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Insulin resistance - Top 30 Publications

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies.

To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children.

Berberine regulates type 2 diabetes mellitus related with insulin resistance.

Insulin resistance (IR) is defined as a series of clinical manifestations for diminished effectiveness of insulin in lowering blood sugar levels caused by decreased sensitivity to insulin of liver, muscle and adipose tissue. IR is the major contributor to the etiology and pathogenesis of type 2 diabetes mellitus (T2DM). Berberine, a traditional Chinese herb extract, has been shown to be safe and effective in lowering blood sugar, alleviating insulin resistance and moderating type 2 diabetes mellitus and its complications. The bioavailability of berberine is extremely low, suggesting that it may play a role in lowering blood sugar and lipid by regulating intestinal flora. Intestinal microbiota may serve as a new potential target for berberine treatment of type 2 diabetes mellitus.

Alfalfa-derived HSP70 administered intranasally improves insulin sensitivity in mice.

Heat shock protein (HSP) 70 is an abundant cytosolic chaperone protein that is deficient in insulin-sensitive tissues in diabetes and unhealthy aging, and is considered a longevity target. It is also protective in neurological disease models. Using HSP70 purified from alfalfa and administered as an intranasal solution, we tested in whether the administration of Hsp70 to diet-induced diabetic mice would improve insulin sensitivity. Both the 10 and 40 μg given three times per week for 26 days significantly improved the response to insulin. The HSP70 was found to pass into the olfactory bulbs within 4-6 hours of a single dose. These results suggest that a relatively inexpensive, plentiful source of HSP70 administered in a simple, non-invasive manner, has therapeutic potential in diabetes.

Smoking, obstructive sleep apnea syndrome and their combined effects on metabolic parameters: Evidence from a large cross-sectional study.

Metabolic disorders have been separately associated with obstructive sleep apnea syndrome (OSAS) and smoking. However, no study has examined their interactions with metabolic parameters, including insulin resistance and dyslipidemia. To investigate whether the combination of OSAS and smoking results in an additive detriment in metabolic disorder parameters, we enrolled consecutive adult men during 2014-2015. Fasted blood samples were taken to determine glucose, insulin, and lipid levels. A questionnaire including an item on smoking pack-year exposure was administered, and the Epworth Sleepiness Scale and overnight polysomnography were performed. Smokers showed higher levels of glucose, insulin, total cholesterol (TC), triglycerides (TG), and low density lipoprotein-cholesterol (LDL-C), but lower high-density lipoprotein cholesterol (HDL-C) levels, than did non-smokers. In addition, the risks for insulin resistance increased with OSAS severity without fully adjustment. An OSAS × smoking interaction was found in insulin resistance after adjusting for potential confounding factors (p = 0.025). Although the difference was not significant, cessation of cigarette smoking seems to have a little benefit for smoking patients with OSAS. A synergistic effect was observed between smoking and OSAS on metabolic disorder parameters. Cessation of cigarette smoking may experience minor benefit for insulin resistance and lipid metabolism in patients with OSAS.

Insulin-like Growth Factor-1 signalling is essential for Mitochondrial Biogenesis and Mitophagy in cancer cells.

Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an Insulin-like Growth Factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells, and whether this contributes to therapy resistance. Here, we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1R tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction indicated by reactive oxygen species (ROS) expression, reduced expression of mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer.

Hyperglycemia is associated with increased bone mineral density and decreased trabecular bone score in elderly Japanese men: The Fujiwara-kyo osteoporosis risk in men (FORMEN) study.

Patients with type 2 diabetes mellitus (T2DM) have an increased fracture risk despite having higher areal bone mineral density (aBMD). This study aimed to clarify the association between glycemic and insulin resistance status and bone microarchitecture, and whether pentosidine and bone turnover markers play any roles in the association.

Diet-induced obesity alters memory consolidation in female rats.

Obesity is a multifactorial disease characterized by the abnormal or excessive fat accumulation, which is caused by an energy imbalance between consumed and expended calories. Obesity leads to an inflammatory response that may result in peripheral and central metabolic changes, including insulin and leptin resistance. Insulin and leptin resistance have been associated with metabolic and cognitive dysfunctions. Obesity and some neurodegenerative diseases that lead to dementia affect mainly women. However, the effects of diet-induced obesity on memory consolidation in female rats are poorly understood. Therefore, the aim of this study was to evaluate the effect of a hypercaloric diet on the object recognition memory of female rats and on possible related metabolic changes. The animals submitted to the hypercaloric diet presented a higher food intake in grams and in calories, resulting in increased weight gain and liposomatic index in comparison with the animals exposed to the control diet. These animals presented a memory deficit in the object recognition test and increased serum levels of glucose and leptin. However, no significant differences were found in the serum levels of insulin, TNF-α and IL-1β, in the index of insulin resistance (HOMA), in the hippocampal levels of insulin, TNF-α and IL-1β, as well as on Akt expression or activation in the hippocampus. Our findings indicate that adult female rats submitted to a hypercaloric diet present memory consolidation impairment, which could be associated with diet-induced weight gain and leptin resistance, even without the development of insulin resistance.

Short-Term Moderate Sleep Restriction Decreases Insulin Sensitivity in Young Healthy Adults.

The literature suggests that severe sleep loss of more than a few hours a night decreases glucose tolerance and insulin sensitivity. The aim of this study was to determine whether moderate sleep restriction had similar effects.

Comprehensive Study of Multiple Stages Progressing to Nonalcoholic Steatohepatitis with Subsequent Fibrosis in SD Rats.

Because of the absence of the time course of histological nonalcoholic fatty hepatitis with subsequent fibrotic progression, the effective approaches available for controlling the onset and progression of non-alcoholic steatohepatitis (NASH) remain limited. Therefore, we detected the serum and liver tissue related lipid metabolism disorder, liver pathology and relative molecular makers alteration dynamically in a high fat-sucrose diet during different time points. High fat-sucrose diet significantly increased the serum lipid level on day 10. The excess lipid accumulation in liver was referred to as simple steatosis after the feeding of a high fat-sucrose diet for 20 days. The high fat-sucrose diet induced a hepatic inflammation response on day 30. Similarly, hepatic fibrosis was also initiated on day 30 and gradually formed from the 30th to the 50th day. Oxidative stress may be related with the process from NASH to liver fibrosis. Insulin resistance was involved in the progression from hepatic steatosis to NASH with hepatic fibrosis from the 20th to the 50th day. In conclusion, we established a high fat-sucrose diet induced nonalcoholic fatty hepatitis with liver fibrosis rat model, which presented the time course of histological nonalcoholic steatohepatitis and the initiation and progression change of characteristic molecular makers in the process from steatosis to hepatic fibrosis.

Fibroblast growth factor-21 and omentin-1 hepatic mRNA expression and serum levels in morbidly obese women with non-alcoholic fatty liver disease.

Fibroblast growth factor-21 (FGF21) and omentin-1 have been recognized as potent antidiabetic agents with potential hepatoprotective activity. The aim of this study was to evaluate hepatic FGF21 and omentin-1 mRNA expression as well as their serum levels as predictive markers of liver injury and insulin resistance in morbidly obese women with non-alcoholic fatty liver disease (NAFLD). This study included 56 severely obese women who underwent intraoperative wedge liver biopsy during the bariatric surgery. Hepatic FGF21 and omentin-1 mRNA were assessed by quantitative real-time PCR, while their serum concentrations were measured with commercially available enzyme-linked immunosorbent assays. The FGF21 serum level was significantly higher in patients with a greater extent of steatosis (grade 2 and 3) compared to those without or with mild steatosis (grade 0 and 1) (P = 0.049). Receiver Operating Characteristic analysis, however, showed poor discriminant power for the FGF21 serum levels in differentiating between more and less extensive steatosis with an AUC = 0.666. There was a tendency towards higher levels of hepatic FGF21 mRNA in patients with lobular inflammation and fibrosis and towards lower levels in the case of hepatocyte ballooning and steatosis. There was a positive mutual correlation between hepatic FGF21 and omentin-1 mRNA levels (r = 0.78; P < 0.001). Fibrosis stage was associated with serum glucose and homeostatic model assessment for insulin resistance (HOMA-IR) (P = 0.03 and P = 0.02, respectively). Serum omentin-1 was not associated with histopathological features. The hepatic omentin-1 mRNA levels showed a tendency to be lower in patients with advanced steatosis and hepatocyte ballooning. In conclusion, our study, which focused on hepatic FGF21 and omentin-1 mRNA expression, confirmed marked expression of both molecules in the liver of morbidly obese patients with NAFLD. More extensive steatosis was associated with evident changes in the serum FGF21 concentration in morbidly obese women with NAFLD, but the difference did not reach statistical significance. The vast amount of fat, both visceral and subcutaneous, in severely obese patients may be the additional source and influence the FGF21 and omentin-1 serum levels.

Diet quality and its implications on the cardio-metabolic, physical and general health of older men: the Concord Health and Ageing in Men Project (CHAMP).

The revised Dietary Guideline Index (DGI-2013) scores individuals' diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project; it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores; it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment - insulin resistance, LDL-cholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI-2013 score was 93·7 (54·4, 121·2); most individuals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL-cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer co-morbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background.

Exploring the cardio-metabolic relevance of T-cadherin: A pleiotropic adiponectin receptor.

T cadherin is a unique member of the cadherin family and is primarily expressed in the cardiovascular system. T cadherin has not been abundantly studied, but the studies conducted to date have explored the impact of this protein on health and the function of organs involved in metabolic regulation.

Metformin - a new old drug.

For many years metformin has been the gold standard in the treatment of type 2 diabetes. According to recommendations of the most important diabetes associations, this is the first-choice drug for use as monotherapy in patients with newly diagnosed type 2 diabetes. Metformin is also recommended in combined treatment when monotherapy is no longer effective. It is then combined with a sulfony-lurea, an incretin, flozin, or insulin, irrespective of the number of insulin injections per day. Besides its properties used in the treatment of diabetes, metformin has been treated for some time as a drug of a so-called pleiotropic activity, as each year brings new reports about its favourable effect in different conditions. At present, the scope of reimbursed indications of this drug has been expanded to include prediabetes, insulin resistance syndromes, and polycystic ovary syndrome. Metformin does not stimulate insulin secretion by the beta cells of the pancreas, and thus it is a drug that does not cause hypoglycaemia. The blood glucose-lowering effect of the drug is a consequence of hepatic glucose production inhibition, and of peripheral tissue (muscle tissue, fatty tissue) sensitisation to the effect of insulin of both endogenous and exogenous origin. The exact mechanism of metformin action at the cellular level remained unknown for a long time. Studies performed in recent years have provided a great deal of information that enables better understanding of the mechanism of action of the drug as well as the clinical effects resulting from its use. Metformin, besides improvement of glycaemia, is neutral to body weight, is cardioprotective, improves lipid profile, and has a probable anti-cancer effect. Metformin accumulation in the intestinal mucosa may interfere with FDG (18F-deoxyglucose) PET-CT image assessment. The aim of this article is a detailed discussion of metformin properties, its mechanisms of action, and clinical effects.

Addison's disease concomitant with corticotropin deficiency and pituitary CRH resistance - a case report.

A 36-year-old woman was found to have a low morning ACTH concentration despite a history of Addison's disease. Past medical history: At the age of 23 years the subject developed Graves's disease, which was treated with radioiodine. At about the same time, she claimed to have two episodes of pancreatitis treated with cholecystectomy. About seven months later she was euthyroid on L-thyroxine (TSH 1.51 mIU/mL) but was admitted with hypotension, hyponatraemia (sodium 109 mmol/L), and low morning cortisol (119 nmol/L). Further investigations confirmed primary adrenal failure with ACTH concentration of 779 pg/mL (ref. range 0-60) prior to the dose of hydrocortisone. About nine years later she complained about tiredness. Clinically she was normotensive and not pigmented. BMI 22.3 kg/m². Periods were regular. ACTH concentration was surprisingly low (ACTH 8.53 pg/mL, ref. range 0-46), despite very low cortisol (3.37 nmol/L). She was admitted for further assessment.

Regulation of hepatic Na(+)/K(+)-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK.

In this study, we assessed whether the disturbed regulation of sodium/potassium-adenosine-triphosphatase (Na(+)/K(+)-ATPase) occurs as a consequence of obesity-induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKα, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150-200 g, 8 weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10 weeks. The activity of hepatic Na(+)/K(+)-ATPase and Rho, and the association of IRS-1/p85 were assessed in liver. Furthermore, the protein level of α1 Na(+)/K(+)-ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, -p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKα, ERα, and ERβ in liver lysates were assessed. The expression of hepatic α1 Na(+)/K(+)-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p < 0.05) and AMPKα (p < 0.05) phosphorylation levels, unchanged level of Na(+)/K(+)-ATPase α1 mRNA, decreased level of Na(+)/K(+)-ATPase activity (p < 0.05), and decreased α1 Na(+)/K(+)-ATPase protein expression (p < 0.01). In liver of HF-fed male rats, results show decreased levels of Na(+)/K(+)-ATPase activity (p < 0.01), both protein and mRNA of α1 subunit (p < 0.05), but significant increase in Rho activity (p < 0.05). Our results indicate significant sex differences in α1 Na(+)/K(+)-ATPase mRNA expression and activation of ERK1/2, AMPKα, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets.

Melatonin, mitochondria, and the metabolic syndrome.

A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.

A syndromic extreme insulin resistance caused by biallelic POC1A mutations in exon 10.

POC1A encodes a protein with a role in centriole assembly and stability, and in ciliogenesis. Biallelic loss of function mutations affecting POC1A cause SOFT syndrome, an ultra-rare condition characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis. Using exome sequencing, we identified a homozygous frameshift mutation (c.1047_1048dupC; p.G337Rfs*25) in a patient presenting with short stature, facial hirsutism, alopecia, dyslipidemia and extreme insulin resistance. The truncating variant affected exon 10, which is retained in only two of the three POC1A mature RNAs, due to alternative processing of the transcript. Clinical discrepancies with SOFT syndrome support the hypothesis that POC1A mutations affecting exon 10 are associated with a distinct condition, corroborating a previous hypothesis based on a similar case. Furthermore, this report provides an additional example of a genetic condition presenting with clinical heterogeneity due to alternative transcript processing. In conclusion, mutations in POC1A exons 10 should be taken into account in patients with extreme insulin resistance and short stature.

Acute oxygen sensing by the carotid body: from mitochondria to plasma membrane.

Maintaining oxygen homeostasis is crucial to the survival of animals. Mammals respond acutely to changes in blood oxygen levels by modulating cardiopulmonary function. The major sensor of blood oxygen that regulates breathing is the carotid body (CB), a small chemosensory organ located at the carotid bifurcation. When arterial blood oxygen levels drop in hypoxia, neuroendocrine cells in the CB called glomus cells are activated to signal to afferent nerves that project to the brainstem. The mechanism by which hypoxia stimulates CB sensory activity has been the subject of many studies over the last 90 years. Two discrete models emerged that argue for the seat of oxygen sensing to lie either in the plasma membrane or mitochondria of CB cells. Recent studies are bridging the gap between these models by identifying hypoxic signals generated by changes in mitochondrial function in the CB that can be sensed by plasma membrane proteins on glomus cells. The CB is important for physiological adaptation to hypoxia, and its dysfunction contributes to sympathetic hyperactivity in common conditions such as sleep-disordering breathing, chronic heart failure, and insulin resistance. Understanding the basic mechanism of oxygen sensing in the CB could allow us to develop strategies to target this organ for therapy. In this short review, I will describe two historical models of CB oxygen sensing and new findings that are integrating these models.

Relationship between sleep duration and childhood obesity: Systematic review including the potential underlying mechanisms.

The prevalence of obesity is continually increasing worldwide. Determining risk factors for obesity may facilitate effective preventive programs. The present review focuses on sleep duration as a potential risk factor for childhood obesity. The aim is to summarize the evidence on the association of sleep duration and obesity and to discuss the underlying potential physiological and/or pathophysiological mechanisms.

Inhibiting protein tyrosine phosphatase 1B to improve regenerative functions of endothelial cells.

Protein tyrosine phosphatase-1B (PTP1B) is an important negative regulator of insulin receptor- and vascular endothelial growth factor receptor-dependent signalings in endothelial cells. Genetic or pharmacological inhibition of PTP1B has been shown to enhance endothelial cell proliferation and migration, and increase nitric oxide production. In vivo, inhibiting PTP1B can reverse endothelial dysfunction, promote angiogenesis, and accelerate wound healing. Intense research is currently continuing in an effort to discover novel selective PTP1B inhibitors, primarily for treating insulin resistance. We propose that these drugs may also represent a new horizon for boosting the regenerative capacities of endothelial cells.

Changes in Lipids and Inflammatory Markers after Consuming Diets High in Red Meat or Dairy for Four Weeks.

There is a body of evidence linking inflammation, altered lipid metabolism, and insulin resistance. Our previous research found that insulin sensitivity decreased after a four-week diet high in dairy compared to a control diet and to one high in red meat. Our aim was to determine whether a relationship exists between changes in insulin sensitivity and inflammatory biomarkers, or with lipid species. Fasting Tumor Necrosis Factor alpha (TNF-α), Tumor Necrosis Factor Receptor II (sTNF-RII), C-reactive protein (CRP), and lipids were measured at the end of each diet. TNF-α and the ratio TNF-α/sTNF-RII were not different between diets and TNF-α, sTNF-RII, or the ratio TNF-α/sTNF-RII showed no association with homeostasis model assessment-estimated insulin resistance (HOMA-IR). A number of phosphatidylethanolamine (PE) and phosphatidylinositol (PI) species differed between dairy and red meat and dairy and control diets, as did many phosphatidylcholine (PC) species and cholesteryl ester (CE) 14:0, CE15:0, lysophosphatidylcholine (LPC) 14:0, and LPC15:0. None had a significant relationship (p = 0.001 or better) with log homeostasis model assessment-estimated insulin resistance (HOMA-IR), although LPC14:0 had the strongest relationship (p = 0.004) and may be the main mediator of the effect of dairy on insulin sensitivity. LPC14:0 and the whole LPC class were correlated with CRP. The correlations between dietary change and the minor plasma phospholipids PI32:1 and PE32:1 are novel and may reflect significant changes in membrane composition. Inflammatory markers were not altered by changes in protein source while the correlation of LPC with CRP confirms a relationship between changes in lipid profile and inflammation.

Treatment of Diabetic Ketoacidosis Associated With Antipsychotic Medication: Literature Review.

The second-generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation, which may be associated with the use of SGAs. This study aims to review published reports of patients with schizophrenia and antipsychotic drug-associated DKA, focusing on the effective management of both conditions.

Nil Whey Protein Effect on Glycaemic Control after Intense Mixed-Mode Training in T2D.

While intense endurance and resistance exercise training and whey protein supplementation have both been shown to independently improve glycaemic control, no known studies have examined the effect of high-intensity mixed-mode interval training (MMIT) and whey supplementation in adults with Type-2 diabetes (T2D).

Role of Endoplasmic Reticulum-Mitochondria Communication in Type 2 Diabetes.

Although mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and disrupted lipid and calcium (Ca(2+)) homeostasis are classically associated with both insulin resistance and β-cell dysfunction in type 2 diabetes mellitus (T2DM), the interplay between these metabolic stresses is less known. Both organelles interact through contact points known as mitochondria-associated membranes (MAM), in order to exchange both lipids and Ca(2+) and regulate cellular homeostasis. Recent evidences suggest that MAM could be an important hub for hormonal and nutrient signaling in the liver and that ER-mitochondria miscommunication could participate to hepatic insulin resistance, highlighting the importance of MAM in the control of glucose homeostasis. Here, we specifically discuss the role of MAM in hormonal and nutrient-regulated signaling pathways supporting a role in the control of glucose homeostasis and analyze the evidences pointing a role of ER-mitochondria miscommunication in T2DM. Collectively, these data suggest that targeting MAM structure and function might be a novel strategy for the treatment of T2DM.

Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies.

Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.

Spin Trapping: A Review for the Study of Obesity Related Oxidative Stress and Na(+)/K(+)-ATPase.

Reactive oxygen species (ROS) have gained attention with mounting evidence of their importance in cell signaling and various disease states. ROS is produced continuously as a natural by-product of normal oxygen metabolism. However, high levels ROS causes oxidative stress and damage to biomolecules. This results in loss of protein function, DNA cleavage, lipid peroxidation, or ultimately cell injury or death. Obesity has become a worldwide epidemic; studies show fat accumulation is associated with increased ROS and oxidative stress. Evidence exists supporting oxidative stress as a factor driving forward insulin resistance (IR), potentially resulting in diabetes. Na(+)/K(+)-ATPase signaling is also a potential source of ROS promoting oxidative stress. The best way to observe radical species in biological systems is electron paramagnetic resonance spectroscopy with spin trapping. EPR spin trapping is an important technique to study the mechanisms driving disease states attributed to ROS.

Worse inflammatory profile in omnivores than in vegetarians associates with the gut microbiota composition.

To describe the abundance of major phyla and some genera in the gut microbiota of individuals according to dietary habits and examine their associations with inflammatory markers, insulin resistance, and cardiovascular risk profile.

Effects of a liquid high-fat meal on postprandial lipid metabolism in type 2 diabetic patients with abdominal obesity.

Postprandial lipemia and lipoprotein lipase (LPL) activity play crucial roles in the pathogenesis of accelerated atherosclerosis. This study aimed to evaluate the postprandial lipid metabolism after the ingestion of a liquid high-fat meal in type 2 diabetic patients with abdominal obesity, and determine if the PvuII polymorphisms of LPL influence their postprandial lipid responses.

Circulating zinc-α2-glycoprotein levels are low in newly diagnosed patients with metabolic syndrome and correlate with adiponectin.

Zinc-α2-glycoprotein (ZAG) is a novel adipokine that reduces insulin resistance, protecting against type 2 diabetes. However, past studies have been contradictory. This cross-sectional study aims to investigate the association of circulating ZAG with metabolic syndrome (MetS) in middle-aged and older Chinese adults.

Patients with Nonalcoholic Fatty Liver Disease Have a Low Response Rate to Vitamin D Supplementation.

Background: Hypovitaminosis D is associated with an increased severity of nonalcoholic fatty liver disease (NAFLD), but reports on the response to cholecalciferol (vitamin D3) supplementation are conflicting.Objective: The objective of this study was to determine if standard vitamin D3 supplementation is effective in NAFLD with hypovitaminosis D.Methods: Sixty-five well-characterized adults [age (mean ± SD): 51.6 ± 12.3 y] with biopsy-proven NAFLD were screened. Forty-two patients (the ratio of men to women was 13:29) had hypovitaminosis D (plasma 25-hydroxyvitamin D [25(OH)D] <30 ng/mL). An observational study was performed in NAFLD patients with hypovitaminosis D treated with 2000 IU cholecalciferol (vitamin D3) daily for 6 mo per clinical practice. Plasma 25(OH)D, hepatic and metabolic panels, and metabolic syndrome components were assessed before and after cholecalciferol supplementation. Body composition was measured by using bioelectrical impedance analysis. The primary outcome measure was plasma 25(OH)D ≥30 ng/mL at the end of the study. Secondary outcomes included change in serum transaminases, fasting plasma glucose, and insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Chi-square, Student's t tests, correlation coefficient, and multivariate analysis were performed.Results: Twenty-six (61.9%) patients had nonalcoholic steatohepatitis (NASH), and 16 (38.1%) had hepatic steatosis. After 6 mo of cholecalciferol supplementation, plasma 25(OH)D ≥30 ng/mL was observed in 16 subjects (38.1%; responders) whereas the remaining 26 patients (61.9%) were nonresponders with plasma 25(OH)D <30 ng/mL. Significantly fewer (P < 0.01) patients with NASH were responders (4 of 26, 15.4%) than those with hepatic steatosis (12 of 16, 75%). Baseline fasting serum alanine aminotransferase, plasma glucose, and HOMA-IR were similar in the responders and nonresponders, but the NASH score on the liver biopsy was lower (16.5%) in the responders (P < 0.001). Nonresponders had a higher fat mass (10.5%) and lower fat-free mass (10.4%) than responders did. End-of-treatment alanine aminotransferase and HOMA-IR improved only in responders. The baseline HOMA-IR and histological NASH score were independent predictors of nonresponse to cholecalciferol supplementation.Conclusions: Daily supplementation with 2000 IU cholecalciferol for 6 mo did not correct hypovitaminosis D in the majority of patients with NASH. Further studies are needed to determine if higher doses are effective. This trial was registered at clinicaltrials.gov as 13-00153.