (40 mg / kg) doses of ASX were given to the experimental animals in the PCOS-induced groups for 7 days. At the end of the experiment, ovarian tissues were evaluated histopathologically, immunohistochemically, and biochemically. When the histopathological findings were examined, many cystic follicles, apoptotic and necrotic cells were found in the follicles in the PCOS group. In addition, significant decrease in apoptotic and necrotic cells were observed in PCOS+MET+ASX and PCOS+ASX groups. In immunohistochemical staining findings, while TNF-α NF-κB and IL-6 expression levels showed significant increase in PCOS group, these expression levels were decreased in PCOS+MET+ASX and PCOS+ASX groups. In the biochemical evaluations, while MDA were increased, SOD were decreased in the PCOS group. MDA level were decreased while SOD levels were increased in the PCOS+MET+ASX and PCOS+ASX groups. In addition to the formation of insulin resistance in the tissue, severe oxidative stress damage occurs in ovarian tissue during PCOS. Metformin improved PCOS by correcting insulin resistance. In this period, the administration of ASX with Metformin protected the ovary from oxidative stress damage.

Insulin resistance and heart failure with preserved ejection fraction. Pathogenetic and therapeutic crossroads

Insulin resistance, which is a fundamental pathogenetic factor of prediabetes, is closely associated with abdominal obesity on the one hand and the development of cardiovascular diseases, heart failure (HF), on the other. The pathogenetic role of insulin resistance is multifaceted and consists in the acceleration of atherosclerosis, the formation of left ventricular myocardial hypertrophy, including through mechanisms that do not depend on blood pressure, as well as the development of its diastolic dysfunction. The latter is the starting point for starting HF with preserved ejection fraction (HFpEF).Compared with patients with HF with reduced ejection fraction, the presence of HFpEF determines a higher frequency of hospitalizations not due to decompensation of heart failure, but due to concomitant diseases, such as destabilization of the course of arterial hypertension, decompensation of type 2 diabetes mellitus, curation of which, in general, has a greater impact in terms of improving prognosis. Thus, in patients with prediabetes and HFpEF, the correction of insulin resistance as the underlying cause and trigger of cardiometabolic disorders can potentially improve not only insulin-glucose homeostasis, but also the parameters of myocardial diastolic function. This literature review is devoted to the accumulated experience of using metformin as a «strategic» antidiabetic drug in HFpEF and considering potential new points of its application as a protector of the cardiovascular system.

Issues of correcting insulin resistance in polycystic ovary syndrome

The article deals with issues of correcting insulin resistance in polycystic ovary syndrome. It has been shown that on the one hand, an increased level of insulin leads to an intensification in the processes of fat synthesis and to blocking of fat decay. On the other hand, an increase in the volume of fat cells is accompanied by a decrease in the density of insulin receptors on their surface and an increase in insulin resistance. Against the background of hyperinsulinemia and insulin resistance, activation of the synthesis of pro-inflammatory cytokines and cytokine-like substances is observed.

Insulin resistance and intestinal microbial metabolites in childhood obesity

The article deals with the study on the content of fecal short-chain fatty acids (SCFA) and their association with insulin resistance in obese children. It was found that intestinal microflora in obese children is characterized by changes in the qualitative composition and increased metabolic activity of the intestinal microflora. A moderate increase of HOMA-IR is accompanied by elevated concentration of anti-inflammatory cytokines, the content of which correlates with that of acetic, propionic acid and a decrease in the metabolic activity of intestinal microflora. The progression of insulin resistance is accompanied by a further increase in the concentration of anti-inflammatory cytokines, the level of HOMA-IR correlates with the level of propionic SCFA. Thus, modulation of SCFA content may be a promising way of therapeutic influence to correct insulin resistance and obesity in children.

ADAM17 cleaves the insulin receptor ectodomain on endothelial cells and causes vascular insulin resistance.

Inflammation and vascular insulin resistance are hallmarks of type 2 diabetes (T2D). However, several potential mechanisms causing abnormal endothelial insulin signaling in T2D need further investigation. Evidence indicates that the activity of ADAM17 (a disintegrin and metalloproteinase-17) and the presence of insulin receptor (IR) in plasma are increased in subjects with T2D. Accordingly, we hypothesized that in T2D, increased ADAM17 activity sheds the IR ectodomain from endothelial cells and impairs insulin-induced vasodilation. We used small visceral arteries isolated from a cross-sectional study of subjects with and without T2D undergoing bariatric surgery, human cultured endothelial cells, and recombinant proteins to test our hypothesis. Here, we demonstrate that arteries from subjects with T2D had increased ADAM17 expression, reduced presence of tissue inhibitor of metalloproteinase-3 (TIMP3), decreased extracellular IRα, and impaired insulin-induced vasodilation versus those from subjects without T2D. In vitro, active ADAM17 cleaved the ectodomain of the IRβ subunit. Endothelial cells with ADAM17 overexpression or exposed to the protein kinase-C activator, PMA, had increased ADAM17 activity, decreased IRα presence on the cell surface, and increased IR shedding. Moreover, pharmacological inhibition of ADAM17 with TAPI-0 rescued PMA-induced IR shedding and insulin-signaling impairments in endothelial cells and insulin-stimulated vasodilation in human arteries. In aggregate, our findings suggest that ADAM17-mediated shedding of IR from the endothelial surface impairs insulin-mediated vasodilation. Thus, we propose that inhibition of ADAM17 sheddase activity should be considered a strategy to restore vascular insulin sensitivity in T2D.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the involvement of ADAM17 in causing impaired insulin-induced vasodilation in T2D. We provide evidence that ADAM17 activity is increased in the vasculature of patients with T2D and support the notion that ADAM17-mediated shedding of endothelial IRα ectodomains is a novel mechanism causing vascular insulin resistance. Our results highlight that targeting ADAM17 activity may be a potential therapeutic strategy to correct vascular insulin resistance in T2D.

Determination of biologically active substances extraction parameters from cranberry leaves

The problem of type 2 diabetes due to its prevalence, severity, and complications is one of the most pressing in the world. Plants of the genus Vaccinium are promising sources for the creation of hypoglycemic and hypolipidemic medicines. Studies have shown that the extract from cranberry leaves, obtained with 50 % ethanol solution has prospects to be used for correcting insulin resistance. Therefore, for creating new medicines based on cranberry leaves, it is necessary to determine the optimal parameters of biologically active substances (BAS) extraction from this raw material. The aim of the research is to determine the parameters of BAS extraction from cranberry leaves (Oxycoccus macrocarpus (Ait.) Pursh) for creating a new dry extract with hypoglycemic activity. Materials and methods. The object of the study was cranberry leaves. Extracts from the leaves were obtained with 50 % ethanol solution in a ratio of 1:10; 1:15; 1:20; 1:25; 1:30 and 1:35 by maceration at room temperature for 8 hours. The extraction was repeated four times with new portions of the extractant, collecting each extract separately. Identification of phenolic compounds was performed by thin-layer chromatography. An assay of phenolic compounds was carried out by spectrophotometric methods. The mass transfer coefficient of each stage (miBAS/Viextragent) was calculated for each indicator and the dependence of these factors on the extraction multiplicity to determine the rational extraction was derived using the software Statistics. Results. Gallic and chlorogenic acids, rutin, quercetin, and hyperoside were detected on TLC of cranberry leaves extracts in comparison with standard samples of substances. The content of the sum of hydroxycinnamic acid derivatives in terms of chlorogenic acid, the number of flavonoids in terms of rutin, and the content of the sum of phenolic compounds in terms of gallic acid were determined. It was established that the exhaustive extraction of BAS with 50 % ethanol solution from the cranberry leaves provides a ratio of 1 to 100–110. It was rational to carry out BAS extraction from cranberry leaves in a ratio of 1:10 twice, this would ensure the maximum yield of BAS at the minimum cost of the extractant. Conclusions. It was found that was rational to extract BAS with 50 % ethanol solution from cranberry leaves in a ratio of 1:10 twice using mathematical and statistical methods. It would be used in the future in the development of extract technology.

Metabolically associated fatty liver disease – a disease of the 21st century: A review

Metabolically associated fatty liver disease (MAFLD) is a widespread chronic disease characterized by increased accumulation of fat in the liver, which is based on metabolic dysfunction. The incidence of MAFLD is well over 20% in most regions of the world and is on an increasing trend. Current thinking considers the etiology and pathogenesis of MAFLD under the concept of "multiple parallel blows". According to this model, the development and progression of the disease are due to the interaction of multiple genetic, environmental and adaptive factors, which include specific genetic polymorphisms (e.g., the PNPLA3 gene) and epigenetic modifications, dietary patterns (e.g. high saturated fat and fructose intake), sedentary activity, obesity, insulin resistance, dysregulation of adipokines, lipotoxicity, oxidative stress, and gut microbiota dysbiosis (small intestinal bacterial overgrowth syndrome). The basis for the diagnosis of MAFLD is the presence of proven hepatic steatosis in combination with one of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, signs of metabolic dysregulation. Nonmedicamental therapies recommended for patients with MAFLD include weight loss (if overweight or obese), reduction of saturated fatty acid and fructose intake, and inclusion of adequate amounts of omega-3 polyunsaturated fatty acids and dietary fibre (psyllium) in the diet. Pharmacotherapy of MAFLD should be aimed at correcting insulin resistance, improving liver function and reducing the risk of associated diseases.

The Human Milk Oligosaccharide 2'-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice.

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2′-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2′-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2′-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2′-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2′-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2′-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2′-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2′-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2′-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2′-fucosyllactose to correct dysmetabolism and insulin resistance.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Risk Factors Analysis and Management of Cardiometabolic-Based Chronic Disease in Low- and Middle-Income Countries.

The epidemic of obesity or adiposity-based chronic diseases presents a significant challenge with the rising prevalence of morbidities and mortality due to atherosclerotic cardiovascular diseases (ASCVD), especially in low- and middle-income countries (LMIC). The underlying pathophysiology of metabolic inflexibility is a common thread linking insulin resistance to cardiometabolic-based chronic disease (CMBCD), including dysglycemia, hypertension, and dyslipidemia progressing to downstream ASCVD events. The complex CMBCD paradigm in the LMIC population within the socio-economic and cultural context highlights considerable heterogeneity of disease predisposition, clinical patterns, and socio-medical needs. This review intends to summarize the current knowledge of CMBCD. We describe recently established or emerging trends for managing risk factors, assessment tools for evaluating ASCVD risk, and various pharmacological and non-pharmacological measures particularly relevant for LMICs. A CMBCD model positions insulin resistance and β-cell dysfunction at the summit of the disease spectrum may improve outcomes at a lower cost in LMICs. Despite identifying multiple pathophysiologic disturbances constituting CMBCD, a large percentage of the patient at risk for ASCVD remains undefined. Targeting dysglycemia, dyslipidemia, and hypertension using antihypertensive, statins, anti-glycemic, and antiplatelet agents has reduced the incidence of ASCVD. Thus, primordial prevention targeting pathophysiological changes that cause abnormalities in adiposity and primary prevention by detecting and managing risk factors remains the foundation for CMBCD management. Therefore, targeting pathways that address mitochondrial dysfunction would exert a beneficial effect on metabolic inflexibility that may potentially correct insulin resistance, β cell dysfunction and, consequently, would be therapeutically effective across the entire continuum of CMBCD.

Features of the ovulatory function restoration in women

Myo-inositol is considered an additional insulin-sensitive supplement that may benefit women with polycystic ovary syndrome (PCOS). Correcting insulin resistance and lowering circulating insulin levels are key therapeutic options in the PCOS treatment, which in turn increase fertility and reduce the risk of type 2 diabetes and early cardiovascular diseases.Research objective: to determine the effectiveness of the Miofolic drug (contains myo-inositol 2000 mg, 5-methyltetrahydrofolate 200 μg, vitamin B12 2,5 μg) for the restoration of ovulatory dysfunction in women with PCOS phenotype A (ovulatory dysfunction + hyperandrogenism + polycystic ovarian structure).Materials and methods. The study included 60 women of reproductive age with PCOS phenotype A. 31 patients (group І) had normal weight, 29 patients (group ІІ) were overweight. Patients of both clinical groups received therapy with Miofolic 2 sachets for 6 months. Also, women in both groups were given recommendations for lifestyle modifications and a diet with limited carbohydrate content.Treatment efficacy was monitored after 3 and 6 months by determining body mass index, free testosterone index, 75 g glucose tolerance test, progesterone levels in the second phase of the menstrual cycle and ultrasound folliculometry.Results. In the first group, ovulatory cycles resumed after 3 months in 38.7% of patients (p < 0.05), and after 6 months in 58.06% (p < 0.01). In the second group, ovulatory cycles resumed after 3 months in 34.4% of women (p < 0.05), and after 6 months in 41.3% (p < 0.05).Conclusions. The results of this study allow us to recommend the Miofolic drug as the main method of inducing ovulation in women with PCOS with and without overweight, the period of the drug use is from 3 to 6 months. A more stable restoration of ovulatory function occurs after 6 months of therapy.

Вплив метформіну на показники тиреоїдної панелі, вуглеводний та ліпідний обмін у хворих на дифузний токсичний зоб та інсулінорезистентність

Метою дослідження було вивчення впливу метформіну на показники тиреоїдних гормонів, вуглеводного та ліпідного обміну хворих з дифузним токсичним зобом та наявною інсулінорезистентністю. У статті наводяться результати дослідження, у якому взяв участь 21 хворий з дифузним токсичним зобом. Лікування проводили у два етапи по 3 місяці кожен. На першому етапі усі пацієнти отримували тиреостатичну терапію тирозолом, а на другому етапі з метою корекції інсулінорезистентності додатково було призначено метформін. Отримані результати свідчать на користь нормалізації індексу HOMA-IR за рахунок зниження рівня глюкози та інсуліну натще, а також деякого підвищення тиреотропного гормона та зниження вільного тироксину в межах референтних норм на тлі комбінованого лікування тирозолом з метформіном.

338-OR: Reversal of Insulin Resistance by Resveratrol and Hesperetin Combination in Overweight and Obese Subjects Correlates with Decrease in Expression of Thioredoxin Interacting Protein

Trans-Resveratrol and hesperetin combination (tRES-HESP) in randomized, double-blind, placebo-controlled crossover study in overweight and obese subjects corrected insulin resistance; healthy aging through functional food study (HATFF, Clinicaltrials.gov identifier NCT02095873). tRES-HESP is an optimized supplement for induction of expression of glyoxalase 1 (Glo1) via activation of transcription factor Nrf2. Increased Glo1 expression decreases reactive metabolite, methylglyoxal (MG), contributing to insulin resistance through glycation-linked unfolded protein formation and activation of the unfolded protein response (UPR). Herein, we report further analysis of study variables and follow-up reverse translational studies. With tRES-HESP treatment, plasma MG correlated negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity - a marker of Nrf2 activation (r = - 0.68, P<0.01). For change from baseline of PBMC gene expression with tRES-HESP treatment (assessed by the Nanostring method), change in area-under-the-curve plasma glucose (ΔAUGg) during oral glucose tolerance tests correlated negatively with change in Glo1 expression (r = - 0.56, P<0.05) and correlated positively with change in expression of thioredoxin interacting protein (TXNIP) (r = 0.59, P<0.05). In reverse translational studies, we found tRES-HESP decreased TXNIP expression by 39 ± 1% (P<0.001) in human hepatocyte-like HepG2 cells and 14 ± 3% in BJ fibroblasts in vitro (P<0.01). tRES-HESP may decrease TXNIP expression by decreasing the MG-driven UPR and by direct Nrf2-driven down regulation. TXNIP is a mediator of insulin resistance in liver and skeletal muscle and impaired pancreatic beta-cell insulin secretion. tRES-HESP is suitable for further evaluation for prevention and treatment of type 2 diabetes where decreased TXNIP may contribute to the therapeutic response. Disclosure M. Xue: None. M. Weickert: None. N. Rabbani: None. P. Thornalley: None. Funding Qatar Foundation; Qatar University

Effects of total flavonoids from Eucommia ulmoides Oliv. leaves on polycystic ovary syndrome with insulin resistance model rats induced by letrozole combined with a high-fat diet

Ethnopharmacological relevanceEucommia ulmoides Oliv. leaves are the dry leaves of Eucommia ulmoides Oliv. Modern studies have shown that Eucommia ulmoides Oliv. leaves and its extracts have many pharmacological effects, such as regulating hypothalamus pituitary ovary (HPO) axis function, estrogen like effects, correcting insulin resistance (IR), regulating lipids, and reducing weight, which are consistent with the clinical manifestations in polycystic ovary syndrome (PCOS) patients. PCOS patients often have HPO axis disorder, low estrogen, high androgen, high IR complication rate, and obesity. Previous preclinical studies have shown that total flavonoids from Eucommia ulmoides Oliv. leaves (TFEL) can improve the imbalance in sex hormone secretion in perimenopausal animal models by regulating the function of the HPO axis. Thus, it is important to understand if flavonoids are the active parts of Eucommia ulmoides Oliv. leaves that interfere with polycystic ovary syndrome with insulin resistance (PCOS-IR), and determine the regulatory role they play in sex hormones and IR? Aim of the studyInvestigate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the ovary and kisspeptin/insulin like growth factor/leptin receptor1/androgen receptor (Kiss1/IGF-1/LEPR/AR) in the HPO axis to determine the mechanism of TFEL intervention in a rat model of PCOS-IR model rats. Materials and methodsA rat model of PCOS-IR was established using a high-fat diet (49 d) combined with letrozole (1 mg/kg·d, for 28 d). Then, metformin (300 mg/kg·d) and TFEL (220 mg/kg·d, 110 mg/kg·d, and 55 mg/kg·d) were administered continuously for 21 days. At the end of the experiment, samples were taken and the related indexes were measured. ResultsTFEL reduced the body weight, Lee's index, ovarian index, ovarian area and ovarian volume, increased serum E2, SHBG levels and ISI, decreased serum levels of T, LEP, INS, and FBG (whole blood), and reduced the HOMA-IR in rats with PCOS-IR. TFEL downregulate Kiss1, IGF-1, and AR in the arcuate nucleus of hypothalamus, and upregulate Kiss1, downregulate IGF-1 and AR in the pituitary gland, and upregulate Kiss1, downregulate IGF-1, LEPR, and AR in the ovary of rats with PCOS-IR. TFEL could downregulate p-IRS-1Ser307, upregulate IRS-1, p-IRS-1Tyr895, PI3Kp85α, p-PI3Kp85α, AKT, p-AKT, and GLUT4 in the ovary, and ameliorated histopathological changes in the ovary and pancreas of rats with PCOS-IR. ConclusionTFEL can inhibit ovarian hyperplasia, regulate disorders of glucose and lipid metabolism and improve the secretion of sex hormones, by regulating the expression of PI3K/AKT signaling pathway-related proteins in the ovary and Kiss1/IGF-1/LEPR/AR in the HPO axis.