Insulin replacement prevents the acquisition but not the expression of morphine-induced conditioned place preference in streptozotocin-induced diabetic rats

Abstract Insulin receptors have distributed in all brain regions, including the nucleus Accumbens (NAc), and where is implicated in the reward properties of drugs. It is well known that insulin signaling can regulate dopamine release. Therefore, in the present study, we tried to examine the effect of insulin replacement on the acquisition and expression of morphine-induced conditioned place preference (CPP) in diabetic rats. Forty-eight male Wistar rats were divided into two non-diabetic (Naïve) and diabetic groups rendered by a single injection of streptozotocin (STZ). These groups separately received insulin (10U/kg) or saline (1 ml/kg) one hour prior to morphine administration (5mg/kg;s.c.) during conditioning days (acquisition phase) or post-conditioning day (expression phase) in the CPP paradigm. In this paradigm, conditioning score (CS) and locomotion activity were recorded by Ethovision. The STZ-induced diabetic rats displayed higher CS compared to naïve rats (P<0.05). This effect was abolished in all diabetic rats that received insulin during conditioning days but not the expression phase. This study has provided evidence that insulin plays a modulatory role in morphine-induced CPP, and insulin replacement during the acquisition phase could reduce the rewarding properties of morphine in diabetes conditions through a possible modulating effect on dopamine release in the NAc region

CD36 gene deletion reduces muscle insulin sensitivity in mice by up-regulating PTP1B expression / 南方医科大学学报

OBJECTIVE@#To investigate the effect CD36 deficiency on muscle insulin signaling in mice fed a normal-fat diet and explore the possible mechanism.@*METHODS@#Wild-type (WT) mice and systemic CD36 knockout (CD36-/-) mice with normal feeding for 14 weeks (n=12) were subjected to insulin tolerance test (ITT) after intraperitoneal injection with insulin (1 U/kg). Real-time PCR was used to detect the mRNA expressions of insulin receptor (IR), insulin receptor substrate 1/2 (IRS1/2) and protein tyrosine phosphatase 1B (PTP1B), and Western blotting was performed to detect the protein expressions of AKT, IR, IRS1/2 and PTP1B in the muscle tissues of the mice. Tyrosine phosphorylation of IR and IRS1 and histone acetylation of PTP1B promoter in muscle tissues were detected using co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP), respectively.@*RESULTS@#CD36-/- mice showed significantly lowered insulin sensitivity with obviously decreased area under the insulin tolerance curve in comparison with the WT mice (P < 0.05). CD36-/- mice also had significantly higher serum insulin concentration and HOMA-IR than WT mice (P < 0.05). Western blotting showed that the p-AKT/AKT ratio in the muscle tissues was significantly decreased in CD36-/- mice as compared with the WT mice (P < 0.01). No significant differences were found in mRNA and protein levels of IR, IRS1 and IRS2 in the muscle tissues between WT and CD36-/- mice (P>0.05). In the muscle tissue of CD36-/- mice, tyrosine phosphorylation levels of IR and IRS1 were significantly decreased (P < 0.05), and the mRNA and protein levels of PTP1B (P < 0.05) and histone acetylation level of PTP1B promoters (P < 0.01) were significantly increased as compared with those in the WT mice. Intraperitoneal injection of claramine, a PTP1B inhibitor, effectively improved the impairment of insulin sensitivity in CD36-/- mice.@*CONCLUSION@#CD36 is essential for maintaining muscle insulin sensitivity under physiological conditions, and CD36 gene deletion in mice causes impaired insulin sensitivity by up-regulating muscle PTP1B expression, which results in detyrosine phosphorylation of IR and IRS1.

Type B insulin resistance syndrome: a systematic review

ABSTRACT A literature review on the clinical, laboratory, and treatment features of type B insulin resistance syndrome (TBIRS). Data from PubMed, the Virtual Health Library and Cochrane database were selected and analyzed using the REDCap application and R statistical program. From 182 papers, 65 were selected, which assessed 119 clinical cases, 76.5% in females and 42.9% in African-Americans, with an average age of 44 years. A common feature of TBIRS is co-occurrence of autoimmune diseases, such as systemic lupus erythematosus (most frequently reported). Hyperglycemia of difficult control was the mostly reported condition. Tests for anti-insulin receptor antibodies were positive in 44.2% of the cases. Disease management comprised fractional diet, insulin therapy (maximum dose given was 57 600 IU/day), plasmapheresis and immunosuppression with several classes of drugs, mainly glucocorticoids. Remission occurred in 69.7% of cases, in 30.3% of these spontaneously. The mortality rate was 15.38%. There was an inverse relationship between anti-insulin antibodies and remission (p = 0.033); and a positive correlation between combined immunosuppressive therapy and remission (p = 0.002). Relapse occurred in 7.6% of the cases. This rare syndrome has difficult-to-control diabetes, even with high doses of insulin, and it is usually associated with autoimmune diseases. Therapeutic advances using immunomodulatory therapy have led to significant improvements in the rate of remission.

Insulina e polimorfismos do gene do receptor de insulina e a suscetibilidade à doença hepática gordurosa não alcoólica / Insulin and insulin receptor gene polymorphisms and susceptibility to nonalcoholic fatty liver disease

ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. OBJECTIVE: Given the pivotal role of insulin resistance in NAFLD, we hypothesized that insulin (INS) and insulin receptor (INSR) gene polymorphisms may be associated with NAFLD risk. METHODS: A total of 312 subjects, including 153 cases with biopsy-proven NAFLD and 159 controls were enrolled in this case-control study. Four polymorphisms in INS (rs3842752, rs689) and INSR (rs1052371, rs1799817) genes were genotyped using PCR-RFLP method. RESULTS: The cases with NAFLD were older and had higher BMI, systolic blood pressure, diastolic blood pressure, as well as higher serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase than the controls (P<0.001). The "TT" genotype of INSR rs1799817 compared with "CC" genotype occurred more frequently in the controls than the cases with NAFLD and the difference remained significant after adjustment for confounding factors (P=0.018; OR=0.10, 95%CI=0.02-0.76). However, no significant difference was found for INS rs3842752, INS rs689, and INSR rs1052371 gene polymorphisms between the cases with NAFLD and the controls either before or after adjustment for the confounders. CONCLUSION: These findings corroborate the hypothesis that genetic polymorphisms related to insulin resistance play a role in NAFLD susceptibility. Specifically, the INSR rs1799817 "TT" genotype had a protective effect for NAFLD. However, our results remain to be validated in other studies.

RESUMO CONTEXTO: A doença hepática gordurosa não alcoólica (NAFLD) é uma preocupação global crescente da saúde definida pelo excesso de teor de gordura hepática na ausência de consumo excessivo de álcool. OBJETIVO: Dado o papel crucial da resistência à insulina no NAFLD, criou-se a hipótese de que os polimorfismos genéticos da insulina (INS) e do receptor de insulina (INSR) podem estar associados ao risco de NAFLD. MÉTODOS: Um total de 312 indivíduos, incluindo 153 casos com NAFLD comprovado por biópsia e 159 controles foram inscritos neste estudo de caso-controle. Quatro polimorfismos em genes INS (rs3842752, rs689) e INSR (rs1052371, rs1799817) foram genotipados utilizando o método PCR-RFLP. RESULTADOS: Os casos com NAFLD foram mais idosos e apresentaram maior IMC, pressão arterial sistólica, pressão arterial diastólica, bem como níveis séricos mais elevados de aspartato aminotransferase, de alanina aminotransferase e de gama glutamil transpeptidase do que os controles (P<0,001). O genótipo "TT" de INSR rs1799817 em comparação com o genótipo "CC" ocorreu com mais frequência nos controles do que os casos com NAFLD e a diferença permaneceu significativa após ajuste para fatores de confusão (P=0,018; OR=0,10, IC95%=0,02-0,76). No entanto, não foi encontrada diferença significativa para INS rs3842752, INS rs689 e INSR rs1052371 polimorfismos genéticos entre os casos com NAFLD e os controles antes ou depois do ajuste para os fatores de confusão. CONCLUSÃO: Esses achados corroboram a hipótese de que os polimorfismos genéticos relacionados à resistência à insulina desempenham um papel na suscetibilidade do NAFLD. Especificamente, o genótipo INSR rs1799817 "TT" teve um efeito protetor para o NAFLD. No entanto, nossos resultados necessitam ser validados em outros estudos.

Expression of tumor-associated vascular insulin receptor in colorectal cancer and its relationship with tumor pathological features / 浙江大学学报·医学版

OBJECTIVE@#To study the expression of tumor associated vascular insulin receptor (TVIR) in colorectal cancer with or without metabolic syndrome (MS) and its relationship with the pathological features of colorectal cancer.@*METHODS@#The expression of TVIR in 220 colorectal cancer specimens was detected by tissue microarray and immunohistochemistry. The relationships between the expression of TVIR and the pathological features (pathological subtypes, histological grade, invasion depth, lymph node metastasis and TNM stage) of colorectal cancer with/without MS were analyzed.@*RESULTS@#The insulin receptor expression was observed in colorectal cancer tissue or border area between cancer and normal tissue, but not in normal intestinal tissue. The high-expression rates of TVIR in MS group was remarkably lower than that of non-MS group (21.6%vs. 41.0%, @*CONCLUSIONS@#s: High-expression of TVIR is associated with aggressive pathological features such as invasion, lymph node metastasis and high TNM stage of colorectal cancer, especially for those patients without MS. TVIR could be a useful biological marker for prognosis of colorectal cancer.

Soluble insulin receptor and metabolic syndrome

The metabolic syndrome describes a group of signs that increase the likelihood for developing type 2 diabetes mellitus, cardiovascular diseases and some types of cancer. The action of insulin depends on its binding to membrane receptors on its target cells. We wonder if blood insulin could travel bound to proteins and if, in the presence of hyperinsulinemia, a soluble insulin receptor might be generated. We used young adult Wistar rats (which have no predisposition to obesity or diabetes), whose drinking water was added 20 % of sugar and that were fed a standard diet ad libitum for two and six months. They were compared with control rats under the same conditions, but that had running water for consumption. At two months, the rats developed central obesity, moderate hypertension, high triglyceride levels, hyperinsulinemia, glucose intolerance and insulin resistance, i.e., metabolic syndrome. Electrophoresis of the rats’ plasma proteins was performed, followed by Western Blot (WB) for insulin and for the outer portion of the insulin receptor. The bands corresponding to insulin and to the receptor external part were at the same molecular weight level, 25-fold higher than that of free insulin. We demonstrated that insulin, both in control animals and in those with hyperinsulinemia, travels bound to the receptor outer portion (ectodomain), which we called soluble insulin receptor, and that is released al higher amounts in response to plasma insulin increase; in rats with metabolic syndrome and hyperinsulinemia, plasma levels are much higher than in controls. Soluble insulin receptor increase in blood might be an early sign of metabolic syndrome.

Effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice / 中国应用生理学杂志

OBJECTIVE@#To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application.@*METHODS@#Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR.@*RESULTS@#Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P＜0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P＜0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P＜0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P＜0.05) in DM + H group (P＜0.05).@*CONCLUSION@#Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.

Telmisartan increases hepatic glucose production via protein kinase C ζ-dependent insulin receptor substrate-1 phosphorylation in HepG2 cells and mouse liver / 영남의대학술지

BACKGROUND: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice.METHODS: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase α (G6Pase-α), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ζ (PKCζ) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice.RESULTS: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a 40 μM concentration without a change in G6Pase-α expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 (p-IRS-1-Ser302) and decreased p-IRS-1-Tyr632 dose-dependently. Telmisartan dose-dependently increased p-PKCζ-Thr410 which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative PKCζ significantly attenuated telmisartan-induced HGP and p-IRS-1-Ser302 and -inhibited p-IRS-1-Tyr632. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased p-IRS-1-Ser302 and decreased p-IRS-1-Tyr632, which was accompanied by an increase in p-PKCζ-Thr410.CONCLUSION: These results suggest that telmisartan increases HGP by inducing p-PKCζ-Thr410 that increases p-IRS-1-Ser302 and decreases p-IRS-1-Tyr632 in a PPARγ-independent manner.

El esqueleto como órgano endocrino: funciones metabólicas de la osteocalcina / The skeleton as an endocrine organ: metabolic functions of osteocalcin

El esqueleto es uno de los sistemas más grandes de un vertebrado y, como tal, es razonable especular que no puede funcionar aislado del resto del organismo. De hecho, sabemos que existen sistemas complejos de regulación cruzada entre el esqueleto y muchos otros órganos. Hoy poseemos herramientas que nos permiten realizar supresión genética en células o tejidos específicos. Esto nos ha permitido comprender cómo los órganos se comunican entre sí y ha revitalizado el concepto de fisiología del organismo como un todo. Efectivamente, los últimos años han sido testigos del descubrimiento de funciones inesperadas que ejerce el esqueleto y que afectan al organismo en su totalidad. Una de tales funciones reconocidas recientemente es el control del metabolismo energético, a través de la secreción de osteocalcina. La osteocalcina es una hormona producida por los osteoblastos que regula la secreción de insulina, la sensibilidad a esta hormona y el metabolismo energético. Los hallazgos iniciales suscitaron varias preguntas fundamentales sobre la naturaleza de la acción de la insulina sobre el hueso. Pero esto solo fue la punta del iceberg. Efectivamente, más adelante se descubrió, mediante el análisis de ratones que carecen del receptor de insulina (Ins R) solamente en osteoblastos, que la acción de la insulina sobre estas células favorecía la homeostasis de la glucosa en todo el cuerpo. Es importante destacar que esta función de la insulina en los osteoblastos opera mediante la regulación negativa de la carboxilación y la biodisponibilidad de la osteocalcina. Más aún, se observó que las vías de señalización de la insulina en los osteoblastos regulan positivamente no solo la formación sino también la resorción del hueso. Curiosamente, parece que las vías de señalización de la insulina en osteoblastos pueden inducir la activación de la osteocalcina mediante la estimulación de la actividad de los osteoclastos. De hecho, el bajo pH generado durante la resorción ósea es suficiente para desencadenar la descarboxilación (y subsiguiente activación) de la osteocalcina. En breve discutiremos dos nuevas proposiciones: 1) los osteoblastos son un blanco utilizado por la insulina para controlar la homeostasis de la glucosa en todo el organismo y 2) la resorción ósea desempeña un papel fundamental en la regulación de la activación de la osteocalcina. (AU)

The skeleton is one of the biggest systems in a vertebrate animal and, as such, it is reasonable to speculate that it cannot function isolated from the rest of the organism. In fact, we know that complex systems exist for the cross-regulation between the skeleton and several other organs. Today, we have the tools that allow us to perform genetic suppression in specific cells or tissues. This has allow us understand the mechanisms by which the organs communicate with each other and has revitalized the concept of organismal physiology as a whole. Studies conducted in recent years have uncovered unexpected functions performed by the skeleton. One of these is the control of global energy metabolism, through the secretion of osteocalcin, a protein produced by osteoblasts that acts as a hormone regulating insulin secretion, insulin sensitivity and energy expenditure. The evidence comes from the analysis of mice lacking insulin receptor (InsR) exclusively in osteoblasts. These mice have a global metabolic phenotype demonstrating that the action of insulin in osteoblasts promotes the homeostasis of glucose throughout the body. This action of insulin in osteoblasts is mediated by the negative regulation of the carboxylation (and bioavailability) of osteocalcin. The decarboxylation (and activation) of osteocalcin, in turn, occurs in the osteoclastic resorption pit. Briefly: the osteoblast is a target used by insulin to control the homeostasis of glucose throughout the body and bone resorption is the mechanism that regulates the activation of osteocalcin. (AU)

Association between Polymorphisms of Insulin and Insulin Receptor Gene with Childhood Obesity in Malay Population / Jurnal Sains Kesihatan Malaysia

Childhood obesity is a global epidemic, which leads to the increasing number of studies on genetic locations associated with obesity-related traits. Polymorphisms of insulin (INS) gene have been shown to be associated with obesity-related phenotypes in Europeans; while insulin receptor (INSR) gene has been associated with energy regulation. Therefore, this study was conducted to investigate the association between the INS (rs689) and INSR (rs3745551) gene polymorphisms with childhood obesity risk in a Malay childhood population. Normal weight (538) and overweight or obese (557) children aged 6-12 years old were genotyped using semi-automated Sequenom iPLEX® Gold. Body mass index (BMI) was calculated from measured body weight and height. The rs689 (T/T: 0.006, A/T: 0.159 and A/A: 0.835) and rs3745551 (G/G: 0.054, A/G: 0.378 and A/A: 0.568) genotype distributions were consistent with Hardy Weinberg equilibrium. The T-minor allele frequency for rs689 was 8.6% and G-minor allele frequency for rs3745551 was 24.3%. Minor allele of INS gene polymorphisms significantly increased risk of obesity among Malay children (sex- and age-adjusted OR=1.580; 95%CI: 1.134-2.201). However, INSR gene polymorphisms were not significantly associated with childhood obesity. In conclusion, the polymorphisms of INS gene, rather than INSR gene, were associated with childhood obesity in the Malay population.

Correlation of Glypican-4 Level with Basal Active Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes Mellitus

BACKGROUND: Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. METHODS: Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level. RESULTS: The subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors. CONCLUSION: GPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels.

Resistencia a la insulina en la mujer: ¿cómo y cuándo evaluarla? / Insulin resistance wing women: how and when evaluated?

La obesidad resulta de un desequilibrio entre la ingesta de alimentos y el gasto energético, lo que conduce a una acumulación excesiva de tejido adiposo. El aumento del tejido adiposo principalmente visceral, se ha relacionado con alteración de factores proinflamatorios y antinflamatorios, que junto a los ácidos grasos libres producto de la lipólisis, parecen estar involucrados en el desarrollo de la resistencia a la insulina. La resistencia a la insulina es muy frecuente en pacientes con síndrome de ovario poliquístico. Aunque la causa exacta del síndrome de ovario poliquístico es aún desconocida, una de las hipótesis más aceptadas en su fisiopatología es la resistencia a la insulina e hiperinsulinemia. Se plantea que la obesidad, resistencia a la insulina e hiperinsulinismo están estrechamente relacionadas y cada una de estas patologías afecta a la otra. La resistencia a la insulina contribuye a la fisiopatología de la diabetes mellitus tipo 2 (DM2) y es un marcador de la obesidad, el síndrome metabólico, y las principales enfermedades cardiovasculares. Por tanto, la cuantificación de la resistencia a la insulina es de gran importancia. Se utilizan varios métodos para evaluar la resistencia a la insulina, algunos se basan en el análisis de la glucosa e insulina en condiciones de ayuno, mientras que otros se basan en pruebas dinámicas. Cada uno de estos métodos tiene sus ventajas y limitaciones. Por lo tanto, la elección óptima y el empleo de un método específico dependen de la naturaleza del estudio que se realiza. Métodos directos establecidos para medir la sensibilidad a la insulina in vivo son relativamente complejos. Se necesita la elaboración de un marcador universal en el diagnóstico de resistencia a la insulina que se pueda aplicar en entornos clínicos y ambulatorios. Actualmente, la determinación de insulina plasmática y estimación de resistencia a la insulina no son requeridas en la práctica clínica diaria.

Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. The increase mainly visceral adipose tissue, has been associated with impaired pro-inflammatory and anti-inflammatory factors, together with the free fatty acid product of lipolysis, appear to be responsible for the development of insulin resistance. The insulin resistance is very common in patients with Polycystic Ovarian Syndrome. Although the exact cause of Polycystic Ovarian Syndrome is still unknown, one of the most commonly accepted hypotheses for underlying pathophysiologic mechanisms is hyperinsulinemia and insulin resistance. It is suggested that obesity, hyperinsulinemia and insulin resistance are closely related and each of these diseases affect the other. The insulin resistance contributes to the pathophysiology of type 2 diabetes mellitus (T2DM) and is a marker of obesity, metabolic syndrome and many cardiovascular diseases. Therefore, quantification of insulin resistance is very important. Some methods rely on steady state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depend on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. There is a need for elaboration of a universal marker in the diagnosis of insulin resistance that could be applied in both clinical and ambulatory settings. Currently, measurements of serum insulin and estimates of insulin resistance are not required for routine clinical management.

A digital volumetric tomography (DVT) study in the mandibular molar region for miniscrew placement during mixed dentition

OBJECTIVE: To assess bone thickness for miniscrew placement in the mandible during mixed dentition by using digital volumetric tomograph (DVT). MATERIAL AND METHODS: A total of 15 healthy patients aged 8-10 years old, with early exfoliated mandibular second deciduous molar, were included. DVT images of one quadrant of the mandible were obtained using Kodak extraoral imaging systems and analyzed by Kodak dental imaging software. The error of the method (EM) was calculated using Dahlberg's formula. Mean and standard deviation were calculated at 6 and 8 mm from the cementoenamel junction (CEJ).Paired t-test was used to analyze the measurements. RESULTS: Buccal cortical bone thickness, mesiodistal width and buccolingual bone depth at 6 mm were found to be 1.73 + 0.41, 2.15 + 0.49 and 13.18 + 1.22 mm, respectively; while at 8 mm measurements were 2.42 + 0.34, 2.48 + 0.33 and 13.65 + 1.25 mm, respectively. EM for buccal cortical bone thickness, mesiodistal width and buccolingual bone depth was 0.58, 0.40 and 0.48, respectively. The difference in measurement at 6 and 8 mm for buccal cortical plate thickness (P < 0.05) and buccolingual bone thickness (P < 0.05) was found to be significant, whereas for mesiodistal width it was insignificant (P > 0.05). CONCLUSION: Bone thickness measurement has shown promising evidence for safe placement of miniscrews in the mandible during mixed dentition. The use of miniscrew is the best alternative, even in younger patients. .

OBJETIVO: avaliar, por meio de tomografia volumétrica digital (TVD), a espessura óssea necessária para a instalação de mini-implante na arcada inferior durante a fase de dentição mista. MÉTODOS: um total de 15 pacientes saudáveis, com idades entre 8 e 10 anos, com segundo molar inferior decíduo irrompido recentemente, foram incluídos no presente estudo. Imagens de TVD da hemiarcada inferior foram obtidas utilizando sistemas de imagens extrabucais Kodak. As imagens foram analisadas por meio do programa de imagens Kodak. O erro do método (EM) foi calculado utilizando a fórmula de Dahlberg. Médias e desvios-padrão foram calculados de 6 a 8mm aquém da junção amelocementária. O teste t foi utilizado para a análise das medidas. RESULTADOS: a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual, a 6mm, foram de 1,73 + 0,41; 2,15 + 0,49; e 13,18 + 1,22 mm, respectivamente. Já a 8mm, os valores foram de 2,42 + 0,34; 2,48 + 0,33; e 13,65 + 1,25mm. O EM para a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual foi de 0,58, 0,40 e 0,48mm, respectivamente. A diferença entre as medidas a 6 e 8mm para a espessura do osso cortical vestibular (p < 0,05) e a espessura óssea vestibulolingual (p < 0,05) foi significativa, embora não tenha sido significativa para a largura mesiodistal (p < 0,05). CONCLUSÃO: a mensuração da espessura óssea demonstra evidências promissoras para a segura instalação de mini-implantes na arcada inferior e na fase de dentição mista. O uso de mini-implantes tem se mostrado a melhor alternativa, mesmo nos casos de pacientes mais jovens. .

Effect of gastric bypass operation on expressions of adipic insulin receptor and insulin receptor substrate-1 in rats with type 2 diabetes mellitus / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the expressions of adipic insulin receptor β(IR-β) and insulin receptor substrate-1 (IRS-1) after gastric bypass (GBP) operation in spontaneous rats with type 2 diabetes mellitus(GK rats) and to elucidate the mechanisms of GBP in improving insulin resistance.</p><p><b>METHODS</b>Thirty male GK rats aged 8 weeks were randomly divided into 3 groups according to the table of random number: the operation group (GBP, 10 rats), the sham operation group (the same sites were cut off as GBP and end to end anastomosis was performed in site, 10 rats) and the diet pairing group (the same kind and weight dieting as the operation group, 10 rats), besides 10 male SD rats aged 8 weeks were used as blank control group (free eating and drinking). Four weeks before and after operation, levels of fasting blood glucose(FPG) and fasting insulin(FINS) were measured, HOMA-IR was calculated respectively, and compared among 4 groups. Then rats were decapitated to retrieve the omentum. Expressions of adipic IR-β and IRS-1 protein were detected by Western blot.</p><p><b>RESULTS</b>Compared with the preoperative levels, the FPG and HOMA-IR decreased significantly 4 weeks after surgery in operation group [(5.13±0.22) vs. (11.73±0.37) mmol/L, 2.16±0.18 vs. 5.10±0.29, P<0.05), reaching the level of blank control group(P>0.05). FINS showed no obvious change in these 4 groups after operation(all P>0.05). Expressions of IR-β and IRS-1 were significantly higher in operation group than those in other 3 groups 4 weeks after the operation(all P<0.05).</p><p><b>CONCLUSIONS</b>Expressions of adipic IR-β and IRS-1 in insulin signal transmission of rats with type 2 diabetes mellitus after GBP are up-regulated, meanwhile insulin resistance can be improved and insulin sensibility increases.</p>

Effects of a Pueraria lobata-root based combination supplement containing Rehmannia glutinosa and aerobic exercise on improvement of metabolic dysfunctions in ovariectomized rats / 한국영양학회지

PURPOSE: There is a fair amount of evidence indicating that increased risk of obesity and insulin resistance is associated with postmenopausal state, but can be modulated by diet and exercise. In this study, we explored whether a Pueraria lobata root-based supplement containing Rehmannia glutinosa (PR) and/or aerobic treadmill exercise can modify the metabolic changes associated with estrogen deficiency. METHODS: Seventy rats were randomly assigned to the following groups for 8 weeks (n=10 per group): SHAM, sham-operated; PR0, ovariectomized (OVX) control; PR200, OVX with PR200 mg/kg B.W; PR400, OVX with PR400 mg/kg B.W; EPR0, OVX with exercise; EPR200, OVX with exercise and PR200 mg/kg B.W; EPR400, OVX with exercise and PR400 mg/kg B.W. RESULTS: OVX induced significant increases in body weight, food intake, fat mass, LDL-cholesterol, and fasting blood glucose, confirming induction of menopausal symptoms. PR supplementation or exercise significantly suppressed the above mentioned changes through different regulatory elements in adipose tissue: PR supplement upregulated adiponectin gene expression and aerobic exercise upregulated adiponectin and insulin receptor gene expression and a combination of PR supplement and aerobic exercise showed an additive effect on adiponectin gene expression. CONCLUSION: Taken together, the results of this study suggest that PR supplement has a potential to provide health benefits in OVX rats through leptin and adiponectin secretion. In addition, the data suggest that combination of exercise and PR would have additive effects on metabolic dysfunction associated with estrogen deficiency.

Resistin Inhibits Insulin Secretion Through Inhibition of Insulin Granule Docking Via Downregulation of Rab3A in Pancreatic Beta-cells / 계명의대학술지

Resistin is a recently described novel adipokine that has been suggested to play an important role in the development of insulin resistance and type 2 diabetes by inhibiting insulin receptor signaling in myocytes and adipocytes. In the present study, we evaluated the direct effect of resistin on insulin secretion in pancreatic beta-cells. After treatment with recombinant resistin for 30 min, changes in glucose uptake, intracellular ATP and calcium levels, and insulin secretion were measured in glucose-stimulated INS-1 cells. The number of insulin granules morphologically docked to the plasma membrane was measured using a total internal reflection fluorescence microscope. Resistin significantly inhibited glucose-stimulated insulin secretion in INS-1 cells. Although resistin had no effects on intracellular glucose uptake, ATP and calcium levels, it caused a significant decrease in the number of docked insulin granules. In addition, the expression of rab3A was decreased after treatment with resistin. These results suggest that resistin can inhibit insulin secretion through inhibition of insulin granule docking via downregulation of rab3A in pancreatic beta-cells. The present finding may also be an important mechanism of resistin for the development of type 2 diabetes.

Estrogen deprivation and excess energy supply accelerate 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice

BACKGROUND/OBJECTIVES: Obesity is a risk factor of breast cancer in postmenopausal women. Estrogen deprivation has been suggested to cause alteration of lipid metabolism thereby creating a cellular microenvironment favoring tumor growth. The aim of this study is to investigate the effects of estrogen depletion in combination with excess energy supply on breast tumor development. MATERIALS/METHODS: Ovariectomized (OVX) or sham-operated C3H/HeN mice at 4 wks were provided with either a normal diet or a high-fat diet (HD) for 16 weeks. Breast tumors were induced by administration of 7,12-dimethylbenz(a)anthracene once a week for six consecutive weeks. RESULTS: Study results showed higher serum concentrations of free fatty acids and insulin in the OVX+HD group compared to other groups. The average tumor volume was significantly larger in OVX+HD animals than in other groups. Expressions of mammary tumor insulin receptor and mammalian target of rapamycin proteins as well as the ratio of pAKT/AKT were significantly increased, while pAMPK/AMPK was decreased in OVX+HD animals compared to the sham-operated groups. Higher relative expression of liver fatty acid synthase mRNA was observed in OVX+HD mice compared with other groups. CONCLUSIONS: These results suggest that excess energy supply affects the accelerated mammary tumor growth in estrogen deprived mice.

Insulin Signaling Network in Cancer.

The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer.

Imunoexpressão hepática de marcadores inflamatórios e de resistência insulínica na esteato-hepatite não alcóolica / Immunohistochemistry pattern of hepatic inflammatory and insulin resistance markers in experimental model of nonalcoholic steatohepatitis

Introduction: The pathophysiology of nonalcoholic steatohepatitis (NAS) includes, basically, insulin resistance, inflammation and oxidative stress. Thus, a study of immunostaining for liver insulin, adiponectin, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) receptors was conducted. Objective: To expand the knowledge about the pathophysiological and molecular mechanisms underlying the experimental model of steatohepatitis in rats fed a high-fat diet. Method: Twenty Wistar rats were divided into two groups: G1 (control, fed a standard diet), and G2 (fed a high-fat diet containing 58% of energy derived from fat, 18% from protein and 24% from carbohydrate). After eight weeks the animals were sacrificed. Blood glucose, insulin, total cholesterol, high-density lipoprotein (HDL), the very low-density lipoproteins (VLDL), triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were determined. The liver tissue was submitted to histopathological analysis, using a NAS score. In immunohistochemistry, we studied the expression of the insulin receptor, adiponectin, TNF-α and iNOS by tissue microarray method. Results and conclusion: There was marked cytoplasmic immunostaining for TNF-α and iNOS mediators in the group on a fat diet. Regarding insulin and adiponectin molecular markers, a reduction of cytoplasmic immunoreactivity of these antigens was observed in the group on a fat diet, reflecting, respectively, the state of hepatocellular inflammation (steatohepatitis) and insulin resistance in this experimental model of fat liver disease...

Introdução: Os mecanismos fisiopatológicos da esteato-hepatite não alcoólica incluem basicamente resistência insulínica, processo inflamatório e estresse oxidativo. Desta forma, um estudo sobre o padrão de imunoexpressão hepática para receptores de insulina, adiponectina, fator de necrose tumoral alfa (TNF-α) e sintase indutível do óxido nítrico (iNOS) foi conduzido. Objetivo: Ampliar os conhecimentos sobre os mecanismos moleculares subjacentes, em modelo experimental de esteato-hepatite. Método: Vinte ratos Wistar com dois meses de idade, pesando de 250 a 300 mg foram subdivididos em dois grupos: G1 (controle normal, submetido à dieta padrão) e G2 (grupo-controle, submetido à dieta hiperlipídica contendo 58% de energia derivada de gorduras, 18% de proteínas e 24% de carboidratos). Após oito semanas, os animais foram sacrificados; o sangue, submetido à análise bioquímica; e o fígado, removido e fixado em formalina tamponada e emblocado em parafina para estudo histopatológico. Para estudo imuno-histoquímico, foi utilizada a técnica de microarranjo de tecido. As lâminas obtidas foram submetidas à incubação com os anticorpos contra adiponectina, receptor de insulina, TNF-α e iNOS. Resultados e conclusão: Observou-se marcada imunoexpressão citoplasmática para os mediadores TNF-α e iNOS no grupo submetido à dieta hiperlipídica. No que diz respeito aos marcadores moleculares insulina e adiponectina, observou-se uma redução da imunoexpressão citoplasmática desses anticorpos no grupo submetido à dieta hiperlipídica, traduzindo, respectivamente, o estado de inflamação hepatocelular (esteato-hepatite) e resistência insulínica, desenvolvidos nesse modelo experimental de doença hepática gordurosa...

Aspectos epidemiológicos de la diabetes mellitus y su relación con los contaminantes ambientales / Epidemiological aspects of diabetes mellitus and its relationship with enviromental pollutants

Biochemical processes involving insulin and its receptor are responsible for regulating carbohydrate and fat metabolism. Disruption of these signaling pathways could lead to obesity, insulin resistance and diabetes, among other health problems. Diabetes has a global impact and its high prevalence has been associated with genetic and environmental factors. Recently, there has been a strong interest in establishing the relationship between type II diabetes and exposure to environmental contaminants, particularly persistent organic pollutants (POPs). This association has is based on epidemiological evidence and results from in vitro and in vivo experiments. In this review, the authors present some of the epidemiological aspects of diabetes, the biochemical pathways involved in insulin action, and how these environmental toxicants have impacted on population, through diverse mechanisms, to produce this disease. While several authors consider that the etiology of diabetes has a very important component derived from exposure to environmental pollutants, it is clear that there is still a substantial amount of work to develop in order to identify cause-effect relationships and the mechanisms involved.

Los procesos bioquímicos que involucran la insulina y su receptor son los responsables de regular el metabolismo de carbohidratos y grasas. La alteración de estas vías de señalización puede conllevar a obesidad, resistencia a la insulina y diabetes, entre otros problemas de salud. La diabetes impacta a nivel global y su alta prevalencia ha sido asociada con factores genéticos y ambientales. Recientemente ha surgido un amplio interés por establecer la relación existente entre la diabetes tipo 2 y la exposición a contaminantes ambientales, en especial los compuestos orgánicos persistentes (COPs). Esta asociación está basada en evidencia epidemiológica y resultados de experimentos in vitro e in vivo. En esta revisión los autores presentan algunos de los aspectos epidemiológicos de la diabetes, las rutas bioquímicas que participan en la acción de la insulina, y como estos tóxicos ambientales han impactado sobre la población, a través de diversos mecanismos, para producir esta enfermedad. Si bien algunos autores consideran que la etiología de la diabetes tiene un componente importante derivado de la exposición a contaminantes ambientales, es claro que aún falta mucho por desarrollar para identificar verdaderas relaciones causa-efecto y los mecanismos involucrados.