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Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL / HL ratio is a determinant of low HDL 2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre β -HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre β -HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived * These authors contributed equally to the work contained in this manuscript. cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown.Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance-and diabetes-associated dyslipidaemia.Keywords Cholesteryl ester transfer protein, high-density lipoproteins, insulin resistance, lecithin:cholesterol ac...

The mechanisms responsible for the decreased high density lipoprotein (HDL) cholesterol levels associated with obesity and insulin resistance are not well understood. Lecithin: cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) are key factors in the esterification of cholesterol in HDL and the subsequent transfer of cholesteryl ester towards apolipoprotein B-containing lipoproteins. Phospholipid transfer protein (PLTP) may be involved in the regulation of HDL particle size. We therefore measured the activities of LCAT, CETP and PLTP using exogenous substrate assays, as well as lipids, lipoproteins, insulin and C-peptide in fasting plasma from eight healthy obese men (body mass index > 27 kg m-2) and 24 non-obese subjects. The obese men had lower levels of HDL cholesterol (P < 0.05) and higher levels of plasma triglycerides (P < 0.05), insulin (P < 0.05) and C-peptide (P < 0.01), as compared to the quartile of subjects with the lowest body mass index (BMI < 22.4 kg m-2). CETP and PLTP activities were elevated in the obese men by 35% (P < 0.01) and by 15% (P < 0.05), respectively. LCAT activity was comparable among the quartiles. Linear regression analysis showed that CETP activity was positively correlated with body mass index (P < 0.02), fasting blood glucose (P < 0.05) and plasma C-peptide (P < 0.05). PLTP activity was positively related to body mass index (P < 0.01), waist to hip circumference ratio (P < 0.001), as well as to fasting blood glucose (P < 0.05) and plasma C-peptide (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Background The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. Methods In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. Findings Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48•7%] women; median age 51•0 years [IQR 40•7-59•7]). 199 415 individuals were included in the derivation cohort (91 786 [48•4%] women) and 199 431 (92 269 [49•1%] women) in the validation cohort. During a maximum follow-up of 43•6 years (median 13•5 years, IQR 7•0-20•1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease eventrates for increasing non-HDL cholesterol categories (from 7•7% for non-HDL cholesterol <2•6 mmol/L to 33•7% for ≥5•7 mmol/L in women and from 12•8% to 43•6% in men; p<0•0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2•6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1•1, 95% CI 1•0-1•3 for non-HDL cholesterol 2•6 to <3•7 mmol/L to 1•9, 1•6-2•2 for ≥5•7 mmol/L in women and from 1•1, 1•0-1•3 to 2•3, 2•0-2•5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of...

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Cyclic Cushing's syndrome (CS) is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolism can occur regularly or irregularly with intercyclic phases ranging from days to years. To formally diagnose cyclic CS, three peaks and two troughs of cortisol production should be demonstrated. Our review of 65 reported cases demonstrates that cyclic CS originates in 54% of cases from a pituitary corticotroph adenoma, in 26% from an ectopic ACTH-producing tumour and in about 11% from an adrenal tumour, the remainder being unclassified. The pathophysiology of cyclic CS is largely unknown. The majority of patients with cyclic CS have clinical signs of CS, which can be either fluctuating or permanent. In a minority of patients, clinical signs of CS are absent. The fluctuating clinical picture and discrepant biochemical findings make cyclic CS extremely hard to diagnose. Clinicians should therefore be aware of this clinical entity and actively search for it in all patients with suspected CS but normal biochemistry or vice versa. Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic CS. Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing. When cyclic CS is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency. In cases of suspected ectopic ACTH production, specific biochemical testing for carcinoids or neuroendocrine tumours is required, including measurements of serotonin in platelets and/or urine, chromogranin A and calcitonin.European Journal of Endocrinology 157 245-254

Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.