Chronic Hyperinsulinemia Research Articles

The impact of obesity on immune response to infection: Plausible mechanisms and outcomes.

Emerging data suggest an association between obesity and infectious diseases. Although the mechanisms underlying this link are not well established, a number of potential factors may be involved. Indeed, the obesity-related vulnerability to infectious diseases could be due to chronic low-grade inflammation, hyperglycemia, hyperinsulinemia, and hyperleptinemia, which lead to a weakening of both the innate and adaptive immune responses. In addition, obesity results in anatomical-functional changes by the mechanical obstacle of excessive adipose tissue that blunt the respiratory mechanisms and predisposing to respiratory infections. Subjects with obesity are also at risk of skin folds and sweat more profusely due to the thick layers of subcutaneous fat, favoring the proliferation of microorganisms and slowing the repair of wounds down. All these factors make subjects with obesity more prone to develop nosocomial infections, surgical site, skin and soft tissue infections, bacteremia, urinary tract infections, and mycosis. Furthermore, infections in subjects with obesity have a worse prognosis, frequently prolonging hospitalization time as demonstrated for several flu viruses and recently for COVID-19. Thus, the aim of this manuscript is to provide an overview of the current clinical evidence on the associations between obesity and infectious diseases highlighting physio pathological insights involved in this link.

Temporal Associations Among Body Mass Index, Fasting Insulin, and Systemic Inflammation

Obesity is associated with a number of noncommunicable chronic diseases and is purported to cause premature death. To summarize evidence on the temporality of the association between higher body mass index (BMI) and 2 potential mediators: chronic inflammation and hyperinsulinemia. MEDLINE (1946 to August 20, 2019) and Embase (from 1974 to August 19, 2019) were searched, although only studies published in 2018 were included because of a high volume of results. The data analysis was conducted between January 2020 and October 2020. Longitudinal studies and randomized clinical trials that measured fasting insulin level and/or an inflammation marker and BMI with at least 3 commensurate time points were selected. Slopes of these markers were calculated between time points and standardized. Standardized slopes were meta-regressed in later periods (period 2) with standardized slopes in earlier periods (period 1). Evidence-based items potentially indicating risk of bias were assessed. Of 1865 records, 60 eligible studies with 112 cohorts of 5603 participants were identified. Most standardized slopes were negative, meaning that participants in most studies experienced decreases in BMI, fasting insulin level, and C-reactive protein level. The association between period 1 fasting insulin level and period 2 BMI was positive and significant (β = 0.26; 95% CI, 0.13-0.38; I2 = 79%): for every unit of SD change in period 1 insulin level, there was an ensuing associated change in 0.26 units of SD in period 2 BMI. The association of period 1 fasting insulin level with period 2 BMI remained significant when period 1 C-reactive protein level was added to the model (β = 0.57; 95% CI, 0.27-0.86). In this bivariable model, period 1 C-reactive protein level was not significantly associated with period 2 BMI (β = -0.07; 95% CI, -0.42 to 0.29; I2 = 81%). In this meta-analysis, the finding of temporal sequencing (in which changes in fasting insulin level precede changes in weight) is not consistent with the assertion that obesity causes noncommunicable chronic diseases and premature death by increasing levels of fasting insulin.

DPP4 Activity, Hyperinsulinemia, and Atherosclerosis.

Obesity and type 2 diabetes are associated with chronic hyperinsulinemia, elevated plasma levels of dipeptidyl peptidase-4 (DPP4), and a pro-atherosclerotic milieu. PubMed search of the term "insulin and atherosclerosis," "hyperinsulinemia," "atherosclerosis," or "cardiovascular outcomes" cross-referenced with "DPP4." Relevant research and review articles were reviewed. Hyperinsulinemia in the setting of insulin resistance promotes vascular inflammation, vascular smooth muscle cell growth, pathological cholesterol profile, hypertension, and recruitment of immune cells to the endothelium, all contributing to atherosclerosis. DPP4 has pleiotropic functions and its activity is elevated in obese humans. DPP4 mirrors hyperinsulinemia's atherogenic actions in the insulin resistant state, and genetic deletion of DPP4 protects rodents from developing insulin resistance and improves cardiovascular outcomes. DPP4 inhibition in pro-atherosclerotic preclinical models results in reduced inflammation and oxidative stress, improved endothelial function, and decreased atherosclerosis. Increased incretin levels may have contributed to but do not completely account for these benefits. Small clinical studies with DPP4 inhibitors demonstrate reduced carotid intimal thickening, improved endothelial function, and reduced arterial stiffness. To date, this has not been translated to cardiovascular risk reduction for individuals with type 2 diabetes with prior or exaggerated risk of cardiovascular disease. DPP4 may represent a key link between central obesity, insulin resistance, and atherosclerosis. The gaps in knowledge in DPP4 function and discrepancy in cardiovascular outcomes observed in preclinical and large-scale randomized controlled studies with DPP4 inhibitors warrant additional research.

Cutaneous Manifestations of Nutritional Excess: Pathophysiologic Effects of Hyperglycemia and Hyperinsulinemia on the Skin.

Hyperglycemia is defined by excess blood glucose and, when persistent, may lead to prediabetic and diabetic states. Insulin is a hormone produced by the beta cells of the pancreas in response to elevated blood glucose. Dysregulated insulin secretion or clearance results in hyperinsulinemia, which also is closely associated with type 2 diabetes mellitus (T2DM) and metabolic disturbances. Hyperglycemia and hyperinsulinemia are endemic within the United States and impart considerable morbidity and mortality. Cutaneous manifestations of chronic hyperglycemia and hyperinsulinemia include acanthosis nigricans (AN), diabetic dermopathy (DD), scleredema diabeticorum (SD), ichthyosiform skin changes, acrochordons, and keratosis pilaris (KP). Necrobiosis lipoidica (NL), bullosis diabeticorum (BD), and generalized granuloma annulare (GA) are more rarely reported in association with hyperglycemia and hyperinsulinemia; however, the strength of these associations remains unclear. It is crucial for dermatologists to recognize these cutaneous manifestations, as they may be the first signs of metabolic syndrome and insulin resistance. Early identification and management of these conditions is key to improving patient health outcomes and reducing health care costs. Herein, we review the clinical presentations of these conditions and their underlying pathophysiologic mechanisms.

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division.

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

Immunohistochemical expression of insulin-like growth factor-1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression.

Chronic hyperinsulinemia due to insulin resistance and elevated levels of insulin-like growth factor (IGF)-1 and IGF-2 are suggestive of a significantly higher risk of endometrial carcinoma. There is a wealth of evidence showing differential expression of IGF-1 isoforms in various types of cancer. In the present study, 99 archived endometrial carcinoma tissue sections were retrospectively assessed by immunohistochemistry for IGF-1Ec isoform expression. Expression of IGF-1Ec was also assessed in nine cases of non-neoplastic endometrial tissue adjacent to the tumor, in 30 cases with normal endometrium and in 30 cases with endometrial hyperplasia. Furthermore, the association between IGF-1Ec and the concurrent expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p53 or survivin was assessed, as well as their combined expression in association with clinicopathological variables. In endometrial carcinoma, IGF-1Ec expression was high in non-endometrioid carcinoma (serous papillary or clear cell carcinoma) compared with that in endometrioid adenocarcinoma. IGF-1Ec expression was also high in the presence of tumoral necrosis. Furthermore, there was a significant correlation between the histological differentiation and the sum of staining intensity and the number of IGF-1Ec immunopositive cells in endometrial carcinoma. There was a moderate negative correlation between co-expression of IGF-1Ec and PTEN, for both the number of immunopositive cells (P=0.006, ρ=−0.343) and the sum of staining (scores and intensity; P=0.006, ρ=−0.343). Furthermore, there was a positive correlation between the sum of staining (scores and intensity) and co-expression of IGF-1Ec and survivin (P=0.043, ρ=0.225). However, there was no association between concomitant expression of IGF-1Ec and p53. These results emphasized the importance of IGF-1Ec expression during development of non-estrogen dependent endometrial adenocarcinoma. IGF-1Ec and PTEN may function opposingly during endometrial carcinogenesis. By contrast, IGF-1Ec and survivin may share common molecular pathways and may promote, in parallel, tumoral development.

Refined Carbohydrate Consumption and Facial Attractiveness.

Since the second half of the 20th century, a massive increase in the consumption of refined carbohydrates has occurred, generating well-described detrimental health effects such as obesity, insulin resistance, type II diabetes, cardiovascular diseases and dental caries. Certain physiological mechanisms involved, particularly through chronic hyperglycaemia and hyperinsulinaemia, suggest that a non-medical trait such as facial attractiveness could also be affected. To explore this possibility, variation in facial attractiveness was evaluated relative to refined carbohydrate consumption. Attractiveness was assessed from facial pictures as judged by raters of the opposite sex. Estimates of refined carbohydrate consumption were based on the glycaemic load of three mealtimes at-higher glycaemic risk (breakfast, afternoon snack and between-meal snack). In the presence of several control variables, facial pictures of women and men with higher between-meal glycaemic loads were preferred by opposite-sex raters. Structural equation modeling suggests that this result is possibly mediated by an increase in apparent age for men and an increase in femininity for women. The different physiological ecologies of the three meals at-higher glycaemic risk are discussed as well as the interpretation of the results in terms of adaptation or maladaptation to the modern and unique dietary environment.

Loss of Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis.

Patients with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin (Alb)Cre+ Cc1flox ( fl ) /fl mice with the liver‐specific null deletion of the carcinoembryonic antigen‐related cell adhesion molecule 1 (Ceacam1; alias Cc1) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated de novo lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD/NASH and atherosclerosis. To this end, mice were propagated on a low‐density lipoprotein receptor (Ldlr)−/− background and at 4 months of age were fed a high‐cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr−/−AlbCre+Cc1fl/fl mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin‐1 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down‐regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1–protein kinase B–endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc‐transforming protein (Shc), activating the Shc–mitogen‐activated protein kinase–nuclear factor kappa B pathway and stimulating endothelin‐1 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver‐specific deletion of Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. Conclusion: Altered CEACAM1‐dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.

Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver

The effect of chronic of hyperinsulinemia in the fetal liver is poorly understood. Here, we produced hyperinsulinemia with euglycemia for ∼8 days in fetal sheep [hyperinsulinemic (INS)] at 0.9 gestation. INS fetuses had increased insulin and decreased oxygen and amino acid (AA) concentrations compared with saline-infused fetuses [control (CON)]. Glucose (whole body) utilization rates were increased, as expected, in INS fetuses. In the liver, however, there were few differences in genes and metabolites related to glucose and lipid metabolism and no activation of insulin signaling proteins (Akt and mTOR). There was increased p-AMPK activation and decreased mitochondrial mass (PGC1A expression, mitochondrial DNA content) in INS livers. Using an unbiased multivariate analysis with 162 metabolites, we identified effects on AA and one-carbon metabolism in the INS liver. Expression of the transaminase BCAT2 and glutaminase genes GLS1 and GLS2 was decreased, supporting decreased AA utilization. We further evaluated the roles of hyperinsulinemia and hypoxemia, both present in INS fetuses, on outcomes in the liver. Expression of PGC1A correlated only with hyperinsulinemia, p-AMPK correlated only with hypoxemia, and other genes and metabolites correlated with both hyperinsulinemia and hypoxemia. In fetal hepatocytes, acute treatment with insulin activated p-Akt and decreased PGC1A, whereas hypoxia activated p-AMPK. Overall, chronic hyperinsulinemia produced greater effects on amino acid metabolism compared with glucose and lipid metabolism and a novel effect on one-carbon metabolism in the fetal liver. These hepatic metabolic responses may result from the downregulation of insulin signaling and antagonistic effects of hypoxemia-induced AMPK activation that develop with chronic hyperinsulinemia.

Reduction of Chronic Hyperinsulinemia (Insulin Resistance) for the Prevention and Treatment of Cancerous Disease: The Crucial Role of Caloric Restriction

Gene’s expression changes with nutrition and physical activity and hormones signaling like insulin. A Western lifestyle may increase cancer risk through alterations in the metabolism of insulin and insulin-like growth factors. The anabolic signals by insulin or IGF-I can promote tumour development by inhibiting apoptosis, and by stimulating cell proliferation. There is dynamic change in gene expression in response to nutritional availability [1]. A clear association between adiposity, physical inactivity and Western diet, and the risk of incident cancer, cancer recurrence and mortality after “curative” surgery is increasing. Insulin Resistance Status characterized by hyperinsulinemia is associated with an excessive increased risk for a number of malignancies. An increasing clinical, biological and epidemiological evidence sustain that Insulin-IGFs System has been implicated in breast, prostate, pediatric, colon-recto and gynecological cancers, including sarcomas, epithelial cancers, multiple myeloma and melanoma. Chronic hyperinsulinaemia may be a cause of cancers of the colon, pancreas, endometrium, breast, prostate, ovarium, and possibly of the lung, and may predispose strongly to melanoma development; reducing the hormone-vitamin D anticancerigen action [2].

The impact of serum visfatin, and resistin levels on insulin resistance in patients with polycystic ovary syndrome

Background and objective: Women with polycystic ovary syndrome serve as a model to estimate the functions of insulin resistance and chronic hyperinsulinemia on serum level of insulin resistance markers. This study aimed to determine the association of the serum visfatin, resistin levels with insulin resistance in patients with polycystic ovary syndrome, and its correlations with various parameters. Methods: This case-control study was performed at the College of Pharmacy, Hawler Medical University in the period between May 2017 and July 2018. It included 100 patients and 100 age matched healthy control group was also enrolled for comparing purposes. Results: Patients had significantly elevated serum visfatin ( 2.46 vs. 1.08 ng/ml), resistin (3.87 vs. 2.46ng/ml), and insulin (17.22 vs. 8.1 µlU/ml) levels than controls. They also had significant elevations in insulin resistance (2.41 vs. 1.92) and β insulin function (94.45 vs. 86.98). There was no significant variation in insulin sensitivity (88.77 vs. 92.08). Conclusion: There was an association between resistin, visfatin, and polycystic ovary syndrome-related insulin resistance. Many recent proteins are now considered as potential new markers of insulin resistance in polycystic ovary syndrome. There was a strong connection between visfatin and resistin with insulin resistance in polycystic ovary syndrome pathophysiology.

The Insulinemic, Inflammatory, and Glycemic Potential of the Diet in Relation to Risk of Type 2 Diabetes

Abstract Objectives Dietary patterns that promote chronic systemic inflammation, hyperinsulinemia, or hyperglycemia may influence type 2 diabetes (T2D) risk. We evaluated an empirical dietary index for hyperinsulinemia (EDIH), empirical dietary inflammatory pattern (EDIP), glycemic index (GI), and glycemic load (GL), and risk of T2D among US postmenopausal women. EDIH and EDIP assess the insulinemic or inflammatory potential of habitual diets, irrespective of macronutrient content, and are based on plasma concentrations of insulin response or inflammatory biomarkers, respectively. The GI and GL assess postprandial glycemic potential based on carbohydrate content of the diet. Methods We calculated dietary scores from baseline food frequency questionnaires among 73,495 participants aged 50–79 years in the Women's Health Initiative Observational Study and Clinical Trials. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for risk of T2D according to quintiles of dietary scores. Results There were 11,009 incident cases of T2D during a median 13.3 years of follow-up. In multivariable-adjusted analyses, participants in the highest dietary score quintiles (consuming the most hyperinsulinemic, proinflammatory, or hyperglycemic diets) were at highest risk of T2D compared to those in the lowest quintiles: EDIH: HR, 1.54(1.37, 1.74); Ptrend < .0001; EDIP: HR, 1.45 (1.29, 1.64); Ptrend < .0001). GI and GL were not associated with T2D risk: GI: HR, 0.99 (0.88, 1.12); Ptrend = 0.94; GL: HR, 0.98 (0.85, 1.12); Ptrend = 0.32. In subgroup analyses, associations of EDIH and EDIP with T2D risk were stronger among overweight or obese than normal-weight women (Pinteraction: EDIH = 0.02, EDIP = 0.003), and findings did not significantly vary by race/ethnicity. Conclusions In this large sample of postmenopausal women, hyperinsulinemic, and pro-inflammatory dietary patterns were associated with higher risk of T2D, more so among overweight and obese women, whereas dietary glycemic potential was not associated with T2D risk. Funding Sources NCI grant # R00CA207736 and the WHI program is funded by NHLBI grant #s HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.

OR20-07 Placentas from Obese Women Are Resistant to the Effect of Insulin on Triglyceride Content Ex Vivo

Background: Obesity affects 25% of pregnant women and is associated with a higher risk of neonatal complications, such as macrosomia and increased adiposity. The placenta may contribute to neonatal adiposity by accumulating and transferring excess lipid in response to maternal hyperinsulinemia. We previously found that insulin promotes a 3-fold increase in placental triglyceride (TG) content in lean women. We hypothesized that obese women have higher placental insulin resistance compared to lean women[FC1] with respect to TG content. Methods: Healthy, lean women (n=12; mean age 34±1 yrs; BMI 22±0.4 kg/m2) and non-diabetic, obese women (n=9; mean age 32±2 yrs; BMI 33±0.4 kg/m2, p<0.0001) consented for placenta collection at elective c-section under fasting conditions. Placental villous explants were immediately flash frozen or cultured for 24 hours, starved, then treated for 48 hours with 0.1nM, 1nM, 10nM, or 100nM of insulin, or vehicle. Lipids were extracted from basal and treated explants using a chloroform-methanol separation protocol. TG content was quantified by spectrophotometer and normalized to weight. Data were analyzed by two-way ANOVA. Results: Basal placenta tissue from obese women contained a 1.5-fold higher level of TG compared to lean women (9.4±0.5 vs 5.7±0.5 mcg/mg, p=0.001). Placental response to insulin in lean women peaked at 1nM insulin (20.2±3.3 mcg/mg), and plateaued at higher doses of 10nM (18.6±3.3 mcg/mg) and 100nM (22.8±2.8 mcg/mg, p=NS respectively). In contrast, placenta explants from obese women required the highest insulin dose of 100 nM for maximal response (23.6±3.2 mcg/mg), and showed a gradual dose response from 0.1 nM insulin (9.5±2), 1nM (14.8±2), 10 nM (16.9±3). At 100nM insulin, the difference in TG content was variable, but on average was 2-fold higher than vehicle treated placenta (vs 11.8±2.5[FC2] [AA3] mcg/mg, p=0.002). Conclusion: Our findings indicate that placenta from obese women develop insulin resistance similar to peripheral tissues, which can be overcome by high insulin doses. This placental insulin resistance likely occurs in response to chronic hyperinsulinemia, leading to interference of insulin signaling pathways, and may protect the neonate from excessive nutrient flux.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities.

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

Pancreastatin inhibitor PSTi8 attenuates hyperinsulinemia induced obesity and inflammation mediated insulin resistance via MAPK/NOX3-JNK pathway

Pancreastatin (PST), a chromogranin A derived peptide has anti-insulin effects and plays a significant role in obesity-induced insulin resistance. In obesity and type 2 diabetes mellitus, both insulin and PST level are elevated, but it is not clearly understood how anti-insulin effect of PST get regulated in hyperinsulinemic state. Simultaneously we have explored pancreastatin inhibitor PSTi8 against the native PST in the same hyperinsulinemic state. In in-vitro studies, we found that PST treatment increases lipid droplets and reactive oxygen species production in 3T3L1 adipocyte cells and theses effects of PST was found synergistic with chronic-insulin treatment. Treatment of PSTi8 in 3T3L1 adipocytes attenuates PST effect on lipid droplet formation and reactive oxygen species production. We further validated these findings in epididymal white adipose tissue of C57BL/6 mice, implanted with mini-osmotic insulin pump with and without PSTi8 for 4 weeks. We found that chronic hyperinsulinemia enhanced PST levels in circulation which in turn induces expression of various pro-inflammatory cytokines and oxidative stress. In addition, it also stimulated the expression of lipogenic genes, fat mass and body weight gain through the regulation of circulating adiponectin level. The change in PST mediated inflammatory and lipogenic parameters were attenuated by PSTi8 treatment, leading to enhanced insulin sensitivity and improved glucose homeostasis. PSTi8 rescue from PST mediated insulin resistance in adipose via inhibition of MAPK and NOX3-JNK stress signalling pathway which stimulates GLUT4 expression through activation of AKT-AS160 pathway. Thus PSTi8 may be a novel therapeutic agent for the treatment of hyperinsulinemia induced obesity and inflammation mediated insulin resistance.

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

Utility of obesity and metabolic dyslipidemia (a non-insulin based determinate of the metabolic syndrome and insulin resistance) in predicting arterial stiffness.

Increased arterial stiffening is not only a hallmark of the aging process but the consequence of many metabolic abnormalities such as insulin resistance (IR), obesity, and metabolic dyslipidemia. In patients with the cardiometabolic syndrome, arterial stiffening is consistently observed across all age groups. A core feature linking obesity and the metabolic syndrome to arterial stiffness has been IR. However, including other metabolic abnormalities such as metabolic dyslipidemia increases the risk prediction of arterial stiffness in a dose-dependent fashion. Chronic hyperinsulinemia also increases the activity of both the systemic and the local RAAS which contributes to the development of arterial stiffness. All of these relevant metabolic features that predict arterial stiffness are appropriately incorporated in the METS-IR used in the current study.

METABOLIC SYNDROME - THIS IS SERIOUS!

Metabolic syndrome is a complex of metabolic, hormonal and clinical disorders that are risk factors for the development of cardiovascular diseases, which are based on insulin resistance and compensatory hyperinsulinemia. The main mechanisms of the effects of chronic hyperinsulinemia on blood pressure are given, and the main symptoms and manifestations of the metabolic syndrome are given. The most common variant of dyslipidemia in the metabolic syndrome is the lipid triad.

Phenformin as an Anticancer Agent: Challenges and Prospects.

Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.

Sex differences in sympathetic activity in obesity and its related hypertension.

The prevalence of obesity is rapidly increasing in the United States, particularly among women. Approximately 60-70% of hypertension in adults may be directly attributed to obesity. In addition, maternal obesity is a major risk factor for hypertensive disorders during pregnancy. The underlying mechanisms for the association between obesity and cardiovascular risk are multifactorial, but activation of the sympathetic nervous system is one significant contributing factor. This brief review summarizes the current knowledge on sex differences in sympathetic activity in obesity and its related hypertension, with a focus on studies in humans. Evidence suggests that abdominal visceral fat, rather than subcutaneous fat, is related to augmented sympathetic activity regardless of sex. Race/ethnicity may affect the relationship between obesity and sympathetic activity. Obesity-related hypertension has an important neurogenic component, which is characterized by sympathetic overactivity. However, sex may influence the association between hypertension and sympathetic overactivity in obese people. Finally, both body weight and sympathetic overactivity seem to be involved in the development of gestational hypertensive disorders in women. Chronic hyperinsulinemia due to insulin resistance, high plasma levels of leptin, and/or obstructive sleep apnea may be responsible for sympathetic overactivity in obesity-related hypertension.