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  • ISSN: 2333-6692
    Early Online
    April-June 2014
    Volume 2, Issue 2
    Short Communication
    Amaresh Reddy P1*, Alok Sachan2 and Suresh V2
    Abstract: Osteoporosis and vertebral compression is a rare but important clinical presentation of Acute lymphoblastic leukaemia.
    Review Article
    Kulvinder Kochar Kaur1*, Gautam Nand Allahbadia2 and Mandeep Singh3
    Abstract: Male hypogonadism refers to low serum testosterone (T) (<200-250ng/dl) checked at 8am in fasting subjects. Secondary hypogonadism with low normal gonadotropins can be due to congenital or acquired causes. Congenital hypogonadotropic hypogonadirm (CHH) is considered when low serum inhibin B levels are found to accompany lowS. FSH/LH and T. The differential diagnosis of CHH includes pituitary tumours /pituitary infiltration, juvenile hemochromatosis and other anterior pituitary functional disorders ruled out by neuroimaging and detailed hormone testing respectively. The abuse of anabolic steroids/opioids/corticosteroids which may result in hormonal changes similar to those seen in CHH need to be excluded. However confusion may result in case of constitutionally delay ed pubrtal growth in adolescents. Following detailed family history a genetic study performed helps to segregate the two commonest forms namely anosmic/hyposmic Kallmann Syndrome (KS) or normosmic IHH. Till date 9 genes(KAL1 (Kallmann syndrome 1)/FGF8(fibroblast growth factor 8)/ FGFR1(fibroblastgrowthfactorreceptor1)/HS6ST1(Heparan -6-O -transferase 1)/PROK2(prokineticin 2)/ PROKR2 (prokineticinreceptor2)/CHD7(chromodomain 7)/WDR11/SEMA3A(semanaphorin 3A)) have been found to be associated with KS and further for nIHH the "ones associated with GnRH function" (KISS1(Tumor metastasis suppressor)/KISSR1(KISS1 receptor)/GNRH(gonadotropin releasing hormone)/GNRHR (gonadotropin releasing hormone receptor)/TAC3(tachychinin 3)/TAC3R (tachykinin receptor3) only 30%-32%of these genes account for KS and isolated GnRH deficiency respectively.Treatment protocol is individualized according to patients requirements; ranging from Tenanthate /pulsatile GnRH therapy/rFSH-hCG or in some specific cases kisspeptin 10 agonists are prospectively being tried as future therapeutic options. Still a lot of work needs to be done on transcription factors considering genetic overlap between midline disorders like septooptic dysplasia, holopresencephaly in KS" given the developmental role of transcription factors in forebrain development as causative genes for KS.
    Research Article
    Betsy B Dokken1*, Craig S Weber2, Jennifer L Mitchell1, Jeffery M Gold1 and Ronald M Lynch2,3
    Abstract: Diabetic patients are at extreme risk for cardiovascular disease. Endothelial dysfunction plays a key role in the development of cardiovascular complications in diabetes. The effects of diabetes on the endothelium are multi-factorial, and include impaired intracellular calcium [Ca2+]i handling, particularly during reperfusion after ischemia. Glucagon-like peptide-1 (GLP-1) forms the basis of a group of agents currently used for glycemic control in type 2 diabetic patients. GLP-1 also improves endothelial function and is cardioprotective after ischemia and reperfusion. The mechanisms behind these effects are unknown. We determined the effects of GLP-1 on cytosolic calcium [Ca2+]i in human coronary microvascular endothelial Cells (HCMVECs), under physiologic conditions and also after simulated ischemia and reperfusion. In HCMVECs, [Ca2+]i was measured with and without treatment with GLP-1 (10 nM) and with and without simulated ischemia and reperfusion. We found that GLP-1 significantly modulates calcium handling in HCMVECs. The rise of ATP-induced [Ca2+]i was attenuated after treatment with GLP-1, both under physiologic conditions and after ischemia and reperfusion. These data reveal a role for GLP-1 in the modulation of [Ca2+]i in HCMVECs, which may be one mechanism by which it improves endothelial function. Given the increased risk of coronary microvascular dysfunction in type 2 diabetes, these findings suggest another potential benefit to the use of GLP-1 based therapies in diabetic patients.
    Bart J.M. Eskens*, H. Vink, J.W.G.E. VanTeeffelen
    Abstract: Recently, we showed that the induction of peripheral insulin resistance in diet-induced obese mice was accompanied by impaired barrier properties of the endothelial glycocalyx in the microcirculation of hindlimb muscle. We hypothesized in the current study that sulodexide, an endothelial glycocalyx mimetic, would improve insulin-mediated glucose disposal in high-fat diet (HFD) fed mice.
    Mice received a HFD for 6 or 18 weeks with or without therapy. Therapy consisted of sulodexide (0.15 mg/mL) or, as a reference, metformin (0.3 mg/mL) in the drinking water in the last two weeks of the HFD feeding period. To evaluate insulin action, mice were anesthetized; subsequently, they received a bolus of 1g/kg glucose via an i.p. cannula (IPGTT) while glucose and insulin levels were monitored for 120 and 90 minutes, respectively.
    Two weeks of sulodexide treatment in the 6 weeks HFD fed mice was associated with significantly lower glucose levels measured during the IPGTT without a significant change in insulin levels. After a HFD for 18 weeks, sulodexide treatment did not significantly reduce glucose levels during the IPGTT yet insulin resistance appeared to be improved, as reflected by a significant decrease of the product of the area under the curve for both the glucose and insulin levels. Two weeks of metformin treatment did not affect glucose tolerance in the 6 weeks HFD fed mice. Metformin did also not affect glucose and insulin levels after 18 weeks of HFD.
    Oral sulodexide treatment for 2 weeks is able to improve insulin-mediated glucose disposal in diet-induced obese mice. Our data indicate that timely treatment with the glycocalyx-mimetic sulodexide can be a potential therapy to alleviate insulin resistance and prevent the development of glucose intolerance and type II diabetes in obesity.
    Istvan Merchenthaler1*, Malcolm V. Lane1, Min Zhan1, and Patricia B. Hoyer2
    Abstract:
    Objectives: Ovariectomy of young rodents is the most frequently used animal model of the menopause. However, the assumption that ovariectomy, causing a rapid loss of ovarian hormones is a general model of menopause in not well supported.
    Several animal models have been developed with the aim of mitigating the human conditions of the menopause. Among these, the ovotoxin 4-vinylcyclohexene diepoxide (VCD) has gained popularity as chronic exposure to low dosing VCD causes apoptosis and subsequent ovarian follicle loss in rats and mice. The objective of these studies was to evaluate the VCD-treated female rat as a model of menopausal hot flush.
    Methods: Fisher 344 rats were dosed daily with VCD (160 mg/kg, i.p.) or vehicle (sesame oil) for 20 days. By three months after the completion of VCD dosing all the animals showed vaginal cytology characteristic for constant diestrus indicating ovarian failure while control animals showed regular estrous cycles. At this point, control animals were ovariectomized. Four weeks later, all the animals were utilized in the morphine-addicted hot flush model.
    Results: VCD-treated rats responded similarly to untreated ovariectomized rats, i.e., a 5-6C increase in their tail skin temperature (representing hot flush) was observed following morphine withdrawal. The tail skin temperature of ovariectomized, estrogen-treated rats increased only 2C following morphine withdrawal.
    Conclusions: VCD-treated rats provide a more physiologically relevant model than young ovariectomized rats for studying menopausal symptoms, including hot flushes, since the gradual decrease in estrogen levels better mimics the human peri-menopausal situation than ovariectomized animals (abrupt decline in estrogens).
    Mini Review
    Junta Imai1, Tetsuya Yamada1, Jo Satoh2 and Hideki Katagiri1*
    Abstract: Type B insulin resistance syndrome (IRS) is characterised by production of autoantibodies against the insulin receptor (IR). These autoantibodies block insulin binding to the IR, resulting in severe insulin resistance. Some patients with this syndrome paradoxically exhibit episodic hypoglycaemia. Relatively burdensome therapies, including immunosuppression andplasmapheresis, are reportedly effective in some patients, but there are as yet no established therapeutic strategies for type B IRS. We experiencedtwo cases with type B IRS who also had immune thrombocytopenic purpura (ITP). In one case, eradication of Helicobacter pylori (HP), aimed at treating ITP, cured type B IRS. In the other case, anti-IR and anti-platelet antibodiesweredetectedonly during pregnancy, and after delivery, these autoantibodies and hypoglycemic symptoms disappeared. These two cases suggest that elimination of immune-disturbing triggers can lead to a complete cure of type B IRS. In this review, we discuss the pathogenesis of type B IRS focusing particularly on the possible involvement of HP infection and the therapeutic potential of HP eradication for the treatment of this refractory syndrome.We recommend that physicians examine type B IRS patients for HP infection and eradicate this microorganism if present, since HP eradication can easily be performed with few adverse effects.
    Special Issue entitled: Low T or True Male Hypogonadism
    Research Article
    Eric Chung1,3*, Osama S Al-Bermani1, Ross P Fowler1 and Michael P Gillman2,3
    Abstract: Testosterone deficiency syndrome (TDS) is a clinical and biochemical syndrome frequently associated with age and co-morbidities and is characterized by deficiency in testosterone and relevant androgen-deficiency symptoms. The main physiological action of testosterone in male sexual function is in sexual desire by regulating the timing of the penile erectile with sex. However sexual dysfunction associated with TDS also includes erectile dysfunction (ED) and delayed ejaculation. The link between ED, testosterone deficiency and cardiovascular disorders is well documented. The recommended tests for men with ED include fasting glucose, cholesterol, lipids and testosterone level. Both ED and TDS are treatable conditions. A range of testosterone preparations are available for supplementation, and the combination of testosterone replacement therapy and phosphodiesterase type 5 inhibitors might improve outcomes in some cases. The selection of the testosterone replacement therapy should be a joint decision between an informed patient and his primary care physician, and regular follow-up should be conducted to assess treatment efficacy and surveillance for adverse events.
    Bruno Lopes Cançado1*, Luiz Carlos Miranda1, Maria Lucia Fleiuss2 and Miguel Madeira2
    Abstract: Bone loss in patients with prostate cancer undergoing anti-androgen therapy is underestimated by physicians. Osteoporosis is a silent condition that can lead to major fracture events. The osteoporosis’s fractures has as consequence a decrease in a patient’s general health and quality of life, an increase in morbidity and mortality, and an increase in the cost to the health care system. The application of preventive measures to avoid osteoporosis results in a simpler and more cost-effective solution, with few drawbacks to the patient, compared with the cost of treatment for osteoporosis-related fractures.
    Srinath Reshmi1, Nauder Faraday2 and Adrian Dobs1*
    Abstract: Epidemiologic studies suggest that cardiovascular disease affects men at an earlier age and may contribute to greater mortality. Cross sectional and prospective studies have considered the role of endogenous testosterone levels in cardiovascular disease and mortality but few prospective or randomized trials have looked at supplemental testosterone therapy and long term cardiovascular outcomes. Recent retrospective studies suggest that testosterone therapy increases the risk of cardiovascular disease and associated mortality, however it is still unclear by what mechanism. In this review we begin with a case report and attempt to summarize the mechanisms by which testosterone may promote arterial thrombosis and hemostasis. Overall testosterone plays a complex role in the thrombotic pathway, and may have different effects when given acutely or long term, especially in those with other modifiable and non-modifiable risk factors for cardiovascular disease.
    Review Article
    Kristin Lichti-Kaiser, Gary ZeRuth and Anton M Jetten*
    Abstract: Congenital hypothyroidism (CH) is the most frequent endocrine disorder in neonates. While several genetic mutations have been identified that result in developmental defects of the thyroid gland or thyroid hormone synthesis, genetic factors have yet to be identified in many CH patients along with the mechanisms underlying their pathophysiology. Mutations in the gene encoding the Krüppel-like transcription factor, GLI-similar 3 (GLIS3) have been associated with the development of a syndrome characterized by congenital hypothyroidism and neonatal diabetes and similar phenotypes were observed in mouse knockout models of Glis3. Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated thyroid stimulating hormone (TSH) and thyroglobulin (TG). However, the inconsistent presentation of clinical features associated with this CH has made it difficult to ascertain a causative mechanism. Future elucidation of the biological functions of GLIS3 in the thyroid will be crucial to the discovery of new therapeutic opportunities for the treatment of CH.
    Antonio Mancini1*, Sebastiano Raimondo1, Chantal Di Segni1, Giovanni Gadotti1, Elena Giacchi2, Marcella Zollino3, Giovanni Neri3, Marco Bonomi4, Luca Persani4,5 and Alfredo Pontecorvi1
    Abstract: Hypogonadism is frequently associated with metabolic syndrome and testosterone levels correlate with parameters which are part of the cluster defining the syndrome itself. Different studies suggest a positive role of testosterone replacement therapy, but different aspects (including the definition of hypogonadism, especially in aging male, and the modality of treatment) still require confirmation. A model to explore the role of testosterone in influencing the beginning and course of the syndrome is early hypogonadism, due to genetic causes (both primary or secondary hypogonadism); moreover, few data are reported in transsexuals, despite the debate on biological bases of gender indentity, and the influence of pharmacological treatment before and after surgical sex reversal. We present here a review of literature and some paradigmatic cases, that seem to reinforce the concept of hypogonadism as a causative factor of metabolic syndrome.
    Special Issue entitled: Cholesterol Subtypes
    Research Article
    Giovanni Viscogliosi1*, Evaristo Ettorre1, Iulia Maria Chiriac2, Paola Andreozzi1 and Mauro Cacciafesta1
    Abstract: We sought to explore whether the adherence to the Mediterranean dietary pattern is associated with better plasma lipid profile, regardless of obesity, insulin resistance and metabolic syndrome.
    Adult outpatients free of clinical cardiovascular diseases, diabetes, previously diagnosed Dyslipidemia and any lipid-lowering medications, were considered. The following features were assessed: HDL and total cholesterol, triglycerides and total to HDL cholesterol ratio. Insulin resistance was assessed through HOMA index. The adherence to Mediterranean dietary (Med Diet) pattern was assessed through a validated 14-item questionnaire.
    Twenty-two out of fifty subjects adhered to Med Diet. Subjects with low adherence had higher prevalence of metabolic syndrome and poorer plasma lipids profile and insulin resistance state. The bivariate regression analysis showed an inverse trend between Med Diet score and total to HDL cholesterol ratio (r= -0.417; p= 0.003) and triglycerides (r= -0.355; p= 0.01), and a positive trend with HDLc (r= 0.279; p=0.04). When multivariable regression models were constructed, the higher Med Diet score predicted higher HDLc (β= 0.340; SE (β)= 0.109; p= 0.016) and lower total to HDLc ratio (β= -0.437; SE(β)= 0.011; p= 0.007) and triglycerides (β= -0.893; SE(β)= 0.438; p= 0.043). Interestingly, whole and abdominal obesity, insulin resistance and presence of metabolic syndrome did not affect the associations.
    Med Diet may be associated to favorable plasma lipids profile, independently of being overweight / obese and having insulin resistance and metabolic syndrome. Further investigations will assess whether the adoption of Med Diet may prevent metabolic disorders and reduce the rate of progression towards clinical cardiovascular diseases.
    Special Issue entitled: Antidiabetic Drug-Metformin
    Mini Review
    Ariane Germeyer1* and Edison Capp1,2,3
    Abstract:
    Objective: About 10% of European couples are suffering infertility problems. The underlying cause is evenly distributed. In the female polycystic ovaries, often associated with anovulatory cycles, contribute to a high extend of underlying problems. Despite the anovulation many of these have an underlying insulin resistance and increased risk of ovarian hyperstimulation syndrome when ovarian hyperstimulation is performed. Last but not least, when conception is achieved the prevalence of recurrent abortion, as well as increased gestational complications are increased in women with polycystic ovaries and /or insulin resistence. Therefore the Off-label use of the anti-diabetic drug metformin has been tested as a treatment option in combination with different reproductive procedures. Last, but not least, since many advantages could be noted in women with PCOS under the metformin therapy, the range of application has been widened. This review will shed some light on the different potential implication of Off-label metformin therapy in reproductive medicine.
    Review Article
    Bodo C Melnik1* and Gerd Schmitz21
    Abstract: Recent progress in molecular medicine has identified the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) as the central regulator of protein and lipid synthesis, cell growth, proliferation, energy metabolism and autophagy. Age-related diseases of Western civilization such as obesity, diabetes mellitus, neurodegenerative diseases, and cancer are associated with enhanced mTORC1 signaling. According to the current opinion, metformin’s primary mode of action is the alteration of cellular energy metabolism stimulating 5-AMP-Activated Protein Kinase (AMPK). However, the notion that AMPK primarily mediates metformin´s anti-hyperglycemic action has recently been challenged, thrusting AMPK-independent effects into the focus of interest. We provide a new viewpoint on metformin´s mode of action as an inhibitor of mTORC1. Metformin´s insulin-lowering and AMPK-activating effects decrease RHEB-mediated stimulation of mTORC1. Independent of AMPK metformin inhibits mTORC1 in a RAG GTPase-dependent manner. Thus, metformin interferes with the two major pathways required for mTORC1 activation: 1) energy- and cell stress-mediated activation of AMPK attenuating the activity of the GTPase RHEB and 2) suppression of amino acid signaling down regulating the activity of lysosomal RAG GTPases. Both RHEB- and RAG GTPase activation, which are required for mTORC1 activation at the lysosomal membrane, are thus suppressed by metformin. Metformin-induced suppression of mTORC1 subsequently decreases S6K1 activity and S6K1-mediated insulin resistance as well as AKT-FoxO1-mediated hepatic gluconeogenesis. Metformin represents an ideal, save and cheap drug targeting the pathogenesis of mTORC1-driven anabolic and hyperproliferative diseases of civilization.
    Shumei Meng*
    Abstract: Metformin as the first line therapy for type 2 diabetes mellitus has its unique attraction for its weight loss and possible macrovascular benefit. In addition, recent accumulating epidemiological and clinical evidence suggests metformin maybe a potential anticancer medication as an adjuvant therapy or a chemoprevention given the increased prevalence of obesity and diabetes mellitus in cancer patients and the low cost and safety of the drug. Metformin may work through multiple pathways to inhibit cancer cell growth and proliferation. Epidemiological and clinical data were summarized in this review. More carefully designed longer and larger randomized controlled trials in selected cancer population in the future are needed.
    Daniela Jakubowicz1* and Markku Seppala2
    Abstract: Polycystic Ovary Syndrome (PCOS) is characterized by ovulatory disturbances, hyperandrogenaemia and hyperinsulinemia secondary to increased insulin resistance. In PCOS, hyperinsulinemic insulin resistance is of interest because skeletal muscle may be resistant to insulin in terms of glucose metabolism, while the ovaries remain sensitive to insulin with regard to stimulation of testosterone biosynthesis. Insulin resistance and hyperinsulinemia are associated with reproductive failure such as early pregnancy loss, and cardiovascular risk and the development of diabetes mellitus later in life. Insulin-sensitizing agents such as metformin improve insulin sensitivity, thereby improving ovulatory cycles and fertility in women with PCOS. Metformin has also been shown to retard progression to type 2 diabetes in PCOS. This review addresses the effects of metformin on reproduction.
    Battsetseg Batchuluun1, Noriyuki Sonoda1,2*, Ryoichi Takayanagi1 and Toyoshi Inoguchi1,2
    Metformin, a first-line agent for type 2 diabetes pharmacotherapy, is one of the most prescribed drugs worldwide. Its glucose lowering effect is mediated through suppressing the hepatic production of glucose, decreasing intestinal glucose absorption and improving glucose uptake and utilization [1].
    Joselyn Rojas*, Mervin Chávez-Castillo, Wheeler Torres, Nailet Arraiz, Mayela Cabrera and Valmore Bermúdez
    Abstract: Dimethylbiguanide (Metformin) is an anti-hyperglycemic drug used in the management of insulin resistance-related diseases like type 2 diabetes mellitus for over 40 years. The molecular mechanisms of action related to its metabolic effects are linked to dependent and independent AMP-dependent kinase (AMPK) activation. Epidemiological evidence has suggested that metformin administration has been associated to lower cancer risk and cancer-related mortality in patients with type 2 diabetes mellitus. Anti-tumoral properties have been described via AMPK-dependent and independent pathways. Metformin is a cationic molecule capable of copper sequestration and subsequent mitochondrial electron transport inhibition, compromising oxidative phosphorylation. Moreover, metformin has also been confirmed to modulate pluripotency in cancer stem cells, blunting their survival and proliferation. Finally, the reduction of vitamin B12 availability has also been suggested to control one-carbon metabolism, DNA synthesis and cytostatic effects. The purpose of this review is to examine the AMPK-independent related mechanisms concerning tumor expansion control and survival.
    Winston Crasto*, Pallavi Rao and Helena Gleeson
    Abstract: Reproductive health is an important domain of women’s health care and broadly encompasses conditions which impact fertility, conception or birth of a healthy infant. Although numerous factors or conditions are associated with infertility, polycystic ovary disease is a well recognised cause. In this regard, metformin which belongs to the biguanide group of drugs and is commonly used as first line treatment in type 2 diabetes has also been commonly employed in the management of infertile women with PCOS with beneficial results. This review examines the evidence base of the utility of metformin in PCOS on ovulation and reproductive outcomes and discusses its role in different aspects of management and in future research.
    Research Article
    Chen-Pin Wang1,2*, Carlos Lorenzo3 and Sara E Espinoza3,4,5,6
    Abstract:
    Objective: To determine whether the protective effect of metformin against death is modified by frailty status in older adults with type 2 diabetes.
    Research Design and Methods: We conducted a cohort study during October 1, 1999-September 30, 2006 among veterans aged 65-89 years old with type 2 diabetes but without history of liver, renal diseases, or cancers, who had sulfonylureas or metformin as the sole antidiabetic drug for ≥180 days. The Cox proportional hazard model was used to compare hazard rates of all-cause mortality between the metformin and sulfonylurea users adjusting for the propensity score of metformin use and covariates: age, race/ethnicity, diabetes duration, Charlson comorbidity score, statin use, smoking status, BMI, LDL, and HbA1c.
    Results: In this cohort of 2,415 veterans, 307 (12.7%) were metformin users, 2,108 (87.3%) were sulfonylurea users, the mean age was 73.7±5.2 years, the mean study period was 5.6±2.3 years, the mean HbA1c at baseline was 6.7±1.0%, 23% had diabetes for ≥10 years, and 43.6% (N=1,048) died during the study period. For patients with and without frailty, the adjusted hazard ratio (HR) of death for metformin vs. sulfonylurea use were 0.92 (95% CI=0.90-1.31, p-value=0.19) and 0.69 (95% CI = 0.60-0.79, p-value<0.001), respectively. Logistic regression analyses showed that metformin (vs. sulfonylurea) was significantly associated with a decreased odds of frailty (OR: 0.66, 95% CI: 0.61-0.71, p-value <.0001)
    Conclusion: Our study suggests that metformin could potentially promote longevity via preventing frailty in older adults with type 2 diabetes.
    Birsen Unsal Koyuncu1 and Mustafa Kemal Balcı2*
    Abstract: In Type 2 Diabetes Mellitus, incretin axes play an important role in terms of progressive beta abnormalities. It was found that enteroendocrin cells in the small bowel have T1R2 and T1R3 taste receptors. Artificial sweeteners and glucose have significant effects on secretion of GLP-1 and GIP hormones from intestine. Recent research studies worked on healthy people showed that glucose triggers release of these hormones by the taste receptors in the L cells. The aim of this study was evaluation of the metabolic effects of dissolved aspartame in the mouth taken before meals in prediabetic patients.
    This cross-over study was done in Akdeniz University, Endocrinology and Metabolism Unit. 54 prediabetic patients were included to this study. Patients were randomly separated to two groups. At the beginning of the study, patients interviewed with specialized diabetes dietitians. The first group was initiated with diet for three months and continued with diet and aspartame during second three months. Diet and aspartame were started in the second group for the first three months. Aspartame was discontinued after three months and patients continued with only diet during the second three months. Two tablets of aspartame (1 tablet equal to 18 mg) before meals were taken by dissolving on the tongue.In the two groups weight, height, BMI, waist circumference, fasting and postprandial blood glucose, hemoglobin A1c (HbA1c), fructosamine, alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, LDL cholesterol, HDL cholesterol, triglycerides and insulin were evaluated at 0, 3 and 6 months.
    In the first group, diet was found effective on losing weight at the end of the third month. After aspartame was added, weight loss continued till the end of the 6 month. In the second group, weight loss was detected with aspartame and diet during the first three months. However; in the second three months, weight gain occurred after aspartame was discontinued. Both groups were compared regarding weight loss in the first and second period. Weight loss in the first group was greater than in the second group during second period (p=0.027). The changes in the other parameters were not found significantly different.
    In conclusion, aspartame has additional effect on weight loss in prediabetic patients. We need long term studies to investigate the relation between weight change and incretins.
    Kamran MA Aziz*
    Abstract: Metformin is currently considered a first line therapy for managing type-2 diabetes for targeting insulin resistance and obesity. However, in usual busy clinical practice, the importance of metformin is sometimes ignored and patients are prescribed directly OHA or shifted to insulin therapy without metformin. Metformin has been shown to counteract dyslipidemia and as a drug for cardiac and renal protection as well. Current research was planned to enroll type-2 patients who were additionally prescribed metformin (with other OHA/insulins) compared to those who were not on metformin; and to compare HbA1c lipids, creatinine, spot urine protein and spot urine protein/creatinine between these two groups of patients. Study included 1590 patients and data were collected for the period of 5 years (January 2009 till January 2014) in the diabetology clinic ofAseer Diabetes Center at initial visits by standardized methodology. Type-1 DM, children (<13 years), pregnant, chronic renal failure, ESRD, and patients intolerant to metformin were excluded from the study. It was observed that 581 (36.6%) type-2 DM subjects were not prescribed metformin. Levels of HbA1c and BMI were lower in the metformin group compared to those without metformin (9.47 ± 2and 27.35versus 9.74± 2.4 and 30.25 ± 5.72; p-values 0.004 and < 0.0001 respectively). Non-HDL-C values were higher for the metformin group (152.6 ± 48 versus 140.4 ± 44; p<0.0001). Levels of creatinine, spot urine protein and spot urine protein/creatinine was higher for the group without metformin therapy (1.1 ± 0.31, 95.23 ± 138, 1.143 ± 3.39 versus 0.89 ± 0.2, 38.92 ± 82.17, 0.425 ± 1.25 with p-values <0.0001, 0.017 and 0.015 respectively). In the current study, metformin provided unique Glycemic and lipid control and cardio-renal protection among type-2 DM patients and should be prescribed to type-2 DM patients while managing diabetes to prevent complications of diabetes.
    Special Issue entitled: Role of Thyroid Hormone in Metabolic Homeostasis
    Review Article
    Stephen Ayers* and Paul Web
    Abstract: Thyroid hormones are central regulators of lipid metabolism and energy homeostasis, which primarily act through Thyroid Hormone Receptors (TRs). Selective Thyroid Hormone Receptor Modulators (STRMs) are chemical analogues of thyroid hormone, designed to preferentially induce beneficial actions of thyroid hormone through specificity for TRβ (isoform specificity) and specific accumulation in liver (tissue selectivity). Although initial results from studies of TH analogs that combine TRβ and tissue selectivity were promising, producing impressive reductions of serum LDLC and triglycerides in animal models and human patients, none of these compounds has progressed beyond the early clinical stage so far. While recent human trials of STRMs have consistently produced impressive improvements in serum lipid parameters, they have also revealed unexpected side effects. Although STRMs have the potential to serve as treatments for hyperlipidemia, these developments make their widespread use in the future highly uncertain.
    Ting Jin and Xiaochun Teng*
    Abstract: Thyroid hormone plays an important role in the regulation of lipid metabolism. It acts predominantly through its nuclear receptors (thyroid hormone receptor á and â) to regulate the gene expression related to lipid metabolism. Both overt hypothyroidism and hyperthyroidism results in abnormalities of lipid profile. However, changes in serum lipid profiles in patients with subclinical hypothyroidism have been inconsistent. In recent years, thyroid receptor â1-selective analogue represents a new class of hypolipidemic compound have been developed. Some of these T3 analogues are very potent in lowering serum cholesterol and triglyceride in animal models and human clinical studies. This mini review will focuses on the mechanisms that affect lipid profile under pathological thyroid conditions, and give brief touch on thyroid analogues.
    Michael L Goodson1* and Brenda J Mengeling2
    Abstract: Thyroid hormone, acting through thyroid hormone receptors is a key regulator of metabolic homeostasis. Repression of transcription is critical component of thyroid hormone signaling and is mediated through the association of corepressor proteins with thyroid hormone receptors. In this review we will discuss recent results elucidating multiple roles for corepressors in mediating thyroid hormones regulation of metabolism.
    Jang-Won Lee1, Nam-Ho Kim1 and Anna Milanesi2*
    Abstract: Skeletal muscle is a plastic organ made by highly specialize fibers with specific and different structure, function and metabolism. Skeletal muscle fibers can adapt, change, recover/regenerate after injury in response to various stimulators including hormones. Thyroid hormones are important players in the homeostasis of several tissue including skeletal muscle and their genomic action mostly depend on the tissue T3 bioavailability and on the distribution of the thyroid receptor isoforms which act as transcription factors and are modulated by T3. Changing in contractile and metabolic proprieties of the muscle fibers has been described in experimental models of hyper and hypothyroidism. Animal models with disruption of thyroid hormone signaling showed different and specific skeletal muscle phenotypes. By focusing on thyroid hormone signaling in skeletal muscle homeostasis, we review T3 specific action on skeletal muscle development, postnatal growth, function and metabolism.
    Ines Donangelo1,2*
    Abstract: Thyroid Hormone (TH) regulates energy balance, lipid metabolism and cardiovascular function. These effects are largely due direct action of TH on peripheral target tissues. However, there is increasing evidence for a direct central action of TH modulating metabolic processes, including regulation of thermogenesis, food intake, hepatic glucose metabolism and cardiovascular tone through direct action in the brain. Here, we review the current understanding of mechanisms including key hypothalamic signaling involved in central TH regulation of energy balance and metabolism.
    Miriam Oliveira Ribeiro*
    Abstract: The amount of energy in the body is highly regulated. The hypothalamus is a key neural structure involved in this process, keeping the intake of food in step with the energy expenditure. The main hypothalamic nuclei involved in energetic metabolism regulation are the arcuate, periventricular, dorsomedial and ventromedial that integrates several peripheral signals, such as leptin and adiponectin. Although is well known that T3 regulates basal metabolism, it also has an important role in feeding behavior regulation since it stimulates neurons that express orexigenic neuropeptides, such as AgRP and NPY found in the arcuate hypothalamic nuclei. The amount of T3 available in the brain depends on the activity of the type 2 deiodinase (D2) that transforms T4 in T3. D2 is expressed in glial cells that are in close contact with the AgRP/NPY expressing neurons in the arcuate hypothalamic nuclei, suggesting that D2 has an important role in the regulation of the feeding behavior and in the body weight.
    Kristin Lichti-Kaiser, Gary ZeRuth, and Anton M Jetten*
    Abstract: Congenital Hypothyroidism (CH) is the most frequent endocrine disorder in neonates. While several genetic mutations have been identified that result in developmental defects of the thyroid gland or thyroid hormone synthesis, genetic factors have yet to be identified in many CH patients along with the mechanisms underlying their pathophysiology. Mutations in the gene encoding the Krüppel-like transcription factor, GLI-similar 3 (GLIS3) have been associated with the development of a syndrome characterized by congenital hypothyroidism and neonatal diabetes and similar phenotypes were observed in mouse knockout models of Glis3. Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated Thyroid Stimulating Hormone (TSH) and thyroglobulin (TG). However, the inconsistent presentation of clinical features associated with this CH has made it difficult to ascertain a causative mechanism. Future elucidation of the biological functions of GLIS3 in the thyroid will be crucial to the discovery of new therapeutic opportunities for the treatment of CH.
    Xuan Yao1,2, Hongfeng Xia1,2, Yu-cheng Wang2,3 and Hao Ying1,2*
    Abstract: It has been known for a long time that thyroid hormone regulates metabolism. Thyroid hormone action is primarily mediated by Thyroid Hormone Receptors (TRs). The transcriptional regulation by TRs is modulated by coregulators including coactivators and corepressors. Emerging evidence suggested that coregulators are critical for metabolic regulation mediated by TR. This review describes recent in vivo findings that improve our understanding of the roles of coregulators and provides an alternative way to enhance our knowledge on TR-mediated metabolic regulation. In order to delineate the complex mechanisms involved, we compare the results obtained from the researches employing different lines of mouse genetically modified. It is found that both corepressors and coactivators are indispensible for the full function of TR. We also discuss the challenge and future direction in the research field of thyroid hormone action in metabolism.
    Mini Review
    Teresa L Mastracci* and Carmella Evans-Molina
    Abstract: A gradually expanding body of literature suggests that Thyroid Hormone (TH) and Thyroid Hormone Receptors (TRs) play a contributing role in pancreatic and islet cell development, maturation, and function. Studies using a variety of model systems capable of exploiting species-specific developmental paradigms have revealed the contribution of TH to cellular differentiation, lineage decisions, and endocrine cell specification. Moreover, in vitro and in vivo evidence suggests that TH is involved in islet β cell proliferation and maturation; however, the signaling pathway(s) connected with this function of TH/TR are not well understood. The purpose of this review is to discuss the current literature that has defined the effects of TH and TRs on pancreatic and islet cell development and function, describe the impact of hyper- and hypothyroidism on whole body metabolism, and highlight future and potential applications of TH in novel therapeutic strategies for diabetes.
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