Volume 5, Number 2, June 2008

EDITORIALThe clock stopped, never to go again…
Professor Peter J Grant

Diabetes Vasc Dis Res 2008;5:75.

REVIEWMammalian hibernation: a naturally reversible model for insulin resistance in man?
Sandra L Martin

Mammalian hibernators such as ground squirrels store massive amounts of fat each autumn. These fat depots serve as the main source of metabolic fuel throughout the winter, gradually decreasing over a period of months until the animals emerge from hibernation each spring. Fat deposition occurs on an approximately annual, i.e. on a circannual, basis. Although this rhythm occurs in the absence of environmental temperature and light cues, it is entrained by the length of daylight, with peak fat deposition occurring as days shorten in the autumn. Here we examine the circ-annual cycle of hibernation, and then explore the similarities and differences between the obligatory, yet reversible, natural obesity and accompanying insulin resistance of natural hibernation, and the pandemic of human obesity and metabolic syndrome.

Diabetes Vasc Dis Res 2008;5:76-81.

POPULAR
TOPICREVIEWThe nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism
Hélène Duez, Bart Staels

Circadian rhythms are normal variations in physiological processes that occur over the period of a day. These rhythms are essential for the organism since they allow anticipatory metabolic regulations to prepare for the up-coming feeding or rest period. Disturbances of the biological clock predispose to metabolic disorders such as dyslipidaemia, insulin resistance and obesity. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. The nuclear receptors Rev-erbα and RORα are clock components involved in the regulation of the core clock circuitry. They are also important regulators of lipid and lipoprotein metabolism, adipogenesis and vascular inflammation. Moreover, they cross-talk with several other nuclear receptors controlling energy homeostasis. Therefore, Rev-erbα and RORα may play a central role in the coordination of metabolic processes and circadian outputs.

Diabetes Vasc Dis Res 2008;5:82-88.

POPULAR
TOPICREVIEWMolecular clocks, type 2 diabetes and cardiovascular disease
Madhu J Prasai, Jyothis T George, Eleanor M Scott

The westernised world is in the midst of an epidemic of type 2 diabetes and associated cardiovascular disease. These closely interlinked conditions have a common pathophysiological basis underpinned by insulin resistance and the metabolic syndrome. Contemporary changes in environmental factors on a background of genetic susceptibility are thought to account for the increases seen. Life on earth is governed by the 24-hour environment of light and darkness cycling with the rotation of the earth. Numerous metabolic and physiological pathways are coordinated to this 24-hour cycle by an endogenous clock. Recent epidemiological evidence and animal data suggest that disturbance of circadian rhythms through genetic and environmental influences on the molecular clock is pivotal in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. This review describes current knowledge on the topic.

Diabetes Vasc Dis Res 2008;5:89-95.

POPULAR
TOPICREVIEWPlatelet hyperactivity in type 2 diabetes: role of antiplatelet agents
Arun Natarajan, Azfar G Zaman, Sally M Marshall

Type 2 diabetes mellitus increases atherothrombotic risk. Platelets in individuals with diabetes show increased activity at baseline and in response to agonists, ultimately leading to increased aggregation. Increased expression of platelet surface adhesion molecules and receptors, enhanced production of thromboxane and thrombin and disturbances in platelet calcium homeostasis are well documented. As intra-arterial thrombi are initiated by platelets, strategies to limit acute thrombotic events have largely focused on antiplatelet agents. Aspirin remains the cornerstone of antiplatelet therapy but appears to have limited benefit in diabetes. Use of thienopyridines and platelet glycoprotein IIb/IIIa receptor inhibitors has been shown to benefit high-risk patient populations. This review summarises the different platelet abnormalities characterised in diabetes and the role of currently used antiplatelet agents.

Diabetes Vasc Dis Res 2008;5:138-144.

POPULAR
TOPICORIGINAL PAPERIndependent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study
Karen Chen, Jason B Lindsey, Amit Khera, James A De Lemos, Colby R Ayers, Abhinav Goyal, Gloria L Vega, Sabina A Murphy, Scott M Grundy, Darren K Mcguire

Diabetes mellitus (DM) has been termed a "coronary disease equivalent", yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk.
Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging.
Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1–1.8; OR 1.8, 95% CI 1.3–2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6–3.2). All analyses of AAP yielded qualitatively similar results.
In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.

Diabetes Vasc Dis Res 2008;5:96-101.

ORIGINAL PAPERAdiponectin attenuates endothelial dysfunction induced by oxidised low-density lipoproteins
Stuart Plant, Brett Shand, Peter Elder, Russell Scott

We investigated whether the adipocytokine, adiponectin, protected the endothelium against damage induced by oxidised low-density lipoprotein cholesterol (oxLDL). Human umbilical vein endothelial cells were cultured with either 200 or 350 µg/ml oxLDL, with or without adiponectin purified from human serum (12 µg/ml). Cellular oxidative status was assessed by measuring reactive oxygen species (ROS), peroxynitrite and glutathione (GSH) levels, while cell function was evaluated by measuring nitric oxide (NO) levels and immunohistochemical examination of proteins in the adherens cell junction.
At a concentration of 200 µg/ml, oxLDL induced a small increase in ROS and peroxynitrite levels, a two-fold increase in GSH levels and no changes in NO levels or localisation of proteins in the adherens junction.
However, 350 µg/ml of oxLDL induced a marked increase in ROS and peroxynitrite levels, a four-fold reduction in GSH levels and a significant decrease in NO levels and disruption of the adherens junctions. Addition of adiponectin to the cultures resulted in maintenance of normal ROS, peroxynitrite and GSH levels, with no change in either NO levels or protein localisation in the adherens junction.
This study demonstrates that adiponectin protects against endothelial dysfunction and cellular disruption induced by oxLDL, with this effect being due, in part, to maintenance of intracellular GSH levels.

Diabetes Vasc Dis Res 2008;5:102-108.

ORIGINAL PAPEREndothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans
Farook Thameem, Sobha Puppala, Nedal H Arar, Michael P Stern, John Blangero, Ravindranath Duggirala, Hanna E Abboud

Genetic variants of the endothelial nitric oxide synthase (eNOS) gene such as T-786C, Glu298Asp and 27bp-VNTR have been examined for their association with type 2 diabetes (T2DM)-related traits in various populations but not in Mexican Americans. However, the results from such studies have been controversial. This study investigated whether these three polymorphisms are associated with T2DM and its related traits in Mexican Americans, a population at high risk for T2DM and its complications. The study participants (n=670; 39 families) were genotyped for the three polymorphisms using polymerase chain reaction followed by restriction fragment length polymorphism assay. Association analyses between these polymorphisms and T2DM and its related phenotypes were carried out using a measured genotype approach as implemented in the computer program SOLAR.
Of the variants examined, only the 27bp-VNTR variant exhibited significant association with high-density lipoprotein cholesterol (HDL-C) (p=0.04) and diastolic blood pressure (DBP) levels (p=0.02) after accounting for trait-specific covariates. The carriers of the rare allele (27bp-VNTR-4a) were found to have decreased HDL-C and increased DBP levels. In conclusion, of the genetic polymorphisms examined at the eNOS locus, only 27bp-VNTR appears to be a minor contributor to the variation in T2DM-related traits in Mexican Americans.

Diabetes Vasc Dis Res 2008;5:109-113.

ORIGINAL PAPERMetabolic syndrome and incidence of type 2 diabetes in patients with manifest vascular disease
Annemarie MJ Wassink, Yolanda Van Der Graaf, Sabita S Soedamah-Muthu, Wilko Spiering, Frank LJ Visseren On Behalf Of The Smart Study Group*

Risk reduction in patients with clinically manifest vascular disease focuses on preventing new vascular events and not on prevention of type 2 diabetes. However, given the common pathophysiological pathways involved in the development of atherosclerosis and type 2 diabetes, it is probable that people with atherosclerotic vascular disease have an elevated risk of type 2 diabetes. The present prospective cohort study investigated the incidence of type 2 diabetes and the effect of the presence of metabolic syndrome on the incidence of type 2 diabetes in 4,022 patients with clinically manifest atherosclerosis, included in the study from September 1996 to June 2006. Patients who died (n=456), who were lost to follow-up (n=84) and those with diabetes at baseline (n=558) were excluded, leaving 2,924 patients for analysis. The incidence of diabetes was assessed by questionnaire (self-reported diabetes).
During 13,726 person-years of follow-up (median follow-up 4.3 years, range 2.4–7.0 years), there were 152 type 2 diabetes cases (5.2%), corresponding to an incidence rate of 11.1 (95% CI 9.4–13.0) per 1,000 person-years. Patients with metabolic syndrome were at increased risk of incident type 2 diabetes compared to those without metabolic syndrome, with an adjusted hazard ratio of 5.7 (95% CI 3.7–8.9) for Revised National Cholesterol Education Program, 6.0 (4.1–9.0) for National Cholesterol Education Program and 4.0 (2.7–6.1) for International Diabetes Federation definitions of metabolic syndrome. Of all metabolic syndrome components, abdominal obesity was most strongly associated with incident type 2 diabetes (94% higher risk of type 2 diabetes for 1 standard deviation (11.3 cm) increase in waist circumference).
In conclusion, patients with manifest atherosclerosis are at high risk of developing type 2 diabetes. Metabolic syndrome identifies those at the highest risk and is an easy to use clinical tool. Abdominal obesity is a strong individual predictor of type 2 diabetes. Patients with manifest atherosclerosis and metabolic syndrome may derive particular benefit from lifestyle interventions focusing on weight reduction.

Diabetes Vasc Dis Res 2008;5:114-122.

ORIGINAL PAPERAdiponectin induces NF-κB activation that leads to suppression of cytokine-induced NF-κB activation in vascular endothelial cells: globular adiponectin vs. high molecular weight adiponectin
Atsuko Tomizawa, Yoshiyuki Hattori, Kikuo Kasai, Yasuko Nakano

Adiponectin circulates in plasma as various isoforms. However, the biological activity of each isoform has not been firmly established. High molecular weight (HMW) adiponectin may be the active form of adiponectin, while a proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), has recently been shown to activate vascular endothelial cells. We compared HMW adiponectin with gAd to investigate whether they could activate nuclear factor kappa B (NF-κB) and suppress cytokine-induced NF-κB activation in vascular endothelial cells. HMW adiponectin was found to activate NF-kB modestly compared to the activation observed with gAd. HMW adiponectin requires a shorter incubation period to demonstrate inhibition against tumour necrosis factor alpha (TNFα)-induced NF-κB activation, compared with gAd. gAd strongly activates NF-κB, thereby inducing the expression of various pro-inflammatory and adhesion molecule genes, and requires a longer incubation period to show inhibition against cytokine-induced NF-κB activation. Thus, HMW adiponectin might function to protect against inflammatory stimuli, while cleavage of adiponectin at inflammatory sites might enhance the inflammatory process.

Diabetes Vasc Dis Res 2008;5:123-127.

POPULAR
TOPICORIGINAL PAPERGenetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study
Kathryn P Burdon, Allison B Lehtinen, Carl D Langefeld, J Jeffrey Carr, Stephen S Rich, Barry I Freedman, David Herrington, Donald W Bowden

Epoxide hydrolase is involved in metabolism of vasoactive and anti-inflammatory epoxyeicosatrienoic acids to their corresponding diols. Consequently, epoxide hydrolase 2 (EPHX2) is a candidate cardiovascular disease (CVD) gene. We investigated EPHX2 for association with subclinical CVD in European American (EA) and African American (AA) families from the Diabetes Heart Study. The R287Q polymorphism was associated with carotid artery calcified plaque (CarCP) in EAs. Other EPHX2 polymorphisms were associated with coronary artery calcified plaque (CorCP), CarCP or carotid artery intima-media thickness (IMT). Polymorphism rs7837347 was associated with all traits in the AAs (p=0.003, 0.001 and 0.017, respectively). Polymorphism rs7003694 displayed association with IMT (p=0.017) and, along with rs747276, a trend towards association with CorCP in diabetic EAs (p=0.057 and 0.080, respectively). These results provide additional evidence that EPHX2 contributes to the risk of subclinical CVD, although the true trait defining polymorphisms may not be identified and the effect size could be small.

Diabetes Vasc Dis Res 2008;5:128-134.

LETTERCarotid artery stenting in the Zucker rat: a novel, potentially ‘diabetes-specific’ model of in-stent restenosis
Aisling C McMahon, Hala Zreiqat, Harry C Lowe

Diabetes Vasc Dis Res 2008;5:145-146.

SHORT REPORTRosiglitazone increases bioactive testosterone and reduces waist circumference in hypogonadal men with type 2 diabetes
Dheeraj Kapoor, Kevin s Channer, T hugh Jones

The purpose of this study was to assess the effect of rosiglitazone on bioavailable, free and total testosterone levels in hypogonadal men with type 2 diabetes. Sixteen type 2 diabetic men with hypogonadism were studied before and after administration of rosiglitazone (8 mg/day) for six months, with assessments performed every two months on two consecutive days. We measured testosterone and sex hormone binding globulin (SHBG), visceral adiposity, high-sensitivity CRP (hs-CRP), lipids, microalbuminuria and blood pressure.
There was a significant increase in free (p=0.01), bioavailable (p=0.007) and total testosterone (p=0.002), as well as SHBG (p=0.03) levels, with rosiglitazone treatment. Waist circumference and waist / hip ratio decreased with the improvement in insulin sensitivity and glycaemic control (p=0.01). There was also a significant reduction in hs-CRP (p=0.02) and urinary albumin excretion. No significant effect on blood pressure or the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL to HDL) was seen.
In conclusion, the insulin-sensitiser rosiglitazone increases bioavailable, free and total testosterone and SHBG levels in hypogonadal men with type 2 diabetes.

Diabetes Vasc Dis Res 2008;5:135-137.