Cardiovascular risk reduction in insulin resistant states

Introduction: Insulin resistance is the hall mark of a number of pathological conditions and is thought to play a major role in the cardiovascular risk associated with them. This thesis critically evaluates two insulin resistant conditions - polycystic ovary syndrome (PCOS) and type 2 diabetes (T2DM) - where there are many unresolved issues. During the course of these studies, the effect of weight loss and medications in modifying cardiovascular risk in these conditions was evaluated.Methods: The first studies focused on a randomised open labelled parallel study of metformin and rimonabant in obese patients with PCOS. Subsquently, an extension to this study was undertaken where patients who were on rimonabant were changed over to metformin, whereas those on metformin were continued on metformin for another 3 months. As part of this study the effect of rimonabant and metformin on incretin hormones in patients with PCOS was studied.The next studies focused on a randomised double blind placebo controlled study on the pleotrophic effect of atorvastatin in patients with PCOS. Subsequent metformin therapy after atorvastatin treatment was undertaken. This study led to the investigation of the effect of simvastatin and atorvastatin on biological variation of lipids in patients with T2DM that has got implications in treating to lipid targets. A corollary to this study was whether the biological variation of LDL calculated using Friedewald formula differed from that of direct LDL.Results: In the first series of studies, after 12 weeks of rimonabant there was a significant reduction in anthropometric and metabolic parameters as well as biochemical hyperandrogenemia in patients with PCOS. There was no change in any of these parameters in the metformin treated group. In three months extension arm to this study, metformin maintained the weight loss as well as enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone. There was a significant and reversible increase in glucose-dependent insulinotropic polypeptide (GIF) levels after 3 months of rimonabant treatment. There were no changes in GIF or glucagon-like peptide-1 (GLP-1) levels with metformin.In the second series of studies it has shown that atorvastatin was effective in reducing inflammation, biochemical hyperandrogenemia and metabolic parameters in patients with polycystic ovary syndrome after a 12 week period compared to placebo. The subsequent effect of three months metformin treatment was augmented by atorvastatin pre-treatment compared to placebo pre-treatment. In the subsequent study it was shown that the coefficient of variation (CV) of TC, LDL, HDL and TG on simvastatin was significant but comparable to atorvastatin in patients with T2DM. However, subsequent directly measured LDL cholesterol was shown to be an order of magnitude more stable when taking equivalent doses of atorvastatin rather than simvastatin.Conclusion: Both weight loss using rimonabant and atorvastatin were effective in reducing biochemical hyperandrogenemia and metabolic profile in patients with PCOS. The effect of rimonabant might be partly mediated through modulating GIF levels

The effect of variation of fatty substances found in the blood on patients with type 2 diabetes. ISRCTN27314990

Background and study aimsHigh blood sugar and fat content are well-recognised risk factors for causing the formation of obstructive plaques in arteries which lead to cardiovascular disease, for example heart attacks. From earlier studies, we know that after eating, high sugar and fat content in the blood seems to have an association with cardiovascular risk in both healthy persons and individuals with type 2 diabetes. This study aims to examine the effect on the body of variation of fat levels in the blood compared to constant fat levels, during a constant high sugar state.Who can participate?This study is open to individuals with type 2 diabetes and non-diabetic individuals between the ages of 30 - 65 years with a body mass index between 27 - 40 kg/m² (overweight or obese).What does the study involve?This study includes one screening visit and two procedural visits during which participants will have sugar infused into their blood. Blood will be drawn at various time points during the procedure for analysis. Participants will be closely monitored by trained medical and nursing staff throughout the procedure. There will be one week break between visit 2 and visit 3 to prevent the carried over effects of infusions. We expect individual participants would be in the study for 3-4 weeks in total.What are the possible benefits and risks of participating?Benefits: No immediate benefits, however, the knowledge gained in the study will help the management of diabetes in the future.Risks: Potential for a reaction to the fatty substance given by the drip and discomfort from the cannula (plastic needle). A fully advanced life support trained research doctor will be present at all times to manage any emergency situation that arises however this is a rare occurrence. All the potential risks will be fully disclosed and discussed with potential participants at screening before he/she consents to take part in the study.Where is the study run from?University of Hull (UK)When is the study starting and how long is it expected to run for?June 2014 to October 2021Who is funding the study?University of Hull (UK

Mediators of Inflammation in Polycystic Ovary Syndrome in Relation to Adiposity

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age group and is associated with a higher cardiovascular risk. Obesity, mainly visceral adiposity, is prevalent in patients with PCOS. Obesity is associated with low-grade inflammation and raised inflammatory cytokines, both of which are also described in patients with PCOS. In this paper, the potential relationships between fat distribution, adipocyte dysfunction and, altered inflammatory markers in patients with PCOS have been discussed

Investigation of pituitary disease

The close relationship between the upper respiratory tract (nose and paranasal sinuses) and the lower respiratory tract (tracheobronchial tree) is something that is manifestly observed by all practising rhinologists. There is strong epidemiological evidence both from cross-sectional and longitudinal studies that rhinitis and asthma are related. Many patients with allergic rhinitis who do not have asthma symptoms demonstrate bronchial hyperresponsiveness, a key feature of asthma. Patients with allergic rhinitis and bronchial hyperresponsiveness are at greater risk of developing asthma than those with normal bronchial challenges. Asthma and rhinitis share many common risk factors. There are many studies which support rhinitis as a risk factor for asthma both in children and adults. There are many anatomical and physiological similarities between the upper and lower airways. Eosinophilic infiltration of the nasal mucosa has been demonstrated in patients with asthma irrespective of the presence of nasal symptoms, further supporting the hypothesis that asthma and rhinitis are clinical manifestations of the same disease

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

  The discovery of kisspeptins in the recent past remoulded current understanding of the neuroendocrine axis relating to the regulation of human puberty and reproduction. Kisspeptins have been recognised to act upstream of GnRH and have been shown to play a vital role in the control of the hypothalamic–pituitary–gonadal axis via regulation of gonadotrophin secretion, onset of puberty, and control of fertility. KNDy (kisspeptin/neurokinin-B/dynorphin) neurons have been suggested to modulate GnRH pulsatile secretion, which is required to support reproductive function in both sexes. They have also been involved in mediating both positive and negative sex steroid feedback signals to GnRH neurons and serve as a vital connection between reproduction and metabolic status of the body. When kisspeptin is administered to healthy humans, and in patients with reproductive disorders, it strongly and directly stimulates GnRH and subsequent LH secretion and enhances LH pulse frequency. These observations suggest that kisspeptins are a potential novel therapeutic approach for treating disorders with either pathologically reduced or augmented gonadotrophins pulsatile secretion and is currently a focus of translational research. Kisspeptins have also been identified in several peripheral reproductive organs, indicating their role in modulation of ovarian function, embryo implantation, and placentation, but a great deal of work remains to be done to explore further in this regard, and the evidence is only available from studies done on animal models. In this review we will mainly focus on current available evidence related to the role of kisspeptins in controlling GnRH pulse frequency, specifically their role in puberty, fertility, and reproduction. We will also be appraising other factors that regulate the kiSS1/Kisspeptin/GPR-54 system. (Endokrynol Pol 2015; 66 (6): 534–547)    Odkrycie kisspeptyn, które miało miejsce całkiem niedawno, odmieniło obecne rozumienie osi neuroendokrynnej, związanej z regulacją okresu dojrzewania i rozrodu. Odkryto, że kisspeptyny działają przed GnRH i odgrywają istotną rolę w kontroli osi podwzgórze–przysadka– nadnercza poprzez regulację wydzielania gonadotropiny, rozpoczęcia okresu dojrzewania oraz kontroli płodności. Zasugerowano, że komórki KNDy (kisspeptyna/neurokinina-B/dynorfina) modulują pulsacyjne uwalnianie GnRH, wymagane, aby wspomagać funkcję rozrodczą u obu płci. Komórki te są również zaangażowane w przekazywanie zarówno pozytywnych, jak i negatywnych sygnałów hormonów płciowych do neuronów GnRH, a także stanowią kluczowe połączenie między reprodukcją i stanem metabolicznym ciała. Kiedy kisspeptyna jest podawana jednostkom zdrowym i pacjentom z zaburzeniami płodności, silnie i bezpośrednio stymuluje GnPH i dalsze uwalnianie LH oraz poprawia częstotliwość impulsów LH. Obserwacje te przedstawiają kisspeptyny jako nowe potencjalne terapeutyczne podejście w leczeniu zaburzeń patologicznie obniżonego lub zwiększonego pulsacyjnego uwalniania gonadotropin i obecnie stanowi główny punkt zainteresowania badań przekładających się na zastosowanie praktyczne. Kisspeptyny zidentyfikowano także w kilku organach obwodowych, uczestnicząc w modulacji czynności jajników, implantacji zarodka oraz placentacji, lecz dalsze badania w tym kierunku będą wymagały jeszcze wiele wysiłku, a dowody można uzyskać jedynie z badań przeprowadzanych na modelach zwierzęcych. W niniejszej pracy autorzy skupili się głównie na obecnie dostępnych dowodach związanych z rolą kisspeptyn w kontrolowaniu częstotliwości impulsów GnRH, a zwłaszcza ich rolą w okresie dojrzewania, płodności oraz reprodukcji. W niniejszym artykule poddano ocenie także inne czynniki regulujące system kiSS1/Kisspeptin/GPR-54. (Endokrynol Pol 2015; 66 (6): 534–547)

The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome

Background There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS) and there is evidence that statins improve metabolic parameters in these patients. However, there is some data to show that statins increase the risk of incipient diabetes. Material and Methods We have previously shown that 12-weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc-analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double blind placebo controlled study, 40 medication naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results There was a significant reduction in HOMA-β (240±3.2vs.177±2.3; pvalue<0.01) after 12 weeks of atorvastatin treatment which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment. There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI) (r2=0.02;p=0.72), testosterone (r2=0.13;p=0.49), SHBG (r2=0.22;p=0.48), hsCRP (r2=0.19;p=0.64), triglycerides (r2=0.09;p=0.12), total cholesterol (r2=0.11;p=0.32) or LDL-C (r2=0.19;p=0.38). Conclusion Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in βcell requirement with improvement of insulin resistance rather than a reduction of βcell function

Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues

Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome

© 2016 John Wiley & Sons Ltd Context: Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. Objective: To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Design: Randomized, open-labelled parallel study. Setting: Endocrinology outpatient clinic in a referral centre. Subjects: Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m 2 were recruited. Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Main outcome measures: Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment. Results: After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment. Conclusion: This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss

Soy protein improves cardiovascular risk in subclinical hypothyroidism : a randomized double-blinded crossover study

© 2017 Endocrine Society. Background: Soy protein with isoflavones appears to have an adverse effect on thyroid function, but it is not known whether it is the protein or isoflavone component that is deleterious. The effect of isoflavone-free soy on thyroid function was determined in patients with subclinical hypothyroidism, with a secondary aim of assessing its effect on cardiovascular risk indices. Methods: This was a randomized, double-blind, crossover study involving 80 patients with subclinical (compensated) hypothyroidism. Patients were randomly assigned to either isolated soy (isoflavone-free) protein (SP) or casein protein (CP) supplementation for 8 weeks, washed out for 8 weeks, and then crossed over for a further 8-week period. Results: Thyroid function was unaffected by either a SP or CP. There were significant decreases in fasting glucose (4.760.6 vs 5.561.4, P < 0.01), insulin resistance (3.3±3.0 vs 3.8±3.4, P = 0.05), total cholesterol (4.4 ± 0.9 vs 5.3 ± 1.2, P < 0.01), triglycerides (0.9 ± 0.5 vs 1.7 ± 0.9, P < 0.1), and highly sensitive C-reactive protein (hsCRP; 0.8 ± 0.7 vs 2.6 ± 2.8, P < 0.01) in the SP group compared with the CP group. Blood pressure, low-density lipoprotein, and high-density lipoprotein remained unchanged in both groups. Conclusion: SP alone had no effect on thyroid function in patients with subclinical hypothyroidism and resulted in a significant reduction in fasting glucose, insulin resistance, total cholesterol, triglycerides, and hsCRP compared with CP