Rachel M. Williamson

Prevalence of and Risk Factors for Hepatic Steatosis and Nonalcoholic Fatty Liver Disease in People With Type 2 Diabetes: the Edinburgh Type 2 Diabetes Study

OBJECTIVE Type 2 diabetes is an established risk factor for development of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and clinical correlates of these conditions in a large cohort of people with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 939 participants, aged 61–76 years, from the Edinburgh Type 2 Diabetes Study (ET2DS)—a large, randomly selected population of people with type 2 diabetes—underwent liver ultrasonography. Ultrasound gradings of steatosis were compared with magnetic resonance spectroscopy in a subgroup. NAFLD was defined as hepatic steatosis in the absence of a secondary cause (screened by questionnaire assessing alcohol and hepatotoxic medication use, plasma hepatitis serology, autoantibodies and ferritin, and record linkage to determine prior diagnoses of liver disease). Binary logistic regression was used to analyze independent associations of characteristics with NAFLD. RESULTS Hepatic steatosis was present in 56.9% of participants. After excluding those with a secondary cause for steatosis, the prevalence of NAFLD in the study population was 42.6%. Independent predictors of NAFLD were BMI, lesser duration of diabetes, HbA1c, triglycerides, and metformin use. These remained unchanged after exclusion of participants with evidence of hepatic fibrosis from the group with no hepatic steatosis. CONCLUSIONS Prevalences of hepatic steatosis and NAFLD were high in this unselected population of older people with type 2 diabetes, but lower than in studies in which ultrasound gradings were not compared with a gold standard. Associations with features of the metabolic syndrome could be used to target screening for this condition.

The Edinburgh Type 2 Diabetes Study: study protocol

BackgroundRisk factors underlying the development and progression of some of the less well-recognised complications of type 2 diabetes, including cognitive impairment and non-alcoholic fatty liver disease, are poorly understood. The Edinburgh Type 2 Diabetes Study was established in 2006 in order to investigate the role of potential risk factors in these complications, as well as to further investigate mechanisms underlying the development and progression of micro and macrovascular disease in type 2 diabetes.Methods and designThe study is designed as a prospective cohort study. Participants recruited at baseline (2006–2007) constitute 1066 men and women aged 60 to 75 years with established type 2 diabetes, living in the Lothian region of central Scotland. Subjects underwent detailed cognitive and physical examination, the latter including measures of micro- and macro-vascular disease, glycaemic control, body fat composition and plasma inflammatory markers, cortisol, lipids and liver function tests. Participants were re-examined after one year with hepatic ultrasonography and additional measures of vascular disease. This paper reports the methods of recruitment to the study and examinations performed at baseline and one year. Follow-up cognitive, vascular and liver assessments are scheduled for 2010–2011 when subjects will have been in the study for 4 years.DiscussionThis study will provide a wealth of epidemiological and biomarker data that should be invaluable in the identification of potentially modifiable, causal risk factors for diabetes-related cognitive impairment, liver dysfunction and vascular disease, which can be targeted for the development of preventive and therapeutic interventions.

Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes. RESEARCH DESIGN AND METHODS Eight hundred thirty-one men and women (aged 60–75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change. RESULTS Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, −0.12) and of subclinical markers with actual 4-year decline (standardized β, −0.12, 0.12, and −0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors. CONCLUSIONS Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.

Metabolic parameters associated with arterial stiffness in older adults with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Objective: Increased arterial stiffness, as measured by pulse wave velocity (PWV), is associated with increased cardiovascular risk in the general population. Few studies have examined factors associated with increased PWV in people with Type 2 diabetes. The aim of this study was to determine whether there was a link between PWV and clinical variables associated with central obesity, in men and women with Type 2 diabetes. Research designs and methods: Eight hundred and sixty individuals [mean age (±SD) 69 (±4) years] from the Edinburgh Type 2 Diabetes Study, underwent applanation tonometry using a high-fidelity micromanometer. PWV was measured by sequentially recording electrocardiogram-gated carotid and femoral artery waveforms. Results: Waist circumference (&bgr; = 0.10, P < 0.01) and waist : hip ratio (&bgr; = 0.10, P < 0.01) were independently associated with PWV, but not with BMI. In a stepwise multiple regression model, mean arterial pressure (&bgr; = 0.26, P < 0.01) and age (&bgr; = 0.23, P < 0.01) were strongly associated with PWV. The associations between the central obesity measures and PWV were independent of age, sex, duration of diabetes and metabolic factors associated with central obesity. Duration of diabetes (&bgr; = 0.10, P < 0.01) and glycated hemoglobin (&bgr; = 0.09, P < 0.01) were also found to be independent predictors of arterial stiffness. Obesity biomarkers such as C-reactive protein, leptin, tumour necrosis factor-&agr; and interleukin-6 were not associated with arterial stiffness. Conclusion: Central obesity in people with Type 2 diabetes was associated with increased arterial stiffness. This association was independent of the conventional factors associated with central obesity and further studies are required to identify the mechanisms involved.

The use of ultrasound to diagnose hepatic steatosis in type 2 diabetes: intra- and interobserver variability and comparison with magnetic resonance spectroscopy.

AIM To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. MATERIALS AND METHODS Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo (1)H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. RESULTS Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2-5.7), 4.1 (3.1-8.5) and 19.4 (12.9-27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. CONCLUSION Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.

Prevalence and markers of advanced liver disease in type 2 diabetes

BACKGROUND Type 2 diabetes is a risk factor for progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis and cirrhosis. We examined the prevalence of advanced liver disease in people with type 2 diabetes and analysed the effectiveness of liver function tests (LFTs) as a screening tool. METHODS Participants (n = 939, aged 61-76 years) from the Edinburgh Type 2 Diabetes Study, a randomly selected population of people with type 2 diabetes, underwent abdominal ultrasonography. Hyaluronic acid (HA) and platelet count/spleen diameter ratio (PSR) were used as non-invasive markers of hepatic fibrosis and portal hypertension. Subjects were screened for secondary causes of liver disease that excluded them from a diagnosis of NAFLD. The efficacy of LFTs [alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT)] in screening for liver disease was determined. RESULTS Cirrhosis was identified by ultrasound in four participants (0.4%). Ten (1.1%) had evidence of portal hypertension (PSR < 909), and two (0.2%) had hepatocellular carcinoma. Fifty-three participants (5.7%) had evidence of hepatic fibrosis (HA > 100 ng/ml in the absence of joint disease); a further 169 had HA > 50 ng/ml. In participants with NAFLD-related fibrosis (HA > 100 ng/ml), 12.5% had an elevated ALT level and 17.5% had an elevated GGT level. CONCLUSION The prevalence of hepatic fibrosis and cirrhosis were lower than expected. The use of LFTs to screen for liver disease missed most cases of fibrosis predicted by raised HA levels.

Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes

OBJECTIVE To investigate determinants of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), including single nucleotide polymorphisms (SNPs), in the DDAH1, DDAH2, and AGXT2 genes and their associations with prevalent and incident cardiovascular disease (CVD) in older adults with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS Prevalent CVD was assessed in men and women aged 60–75 years with type 2 diabetes as part of the Edinburgh Type 2 Diabetes Study (ET2DS), and the participants were prospectively followed up for 4 years for incident CVD. Dimethylarginines were measured in 783 of these subjects, and genotyping for tag SNPs in the DDAH1, DDAH2, and AGXT2 genes was performed in 935 subjects. RESULTS Plasma ADMA levels were significantly associated with SNPs in DDAH1 (top SNP rs1554597; P = 9.0E-09), while SDMA levels were associated with SNPs in AGXT2 (top SNP rs28305; P = 1.3E-04). Significant, independent determinants of plasma ADMA were sex, L-arginine, creatinine, fasting glucose, and rs1554597 (all P < 0.05; combined R2 = 0.213). Determinants of SDMA were age, sex, creatinine, L-arginine, diabetes duration, prevalent CVD, and rs28305 (all P < 0.05; combined R2 = 0.425). Neither dimethylarginine was associated with incident CVD. None of the investigated SNPs were associated with overall CVD, although subgroup analysis revealed a significant association of AGXT2 rs28305 with intermittent claudication. CONCLUSIONS Our study in a well-characterized population with type 2 diabetes does not support reported associations or causal relationship between ADMA and features of diabetes or CVD.

Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People With Type 2 Diabetes The Edinburgh Type 2 Diabetes Study

OBJECTIVE Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation. RESEARCH DESIGN AND METHODS People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia. RESULTS Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA1c, BMI, and treatment type. CONCLUSIONS Daytime sleepiness may be a novel risk factor for hypoglycemia.

GLUCOCORTICOID TREATMENT AND IMPAIRED MOOD, MEMORY AND METABOLISM IN PEOPLE WITH DIABETES: THE EDINBURGH TYPE 2 DIABETES STUDY

Objective Both type 2 diabetes and glucocorticoid therapy are highly prevalent. Although people with type 2 diabetes may be more susceptible to adverse effects of glucocorticoids, and it is recommended that glucocorticoid therapy is avoided for fear of worsening glycaemic control, the extent to which this advice is followed and the consequences when glucocorticoids are prescribed are poorly documented. The aim was to assess the characteristics of people with type 2 diabetes prescribed glucocorticoids in a real-world setting and to quantify resulting adverse effects. Design Cross-sectional cohort study. Methods Cardiometabolic variables, body fat distribution, cognitive function and mood were studied in the 1066 participants of the Edinburgh Type 2 Diabetes Study, of whom 162 (15%) were taking systemic, topical or inhaled glucocorticoids. Results Glucocorticoid therapy was more common in women and in smokers but was not avoided in patients with diabetic complications or cardiovascular risk factors. People taking glucocorticoids were more centrally obese with slightly higher HbA1c and total serum cholesterol but were no more likely to have hepatic steatosis or hypertension. Glucocorticoid treatment was associated with substantially lower mood and greater anxiety. Women taking glucocorticoid therapy were twice as likely to report depressive symptoms compared with those not taking treatment. Glucocorticoid therapy was also associated with poorer cognitive function among those with subclinical atherosclerosis, as indicated by low ankle–brachial pressure index. Conclusions Glucocorticoids are prescribed commonly for people with type 2 diabetes despite being associated with adverse indices of glycaemic control, cardiovascular risk factors, mood and cognitive function.

Non‐invasive hepatic biomarkers (ELF and CK18) in people with type 2 diabetes: the Edinburgh type 2 diabetes study

Type 2 diabetes is an established risk factor for the presence and progression of fatty liver. Little is known about the distributions and correlates of hepatic non‐invasive biomarkers in community‐based populations with diabetes, unselected for liver disease. We aimed to identify the distribution of, and metabolic risk factors associated with serum cytokeratin‐18 (CK18) and the Enhanced Liver Fibrosis score (ELF), in a large, representative cohort of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study, ET2DS).