Decreased Insulin Sensitivity Research Articles

Sweet dreams or bitter nightmare: a narrative review of 25 years of research on the role of sleep in diabetes and the contributions of behavioural science

The aim of this review was to provide an overview of developments, clinical implications and gaps in knowledge regarding the relationship between diabetes and sleep over the past 25 years, with special focus on contributions from the behavioural sciences. Multiple prospective observational and experimental studies have shown a link between suboptimal sleep and impaired glucose tolerance, decreased insulin sensitivity and the development of type 2 diabetes. While prevalence rates of suboptimal sleep vary widely according to definition, assessment and sample, suboptimal subjective sleep quality appears to be a common reality for one-third of people with type 1 diabetes and over half of people with type 2 diabetes. Both physiological and psychosocial factors may impair sleep in these groups. In turn, suboptimal sleep can negatively affect glycaemic outcomes directly or indirectly via suboptimal daytime functioning (energy, mood, cognition) and self-care behaviours. Technological devices supporting diabetes self-care may have both negative and positive effects. Diabetes and its treatment also affect the sleep of significant others. Research on the merits of interventions aimed at improving sleep for people with diabetes is in its infancy. Diabetes and sleep appear to be reciprocally related. Discussion of sleep deserves a central place in regular diabetes care. Multi-day, multi-method studies may shed more light on the complex relationship between sleep and diabetes at an individual level. Intervention studies are warranted to examine the potential of sleep interventions in improving outcomes for people with diabetes.

Molecular Docking Guided Screening of Phytoconstituents from Artemisia iwayomogi as Potential PPARδ Agonists

Metabolic syndrome is a disease condition characterized by decreased insulin sensitivity, hyperlipidemia, abdominal obesity, hypertension, and myocardial diseases, primarily related to a high-fat diet and lack of physical exercise. Peroxisome proliferator-activated receptor (PPAR) δ stimulation changes the body’s energy fuel preference to fats from sugar. PPARδ is expressed universally in all tissues of the human body, particularly those involving lipid metabolism. PPARδ is an evolving pharmacological target for the pharmacotherapeutics of diseases linked to metabolic syndrome. Artemisia iwayomogi ethanol extract was reported as PPARδ agonist and reduced diet-induced overweight via stimulation of fatty acid oxidation in the skeletal muscles. The present study is designed to evaluate in silico some phytoconstituents, including 4 coumarins, 12 flavonoids, 5 phenolic compounds and 7 caffeoyl-quinic acid derivatives found in A. iwayomogi to explore their binding mode and interactions with the PPARδ protein. A total of 28 compounds evaluated in silico, 16 compounds displayed good binding free energy, and significant docking interactions with the binding site residues of PPARδ protein supporting the in vitro PPARδ agonistic activity of A. iwayomogi extract. Amongst these, scopolin, patuletin, patuletin-3-glucoside, 1,2-bis(4-hydroxy-3-methoxyphenyl)prop-1,3-diol, 3-caffeoylquinic acid, and 1,3-dicaffeoylquinic acid displayed most significant binding interactions with binding site residues of PPARδ. This information can be utilized for developing potent and non-toxic natural PPARδ agonists for the management of disorders related to metabolic syndrome.

12 Effects of excess iron and dietary fat on lipid metabolism

Abstract Diets rich in fat and energy are associated with metabolic syndrome. Imbalanced systemic iron status has long been epidemiologically associated with obesity-related diseases. The aim of this study is to investigate the interaction between dietary fat and injected iron in the context of glucose and lipid metabolism. C57BL6/J mice were divided into four groups and fed normal chow (NC) and high-fat diet (HFD) with adequate or excess iron for 16 weeks. Excess iron was added by intraperitoneal injection with iron dextran (120 mg/g of body weight) every other week from 4th week (NC+Fe and HFD+Fe), six times in total. The results showed that high iron levels decreased the growth rates of mice without affecting their feed intake. High iron levels increased the adipocyte numbers by 1.6-fold in subcutaneous adipose tissue (SAT) and 3.5-fold in visceral adipose tissue (VAT), while excess iron inhibited their adipocyte hypertrophy. These changes were paralleled by alterations in the levels of enzymes related to hepatic lipid storage and β-oxidation. Especially two key enzymes, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) (P < 0.01) and fat specific protein 27 (FSP27) (P < 0.01) were markedly decreased in iron-treated groups compared with their counterparts. In addition, high iron levels decreased insulin sensitivity by increasing 15% of fasting blood glucose and 23% of insulin levels and the average under curve of intraperitoneal glucose tolerance test (IPGTT) was also decreased (P < 0.05). These results were consistent with the decrease of mRNA expression of enzymes related to hepatic gluconeogenesis, phosphoenolpyruvate carboxykinase 1 (PCK1) (P < 0.05) and fructose-1,6-bisphosphatase 1 (FBP1) (P < 0.05) in iron-treated mice. Thus, high-fat diets and iron overload were associated with insulin resistance, modified lipid deposition and iron metabolism. High iron levels could protect mice from high-fat diet induced obesity by decreasing insulin sensitivity.

Metabolic syndrome agravates cardiovascular, oxidative and inflammatory dysfunction during the acute phase of Trypanosoma cruzi infection in mice

We evaluated the influence of metabolic syndrome (MS) on acute Trypanosoma cruzi infection. Obese Swiss mice, 70 days of age, were subjected to intraperitoneal infection with 5 × 102 trypomastigotes of the Y strain. Cardiovascular, oxidative, inflammatory, and metabolic parameters were evaluated in infected and non-infected mice. We observed higher parasitaemia in the infected obese group (IOG) than in the infected control group (ICG) 13 and 15 days post-infection. All IOG animals died by 19 days post-infection (dpi), whereas 87.5% of the ICG survived to 30 days. Increased plasma nitrite levels in adipose tissue and the aorta were observed in the IOG. Higher INF-γ and MCP-1 concentrations and lower IL-10 concentrations were observed in the IOG compared to those in the ICG. Decreased insulin sensitivity was observed in obese animals, which was accentuated after infection. Higher parasitic loads were found in adipose and hepatic tissue, and increases in oxidative stress in cardiac, hepatic, and adipose tissues were characteristics of the IOG group. Thus, MS exacerbates experimental Chagas disease, resulting in greater damage and decreased survival in infected animals, and might be a warning sign that MS can influence other pathologies.

Prevention of Potential Adverse Metabolic Effects of a Supplementation with Omega-3 Fatty Acids Using a Genetic Score Approach

Introduction: The consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) has been reported to have beneficial health effects, notably, by reducing plasma triglyceride levels. Nonetheless, a concomitant decrease in insulin sensitivity has also been observed, but is highly variable among subjects. Herein, we aimed to determine the importance of the genetic background in the interindividual variability of the insulin sensitivity response following an n-3 PUFA supplementation. Methods: A total of 210 participants completed a 6-week n-3 PUFA supplementation with 5 g/day of fish oil (providing 1.9–2.2 g of eicosapentaenoic acid + 1.1 g of docosahexaenoic acid). Insulin resistance was estimated by the homeostatic model assessment (HOMA-IR), and participants were further classified as high-risk or low-risk depending on their HOMA-IR change following the n-3 PUFA supplementation, as compared to pre-supplementation values. Genome-wide genotyping data were obtained for 138 participants using HumanOmni-5-Quad BeadChips containing 4,301,331 single nucleotide polymorphisms. A genome-wide association analysis (GWAS) was carried out between high-risk and low-risk participants. The population study was split into training (60%) and testing (40%) datasets to assess the predictive accuracy of a genetic risk score (GRS) constructed by summing the number of risk alleles. Results: Following the n-3 PUFA supplementation, 32 participants had increased HOMA-IR as compared to initial values and were classified as high risk (23.2%), whereas remaining subjects were classified as low risk (n = 106, 76.8%). A total of 8 loci had frequency differences between high-risk and low-risk participants at a suggestive GWAS association threshold (p value <1 × 10^–5). After applying 10-fold cross validation, the GRS showed a significant association with the risk of increased HOMA-IR in the testing dataset (OR = 3.16 [95% CI, 1.85–7.14]), with a predictive accuracy of 0.85, and explained 40% of variation in HOMA-IR change. Conclusions: These results suggest that the genetic background has a relevant role in the interindividual variability observed in the insulin sensitivity response following an n-3 PUFA supplementation. Subjects being at risk of insulin sensitivity lowering following an n-3 PUFA supplementation may be identified using genetic-based precision nutrition approaches.

Effect of SGLT-2 Inhibitor Therapy on Cardiovascular Health in Diabetes Mellitus Patients

Cardiovascular disease has become a major cause of mortality and morbidity in patients with type 2 diabetes mellitus. The main factors that increase the risk of cardiovascular disease include chronic hyperglycemia, decreased insulin sensitivity, visceral adiposity, and particularly hypertensive comorbidity and increased arterial stiffness. Meanwhile, sodium-glucose co-transporter-2 inhibitors, a new category in diabetes therapy are known to reduce blood glucose in patients by increasing glycosuria through inhibition of urinary glucose reabsorption. The therapy also produces glucose-induced osmotic diuresis, weight loss, and lowered blood pressure. The aim of this literature review is to determine the effect of sodium-glucose co-transporter-2 inhibitors on cardiovascular health in diabetes mellitus patients. This study is a literature review involving 20 literature sources from 3 national journals and 17 international journals with the keywords used include diabetes mellitus, cardiovascular and SGLT-2 inhibitors. Several studies have significantly demonstrated the effect of SGLT-2 inhibitors on cardiovascular health, as seen by a reduction in mortality and hospitalization of heart failure, better blood pressure and renal outcome, improved heart function in diabetic cardiomyopathy and myocardial ischemia.

EFFECT OF TLR4 INHIBITION IN FAT-INDUCED INSULIN RESISTANCE IN HUMAN SUBJECTS

Older and obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+placebo (12 mg every 12 h); Intralipid (30 ml/h)+placebo; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+placebo and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen with aging and obesity.

Anti-Aging Effects of Schisandrae chinensis Fructus Extract: Improvement of Insulin Sensitivity and Muscle Function in Aged Mice.

Schisandrae chinensis Fructus has a long history of medicinal use as a tonic, a sedative, and an antitussive drug. In this study, we investigated the beneficial effects of Schisandrae chinensis Fructus ethanol extract (SFe) on metabolism in an aged mouse model. Sixteen-month-old C57BL/6J mice were fed with a diet supplemented with SFe for 4 months. Insulin sensitivity was lower at 20 months of age than at 16 months of age; however, the decrease in insulin sensitivity was less in SFe-fed mice. SFe supplementation also appeared to improve glucose tolerance. Body weight gain was lower in SFe-fed mice than in mice fed the control diet. Body fat mass was lower and the lean mass was higher in SFe-fed mice. In addition, the grip strength was enhanced in SFe-fed mice. Histological analysis of the tibialis anterior muscle showed that the size of myofiber and slow-twitch red muscle was increased by SFe supplementation. The expression of proteins related to muscle protein synthesis such as phospho-Erk1 and phospho-S6K1 was increased by SFe supplementation. The mRNA expression of genes related to myogenesis and their encoded proteins such as MyoD, Myf5, MRF4, myogenin, and myosin heavy chain, was increased, whereas that of genes related to muscle degradation, such as atrogin-1, MuRF-1, and myostatin, were decreased relative to control mice. These results suggest that SFe supplementation might have beneficial effects for the improvement of insulin sensitivity and inhibition of muscle loss that occur with aging.

Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis.

Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or 'lipokine') to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans. Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic-euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance. Circulating palmitoleate was proportional to fat mass (r = 0.21, p < 0.0001) and total NEFA levels (r = 0.19, p < 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. β] = 0.16, p < 0.0001), liver insulin resistance (std. β = -0.14, p < 0.0001), beta cell function (potentiation: std. β = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. β = -0.24, p < 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. β = 0.07, p = 0.04). We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism.

CHANGES IN LIPIDS IN PATIENTS WITH ALCOHOLIC CIRRHOSIS OF THE LIVER ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE DEPENDING ON THE STAGE OF DECOMPENSATION

Abstract. With the global growth of obesity, fatty liver, which is characteristic to alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), becomes one of the most common among hepatic pathological changes throughout the world. Both ALD and NAFLD are associated with a lipid metabolism disorder. There are three main sources of excessive accumulation of lipids in the liver: increased lipolysis of visceral adipose tissue, accompanied by excessive intake of free fatty acids (FFA) from adipose tissue (59%), activation of de novo liver lipogenesis (26%) and high calorie and/or fat content in the diet (15%). Excessive input of FFA in adipose tissue leads to “overloading” of fat cells that are no longer able to contain such an amount of FFA and the accumulation of fat in other tissues of the body that is not adapted for such function – in the liver, pancreas, muscles, etc. Such ectopia and large amount of FFA in the body result in a decrease in insulin sensitivity and the development of lipotoxicity. The consequence of these processes is a disorder of the synthesis of adipokines.&#x0D; The purpose of the research was to study the changes of lipids in patients with alcoholic liver cirrhosis (ALC) associated with NAFLD depending on the stage of decompensation. The study included 204 patients. Among them, 78 patients (Gr. I) had ALC and 126 patients (Gr. II) had a combination of ALC with NAFLD. Patients were subgrouped according to compensation classes by the Child-Pugh score (A, B, C). Diagnosis was verified using clinical and laboratory-instrumental methods in accordance with the order of the Ministry of Health of Ukraine No. 826 dated November 6, 2014, adapted clinical guidelines "Non-Alcoholic Fatty Liver Disease", 2014, adapted clinical guidelines "Alcoholic Liver Disease", 2014, adapted clinical guidelines " Liver Cirrhosis, 2017 (State Expert Centre of the Ministry of Health of Ukraine, Ukrainian Gastroenterology Association, Kyiv), recommendations of the European Association for the Study of Liver, Diabetes and Obesity (EASL-EASD-EASO, 2016).&#x0D; Higher levels of total cholesterol, lipoprotein cholesterol of low and very low density, atherogenic coefficient and triacylglycerides were in patients of classes A and B. Patients of group II had higher rates than those in group I (p&lt;0.05). The content of lipoprotein cholesterol of high density in patients of group II was significantly lower in comparison with patients in group I (p&lt;0.05). With the progression of the liver cirrhosis the level of leptin decreased, while the levels of adiponectin increased. The higher content of leptin in patients of classes A and B is accompanied not only by the impaired liver function, but also by its increased release from adipose tissue. In patients of class C fat depot is exhausted, therefore the level of leptin decreases. Moreover, this decrease correlates with the severity of the disease and the prognostic MELD score. The level of adiponectin was lowered in class A patients and increased in patients with more severe course and correlated with severity of the disease and MELD score. The revealed correlation between the levels of leptin and adiponectin with the degree of severity of the liver cirrhosis and the prognostic MELD score allows considering their changes for assessment of the severity of the liver cirrhosis and predicting the course of the disease.&#x0D; &#x0D; Keywords: alcoholic liver disease; non-alcoholic fatty liver disease; cirrhosis; leptin; adiponectin.

Prolonged plasma glucose elevation on oral glucose tolerance test in young healthy Japanese individuals.

AimsThis study aims to assess insulin secretion and resistance through oral glucose tolerance test (OGTT) among young Japanese individuals.Subjects and methodsWe enrolled 595 young healthy Japanese individuals aged 22‐29 years. They underwent an OGTT, and their results were divided into 4 groups (I‐IV), according to the time at which their plasma glucose concentration declined below the fasting glucose concentration (30, 60 or 120 minutes or never as groups I, II, III and IV, respectively).ResultsWe classified 575 normal glucose‐tolerant subjects into 4 groups (I‐IV) with I: 28 (4.9%), II: 120 (20.9%), III: 143 (24.9%) and IV: 284 (49.4%) individuals. The Matsuda, insulinogenic and disposition indices were decreased from groups I to IV. ROC curves of disposition index reflecting the composition of insulin secretion and sensitivity classified the prolonged glucose elevation group (group III + IV) from the rapid glucose lowering group (group II; AUC = 0.847).ConclusionsEven in a young and healthy Japanese individual within the physiological range of glycaemic control, there is a sequential decrease in insulin sensitivity and secretion.

Impact of lifestyle modifications on obesity and biochemical parameters at different time intervals in newly diagnosed patients with type 2 diabetes mellitus – A randomized controlled trial

Impact of lifestyle modifications on obesity and biochemical parameters at different time intervals in newly diagnosed patients with type 2 diabetes mellitus – A randomized controlled trial - IJCAP- Print ISSN No: - 2394-2118 Online ISSN No:- 2394-2126 Article DOI No:- 10.18231/j.ijcap.2019.062, Indian Journal of Cli

The saturated fatty acid palmitate induces insulin resistance through Smad3-mediated down-regulation of FNDC5 in myotubes

Elevated plasma free fatty acid (FFA) levels are associated with insulin resistance and can cause lipotoxicity in skeletal muscles. In response to FFAs, skeletal muscle can secrete a variety of cytokines. Irisin, one such muscle-secreted cytokine, can improve glucose tolerance, glucose uptake, and lipid metabolism. It is produced by the transmembrane protein fibronectin type Ⅲ domain containing 5 (FNDC5) by specific proteases. The purpose of this study was to investigate the regulatory mechanisms of the FNDC5 response to palmitate and their relationships with insulin resistance in C2C12 myotubes. RNA sequencing analysis results from C2C12 myotubes treated with palmitate showed that palmitate could activate the TGF-β signaling pathway. Palmitate directly affected the expression of Smad3, but not its phosphorylation level, in C2C12 myotubes. Furthermore, knockdown and knockout of Smad3 alleviated the inhibitory effect of palmitate on the expression of FNDC5. In contrast, overexpression of Smad3 aggravated the inhibition of FNDC5 expression. There is a Smad3 binding motif in the −660 bp to −649 bp region of the Fndc5 promoter. CRISPR/Cas9 knockout of this region also alleviated the inhibition of FNDC5 expression in response to palmitate. More importantly, inhibition of FNDC5 expression mediated by Smad3 led to a decrease in insulin sensitivity in C2C12 myotubes. Collectively, these findings suggest that palmitate could induce insulin resistance through Smad3-mediated down-regulation of the Fndc5 gene.

Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation.

Chromogranin A (CgA)—the index member of the chromogranin/secretogranin secretory protein family—is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA‐related polypeptides, consisting of full‐length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full‐length CgA and various CgA‐derived peptides, including vasostatin‐1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N‐terminal fragment of vasostatin‐1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C‐terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full‐length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.

Development of Insulin Resistance after Prolonged Exposure to Glucocorticoid Hormones as One of the Mechanisms of Transformation of Their Gastroprotective Effect into a Proulcerogenic Action

This work continues our studies of the mechanisms of transformation of the initial gastroprotective action of glucocorticoid hormones into a proulcerogenic action. Experiments on rats tested the suggestion that the development of insulin resistance after prolonged exposure to glucocorticoid hormones may be one of the mechanisms of this transformation. This was addressed by studying the effects of dexamethasone, corticosterone, and hydrocortisone on insulin sensitivity at different time points after single doses of pharmacological size. Insulin sensitivity was evaluated in terms of the decrease in the blood glucose level 1.5 h after administration of insulin (2 IU/kg, i.p.). Decreases in glucose levels were expressed as percentages of baseline (pre-insulin) glucose levels. The results indicated that at those time points at which these hormone had previously been found to have gastroprotective actions, insulin sensitivity remained unaltered from that in control animals. Administration of dexamethasone and hydrocortisone after prolonged exposure led to decreases in insulin sensitivity at those time points at which their proulcerogenic effects had been seen. Increases in the duration of exposure to corticosterone did not produce any changes in insulin sensitivity or transformation of its gastroprotective effect into a proulcerogenic action. These data support the suggestion that the development of insulin resistance after prolonged exposure to glucocorticoid hormones can be regarded as one of the mechanisms of the transformation of their gastroprotective effects into proulcerogenic actions.

Current Opinion on Usage of L-Carnitine in End-Stage Renal Disease Patients on Peritoneal Dialysis.

The advantages of peritoneal dialysis (PD) over hemodialysis (HD) are well-documented. Notwithstanding, only a small proportion of patients with end-stage renal disease (ESRD) are managed with PD. This may be related to the high glucose load that PD solutions in current use have on the patient. The effects of such excess glucose include the relatively early limitation of the ultrafiltration capacity of the peritoneal membrane, and the metabolic effects associated with hyperglycemia, e.g., decreased insulin sensitivity. This article describes the advantages that may be realized by the glucose-sparing effects of substituting part of the glucose load with other osmotically active metabolites, particularly L-carnitine. The latter is anticipated to have metabolic advantages of its own, especially as in PD patients, high plasma concentrations can be achieved in the absence of renal clearance. Besides its better biocompatibility, L-carnitine demonstrates anti-anemia action due to its effects on erythropoiesis, and positive effects on the longevity and deformability of erythrocytes. Observations from our trials on the use of carnitine-enriched PD solutions have demonstrated the effectiveness of L-carnitine as an efficient osmolyte in PD, and its favorable effect on the insulin sensitivity of the patients. The significance of these findings for future developments in the use of PD in the management of patients with ESRD is discussed.

Mice lacking angiotensin type 2 receptor exhibit a sex-specific attenuation of insulin sensitivity

The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.

Macroprolactinaemia modulates cardiometabolic effects of fenofibrate in men with atherogenic dyslipidaemia: A pilot study.

Cardiometabolic effects of hypolipidaemic agents depend on plasma levels of monomeric prolactin. Although macroprolactinaemia seems to be associated with increased cardiometabolic risk, no previous study has investigated whether macroprolactinaemia modulates pleiotropic effects of hypolipidaemic agents. The study population included two age-, weight-, blood pressure- and lipid-matched groups of men: 12 men with elevated levels of big-big prolactin and 16 men with prolactin levels within the reference range. Because of atherogenic dyslipidaemia, all subjects were treated for 6months with fenofibrate (200mg daily). Glucose homeostasis markers and plasma lipids, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine and 25-hydroxyvitamin D, were determined in patients at the beginning and at the end of the study. Men with elevated levels of big-big prolactin were characterized by higher levels of hsCRP and fibrinogen and lower levels of 25-hydroxyvitamin D as well as decreased insulin sensitivity than subjects with prolactin levels within the reference range. In men without macroprolactinaemia, fenofibrate decreased circulating levels of total and LDL cholesterol, triglycerides, uric acid, hsCRP and fibrinogen, and increased concentrations of HDL cholesterol, homocysteine and 25-hydroxyvitamin D, as well as improved insulin sensitivity. In subjects with macroprolactinaemia, fenofibrate action was limited to the changes in HDL cholesterol, triglycerides, hsCRP and homocysteine. With the exception of homocysteine, cardiometabolic effects of fenofibrate were stronger in subjects without than in subjects with elevated levels of big-big prolactin. The results of the study indicate that macroprolactinaemia exerts a negative impact on cardiometabolic effects of fenofibrate.

Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement.

Decreased insulin sensitivity in patients with hypopituitarism without GH replacement (pHP-WGHR) remains conflicting in literature. It is known that these patients present a decrease in free fat mass and an increase in fat mass. Typically, these kinds of alterations in body composition are associated with a decrease in insulin sensitivity; however, there is no consensus if this association is found in pHP-WGHR. Thus, we investigated pHP-WGHR regarding insulin sensitivity by euglycemic hyperinsulinemic clamp, the gold standard method, and body composition. In a cross-sectional study, we evaluated 15 pHP-WGHR followed up in a Service of Neuroendocrinology and 15 individuals with normal pituitary function as a control group with similar age, gender and body mass index. Insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp and homeostatic model assessment insulin resistance (HOMA-IR). Kappa coefficient evaluated the agreement between these two methods. Percentage of fat mass, percentage of free fat mass, fat mass weight and free fat mass weight were assessed by electrical bioimpedance. The pHP-WGHR presented similar insulin sensitivity to control group by euglycemic hyperinsulinemic clamp, both by the M-value, (p = 0.0913) and by the area under the glucose infusion rate curve, (p = 0.0628). These patients showed lower levels of fasting glycemia (p = 0.0128), insulin (p = 0.0007), HOMA-IR (p = 0.009). HOMA-IR shows poor concordance with euglycemic hyperinsulinemic clamp (Kappa = 0.16) in pHP-WGHR, while in the control group the agreement was good (Kappa = 0.53). The pHP-WGHR presented higher values of percentage of fat mass (p = 0.0381) and lower values of percentage of free fat mass (p = 0.0464) and free fat mass weight (0.0421) than the control group. This study demonstrated that the insulin sensitivity evaluated by euglycemic hyperinsulinemic clamp in pHP-WGHR was similar to individuals with normal pituitary function, despite the pHP-WGHR presenting higher fat mass percentage. HOMA-IR was not a good method for assessing insulin sensitivity in pHP-WGHR.

Increased body fat and reduced insulin sensitivity are associated with impaired endothelial function and subendocardial viability in healthy, non-Hispanic white adolescents.

Cardiovascular disease has its origins in adolescents. Endothelial dysfunction, arterial stiffness, and decreased endocardial oxygen supply: demand ratios are early functional markers of cardiovascular risk. The goal of this study was to determine the relationships of these markers to physical, inflammatory, and metabolic markers in healthy non-Hispanic, white adolescents. Thirty-four of the 75 subjects were female. Mean age was 15.0 ± 1.7 years and mean body mass index (BMI) was 22.0 ± 5.8 kg/m2 (mean ± SD). Reactive hyperemia was measured using venous occlusion plethysmography. Arterial tonometry was used to measure the augmentation index (AIx75 ) and the Buckberg subendocardial viability ratio. Blood samples were taken to measure inflammatory and lipid markers and oral glucose tolerance test was used to assess insulin sensitivity. Reactive hyperemia decreased as body mass and fat mass increased. It also decreased with increasing neutrophil count. The Buckberg index was higher in males and was positively related to insulin sensitivity even when accounting for age, sex, and resting heart rate. AIx75 was not related to any of the other variables. These results demonstrate that increased fat mass and decreased insulin sensitivity are related to poorer vascular function and cardiac risk in adolescents before the development of actual cardiovascular disease.