A novel therapeutic strategy for pancreatic neoplasia using a novel RNAi platform targeting PDX-1

Bi-functional shRNA (bi-shRNA), a novel RNA interference (RNAi) effector platform targeting PDX-1 utilizing a systemic DOTAP-Cholesterol delivery vehicle, was studied in three mouse models of progressive pancreatic neoplasia. Species-specific bi-functional PDX-1 shRNA (bi-shRNAPDX-1) lipoplexes inhibited insulin expression and secretion while also substantially inhibiting proliferation of mouse and human cell lines via disruption of cell cycle proteins in vitro. Three cycles of either bi-shRNA<sup>mousePDX-1</sup> or shRNA<sup>mousePDX-1</sup> lipoplexes administered intravenously prevented death from hyperinsulinemia and hypoglycemia in a lethal insulinoma mouse model. Three cycles of shRNA<sup>mousePDX-1</sup> lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of pancreatic neoplasia. Moreover, three cycles of the bi-shRNA<sup>humanPDX-1</sup> lipoplexes resulted in near complete ablation of tumor volume and considerably improved survival in a human PANC-1 implanted SCID-mouse model. Human pancreatic neoplasia specimens also stained strongly for PDX-1 expression. Together, these data support the clinical development of a novel therapeutic strategy using systemic bi-shRNA<sup>PDX-1</sup> lipoplexes against pancreatic neoplasia

The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Examining the role of insulin in the regulation of cardiovascular health

A substantial body of evidence has reported that insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood. Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed

Central Obesity and BMI Associated with Different Phenotypes of Polycystic Ovary Syndrome in Adolescent

Adipose tissue distribution is effective in metabolic complications resulting from obesity. Fat accumulation in the body, particularly increase in visceral fat, is a major risk factor of diabetes and cardiovascular diseases. The present study aimed to determine the prevalence of obesity and android obesity based on various phenotypes of Polycystic Ovarian Syndrome (PCOS) in 14-18 year old high-school girl students in Shiraz in 2009. This descriptive study was conducted on 14-18 year old high-school girl students in Shiraz in 2009. Considering the confidence coefficient of 95% and loss rate of 20%, a 3190subject sample size was determined for the study. The participants were selected through purposive sampling. After obtaining written informed consents, demographic information questionnaire was completed and the participants were examined regarding hirsutism, acne, alopecia, and menstrual disorders. Besides, the criteria proposed by Adams et al. were employed to diagnose PCOS in sonography. Android obesity and Body Mass Index (BMI) were evaluated, as well. The results of independent t-test showed no significant difference among various phenotypes of PCOS regarding mean android obesity and BMI (P>0.05). The results of the present study revealed no significant relationship between girl adolescents\u27 obesity and various phenotypes of PCOS. However, adolescents should be informed about the long-term hyperandrogenic outcomes which are accompanied by insulin secretion and endanger their health after the age of 40 years

A case of acanthosis nigricans in a HIV-infected patient

Background: To date, very little information is available concerning the relationship between acanthosis nigricans (AN) and infection with human immunodeficiency virus type 1 (HIV-1). Case presentation: Herein, we report the case of a middle-aged man admitted for fever and progressively worsening dyspnea in the context of an opportunistic pneumonia and firstly diagnosed with acquired immunodeficiency syndrome (AIDS). At the time of diagnosis, physical examination revealed the presence of a palpable, hyperpigmented skin lesion on the left areola with surface desquamation and velvety texture consistent with AN. Of note, the most common primary etiologies related to AN were excluded and the complete regression of the skin lesion was observed once antiretroviral therapy was started. Conclusion: This is the second report of AN found in patients with AIDS and apparently responsive to prolonged antiretroviral treatment. Possible explanations of this association are still not completely understood, probably related to virus-induced changes in lipid metabolism. Our experience suggests that HIV testing should always be considered in the setting of apparently idiopathic AN

Hyperprolactinemia induced by hCG leads to metabolic disturbances in female mice

The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin β-subunit (hCGβ+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGβ+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGβ+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGβ+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies.Fil: Ratner, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Stevens, Guillermina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bonaventura, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Poutanen, Matti. University of Turku; FinlandiaFil: Calandra, Ricardo Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Huhtaniemi, Ilpo T.. University of Turku; FinlandiaFil: Rulli, Susana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model.

Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the KrasG12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-KrasG12D/+;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months. After 3 months, metformin prevented HFCD-induced weight gain, hepatic steatosis, depletion of intact acini, formation of advanced PanIN lesions, and stimulation of ERK and mTORC1 in pancreas. In addition to reversing hepatic and pancreatic histopathology, metformin normalized HFCD-induced hyperinsulinemia and hyperleptinemia among the 9-month cohort. Importantly, the HFCD-increased PDAC incidence was completely abrogated by metformin (p < 0.01). The obesogenic diet also induced a marked increase in the expression of TAZ in pancreas, an effect abrogated by metformin. In conclusion, administration of metformin improved the metabolic profile and eliminated the promoting effects of diet-induced obesity on PDAC formation in KC mice. Given the established safety profile of metformin, our findings have a strong translational potential for novel chemo-preventive strategies for PDAC