[Donohue syndrome and use of continuous subcutaneous IGF1 pump therapy].

Donohue syndrome (DS), also called Leprechaunism, is the most severe form of insulin resistance associated with biallelic mutations in INSR gene (OMIM: 147670). The approximate incidence of this syndrome is 1 per 1000000 births. Patients are present with typical clinical features such as intrauterine growth retardation, facial dysmorphism, severe metabolic disturbances, hepatomegaly and hypertrophic cardiomyopathy. Most DS patients die within the first two years of life due to respiratory infections, severe hypoglycemia or progressive cardiomyopathy. Treatment options are limited and no specific therapy exist for DS. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance including DS.We report the case of a male patient with genetically confirmed Donohue syndrome, successfully treated with continuous subcutaneous IGF1 infusion via insulin pump. We observed improvement of glycemic control, liver function and cardiac hypertrophy regression following 15-month IGF1 therapy.

Antidiabetic effects of nerolidol through promoting insulin receptor signaling in high-fat diet and low dose streptozotocin-induced type 2 diabetic rats.

The present study was designed to investigate the antidiabetic effect of nerolidol on high-fat diet and streptozotocin-induced diabetic rats. Type 2 diabetes was induced in animals by feeding them a high-fat diet for 4 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg body weight). Diabetic rats were treated with nerolidol (25 mg/kg BW) for 28 days. Results showed that nerolidol treatment significantly reduced (p < 0.05) the level of elevated glucose, glycosylated hemoglobin and improved (p < 0.05) the body weight and insulin level. Nerolidol also considerably improved (p < 0.05) the carbohydrate metabolic enzyme activities and increased the glycogen storage in the liver of diabetic rats. Increased serum triglycerides, total cholesterol (C), low-density lipoproteins-C and very low-density lipoproteins-C levels were significantly lowered (p < 0.05), while reduction of serum high-density lipoprotein-C was alleviated after administration of nerolidol. In addition, nerolidol attenuated oxidative stress markers by significantly increasing (p < 0.05) the levels of superoxide dismutase, catalase, reduced glutathione, and lowering (p < 0.05) the level of thiobarbituric acid reactive substances, and lipid hydroperoxide. Similarly, nerolidol showed its pharmacological effects against hepatic markers via restoring (p < 0.05) the alleviated level of alanine transaminase, aspartate aminotransferase, and alkaline phosphatase. Finally, it improved insulin-dependent glucose transport in skeletal muscle by enhancing and activating glucose transporter protein-4. These findings confirmed the antidiabetic potential of nerolidol in type 2 diabetic rats. This may be related to a high antioxidant capacity, the restoration of plasma insulin and lipid levels, and the activation of insulin signaling in STZ/HFD-induced diabetic rats.

The impact of HCV eradication on hyperglycemia, insulin resistance, cytokine production, and insulin receptor substrate-1 and 2 expression in patients with HCV infection.

Virological responses after hepatitis C virus (HCV) treatment may alleviate liver disease and extra-hepatic manifestations. Our study aims to explore the impact of HCV eradication on the glycemic status, insulin resistance, cytokine production, and insulin receptor substrate (IRS)-1 and 2 gene expression levels in HCV-hyperglycemic patients. A total of 90 participants were allocated as follows: Group 1 included 30 healthy subjects as controls, and Group 2 included 60 HCV-hyperglycemic patients treated with a direct-acting antiviral (DAA) regimen and further subdivided into HCV-pre-diabetic and HCV-diabetic groups. Laboratory assays screened patients before and after treatments. Our data showed an excellent rate of virological responses in HCV groups after HCV treatment. Moreover, HCV eradication significantly ameliorated blood glucose levels and insulin resistance biomarkers in HCV-hyperglycemic patients compared with baseline values. Also, interleukin (IL)-6, IL-17, IL-23, and IL-27 levels were significantly ameliorated after viral clearance in HCV-hyperglycemic patients compared with baseline values. Similarly, IRS-1 and 2 mRNA expression levels were upregulated in these patients post-HCV treatment compared with baseline values. HCV clearance ameliorated hyperglycemia, cytokine production, and enhanced insulin sensitivity. Future researches will be needed to explore the effects of cytokines and IRS on HCV infection and treatment on a large cohort.

Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts.

Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.

Oral administration of NPC43 counters hyperglycemia and activates insulin receptor in streptozotocin-induced type 1 diabetic mice.

INTRODUCTION: Adenosine, 5'-Se-methyl-5'-seleno-,2',3'-diacetate (NPC43) is a recently identified small, non-peptidyl molecule which restores normal insulin signaling in a mouse model of type 2 diabetes (Lan et al). The present study investigated the ability of NPC43 as an oral and injectable insulin-replacing agent to activate insulin receptor (INSR) and counter hyperglycemia in streptozotocin (STZ)-induced type 1 diabetic (T1D) mice. RESEARCH DESIGN AND METHODS: In this study, STZ was intraperitoneally injected into wild-type mice to induce hyperglycemia and hypoinsulinemia, the main features of T1D. These STZ-induced T1D mice were given NPC43 orally or intraperitoneally and blood glucose levels were measured using a glucometer. Protein levels of phosphorylated and total Insrß, protein kinase B (Akt) and AS160 (critical for glucose uptake) in the skeletal muscle and liver of STZ-induced T1D mice following oral NPC43 treatment were determined by western blot analysis. In addition, hepatic expression of activated Insr in STZ-induced T1D mice after intraperitoneal NPC43 treatment was measured by ELISA. Student's t-test was used for statistical analysis. RESULTS: Oral administration of NPC43 at a dose of 5.4 or 10.8 mg/kg body weight (mpk) effectively lowered blood glucose levels in STZ-induced T1D mice at ≥1 hour post-treatment and the glucose-lowering activity of oral NPC43 persisted for 5 hours. Blood glucose levels were also reduced in STZ-induced T1D mice following intraperitoneal NPC43 (5.4 mpk) treatment. Protein levels of phosphorylated Insrß, Akt and AS160 were significantly increased in the skeletal muscle and liver of STZ-induced T1D mice after oral NPC43 (5.4 mpk) treatment. In addition, activation of hepatic Insr was observed in STZ-induced T1D mice following intraperitoneal NPC43 (5.4 mpk) treatment. CONCLUSIONS: We conclude that NPC43 is a de facto fast-acting oral and injectable insulin mimetic which activates Insr and mitigates hyperglycemia in a mouse model of T1D.

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells.

Wolbachia-infected mosquitoes are refractory to super-infection with arthropod-borne pathogens, but the role of host cell signaling proteins in pathogen-blocking mechanisms remains to be elucidated. Here, we use an antibody microarray approach to provide a comprehensive picture of the signaling response of Aedes aegypti-derived cells to Wolbachia. This approach identifies the host cell insulin receptor as being downregulated by the bacterium. Furthermore, siRNA-mediated knockdown and treatment with a small-molecule inhibitor of the insulin receptor kinase concur to assign a crucial role for this enzyme in the replication of dengue and Zika viruses in cultured mosquito cells. Finally, we show that the production of Zika virus in Wolbachia-free live mosquitoes is impaired by treatment with the selective inhibitor mimicking Wolbachia infection. This study identifies Wolbachia-mediated downregulation of insulin receptor kinase activity as a mechanism contributing to the blocking of super-infection by arboviruses.

Controversies in Management of Hyperkalemia.

BACKGROUND: Hyperkalemia is a common electrolyte disorder that can result in morbidity and mortality if not managed appropriately. OBJECTIVES: This review evaluates the classic treatments of hyperkalemia and discusses controversies and new medications for management. DISCUSSION: Potassium (K+) plays a key role in determining the transmembrane potentials of "excitable membranes" present in nerve and muscle cells. K+ is the predominant intracellular cation, and clinical deterioration typically ensues when patients develop sufficiently marked elevation in extracellular fluid concentrations of K+ (hyperkalemia). Hyperkalemia is usually detected via serum clinical laboratory measurement. The most severe effect of hyperkalemia includes various cardiac dysrhythmias, which may result in cardiac arrest and death. Treatment includes measures to "stabilize" cardiac membranes, to shift K+ from extracellular to intracellular stores, and to promote K+ excretion. Calcium gluconate 10% dosed 10 mL intravenously should be provided for membrane stabilization, unless the patient is in cardiac arrest, in which case 10 mL calcium chloride is warranted. Beta-agonists and intravenous insulin should be given, and some experts recommend the use of synthetic short-acting insulins rather than regular insulin. Dextrose should also be administered, as indicated by initial and serial serum glucose measurements. Dialysis is the most efficient means to enable removal of excess K+. Loop and thiazide diuretics can also be useful. Sodium polystyrene sulfonate is not efficacious. New medications to promote gastrointestinal K+ excretion, which include patiromer and sodium zirconium cyclosilicate, hold promise. CONCLUSIONS: Hyperkalemia can be deadly, and treatment requires specific measures including membrane stabilization, cellular shift, and excretion.

Síndrome dos ovários policísticos e insulina: revisão do vínculo fisiopatológico e do tratamento com sensibilizadores de insulina / Polycistic ovary syndrome and insulin: revision of entail physiopathologic and insulin sensitizing agents treatment

A síndrome dos ovários policísticos (SOP) é uma desordem complexa que engloba um amplo espectro de sinais e sintomas, predominando aqueles de disfunção ovariana. Acomete cerca de 10 por cento das mulheres em idade reprodutiva. Resistência insulínica e hiperinsulinemia desempenham papel importante na patogênese da doença. Nesse contexto, a utilização de sensibilizadores de insulina (metformina e glitazonas) tem sido recentemente proposta como terapia de escolha para muitas mulheres com SOP. O uso desse agentes está associado a decréscimo nos níveis de androgênios e gonadotropinas, melhora na tolerência à glicose, perfil lipídico e função endotelial com redução dos marcadores de doença aterosclerótica subclínica. O tratamento é potencialmente útil no controle do hiperandrogenismo, das alterações metabólicas e particularmente da fertilidade.

Polycystic ovary syndrome is a complex disorder that encompasses a wide range of signs and symptoms, mainly those related with ovarian dysfunction, and affects about 10 per cent of women during their reproductive years. Insulin resistance and hyperinsulinemia play important role in the pathogenesis of the disease. So, insulin-sensitizing agents (metformin and glitazones) have been recently proposed as the therapy of choice for many women with polycystic ovary syndrome. Insulin sensitizer treatment has been associated with a reduction in serum androgen levels and gonadotropins, improvement in glucose tolerance, lipid profile and endothelial function with reduction in sub-clinica atherosclerotic markers. The treatment is potentially useful in the control of hyperandrogenism, metabolic changes and improvement of fertility.

Guías clínicas de tratamiento de la diabetes tipo 2: limitaciones del tratamiento escalonado / Clinical guidelines in the therapy of type 2 diabetes: limitations of stepped treatment

Se han revisado las recomendaciones terapéuticas en la diabetes mellitus tipo 2 del European Diabetes Policy Group de la Intemational Diabetes Federation (IDF; 1999), del Scottish Intercollegiate Guidelines Network (SIGN; 2001), del National Institute for Clínical Excellence (NICE; 2002), de la American Association of Clinical Endocrinologists (AACE; 2002), del New Zealand Guidelines Group (NZGG; 2003) y de la Canadian Diabetes Association (CDA; 2003). En España; estas recomendaciones han sido recogidas en la "Guía de tratamiento de la diabetes tipo 2 en Atención Primaria". La American Diabetes Association (ADA) no ha emitido ningún posicionamiento reciente sobre el tratamiento farmacológico de la DM2 y su última publicación al respecto data de 1999. La opción terapéutica que se seleccione estará supeditada a diversos aspectos de la enfermedad como son el estado ponderal (obesidad o normopeso), grado de resistencia a la insulina, grado de déficit de secreción de insulina, grado de control metabólico y la cifra de HbA1c, predominio de la hiperglucemia en ayunas o bien en estadio postprandial, así como de la existencia de las distintas complicaciones crónicas u otros procesos concomitantes (insuficiencia renal, cardiaca o hepática)

Therapeutic guidelines on type 2 diabetes from the European Diabetes Policy Group de la lntemational Diabetes Federation (IDF; 1999), the Scottish Intercollegiate Guidelines Network (SIGN; 2001), the National Institute for Clinical Excellence (NICE; 2002), the American Association of Clinical Endocrinologists (AACE; 2002), the New Zealand Guidelines Group (NZGG; 2003) and the Canadian Diabetes Association (CDA; 2003) were reviewed. In Spain, these recommendations have been included on the "Guía de tratamiento de la diabetes tipo 2 en Atención Primaria". The American Diabetes Association (ADA) has not particularly published any recent positional statement on pharmacological treatment of type 2 diabetes and its last publication is from 1999. The best therapeutic option will be selected taken into account the degree of adiposity (lean or obese), insulin resistance, defect of insulin secretion, metabolic control and HbA1c and predominant basal hyperglycemia or postprandial hyperglycemia. The presence of chronic diabetic complications or other concomitant diseases (renal or hepatic failure, congestive heart disease) are also important