Kirsten E. Peters

A comprehensive investigation of variants in genes encoding adiponectin ( ADIPOQ ) and its receptors ( ADIPOR1/R2 ), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome

BackgroundLow levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals.MethodsSixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling.ResultsMeta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134).ConclusionsGenetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

Effect of Continuous Positive Airway Pressure Therapy on Cardiovascular Risk Factors in Patients with Type 2 Diabetes and Obstructive Sleep Apnea

CONTEXT Few prospective intervention studies have examined the effect of continuous positive airway pressure (CPAP) therapy on cardiovascular disease (CVD) risk factors in diabetes. OBJECTIVE Our objective was to determine whether CPAP improves CVD risk factors in patients with type 2 diabetes and obstructive sleep apnea (OSA). DESIGN AND SETTING This was a randomized parallel group intervention trial in an urban Australian community. PATIENTS Fifty-nine participants of the Fremantle Diabetes Study Phase II at high risk for OSA consented to confirmatory polysomnography followed by randomization to a 3-month CPAP intervention initiated early (<1 wk) or late (1-2 months). MAIN OUTCOME MEASURES Patients were assessed before and 1 and 3 months after CPAP started. Tests for repeated measures were used to compare variables of interest over time. RESULTS Forty-four patients (75%) completed the study. Their mean ± sd age was 66.1 ± 8.8 yr, and 61.4% were male. Completers and noncompleters had similar age, sex, diabetes duration, apnea-hypopnea index, and Epworth Sleepiness Scale (P ≥ 0.29). There were no differences in outcome between early and late randomization, and the data were pooled. The Epworth Sleepiness Scale decreased between entry and 1 month [-4.8 (-6.5 to -3.1), P < 0.001]. Blood pressure improved between entry and 3 months (from 149 ± 23/80 ± 12 to 140 ± 18/73 ± 13 mm Hg; P ≤ 0.007). Pulse rate declined within the first month [-6 (-10 to -2) beats/min, P = 0.002]. Glycemic control and serum lipids, which were mostly within recommended target ranges at entry, did not change. CONCLUSIONS Three months of CPAP in community-based people with type 2 diabetes significantly decreased blood pressure and pulse rate but did not influence metabolic control.

Polymorphisms associated with normal memory variation also affect memory impairment in schizophrenia

Neurocognitive dysfunction is a core feature of schizophrenia with particularly prominent deficits in verbal episodic memory. The molecular basis of this memory impairment is poorly understood and its relatedness to normal variation in memory performance is unclear. In this study, we explore, in a sample of cognitively impaired schizophrenia patients, the role of polymorphisms in seven genes recently reported to modulate episodic memory in normal subjects. Three polymorphisms (GRIN2B rs220599, GRM3 rs2189814 and PRKCA rs8074995) were associated with episodic verbal memory in both control and patients with cognitive deficit, but not in cognitively spared patients or the pooled schizophrenia sample. GRM3 and PRKCA acted in opposite directions in patients compared to controls, possibly reflecting an abnormal brain milieu and/or adverse environmental effects in schizophrenia. The encoded proteins balance glutamate signalling vs. excitotoxicity in complex interactions involving the excitatory amino acid transporter 2 (EAAT2), implicated in the dysfunctional glutamatergic signalling in schizophrenia. Double carrier status of the GRM3 and PRKCA minor alleles was associated with lower memory test scores and with increased risk of schizophrenia. Single nucleotide polymorphism (SNP) rs8074995 lies within the PRKCA region spanned by a rare haplotype associated with schizophrenia in a recent UK study and provides further evidence of PRKCA contribution to memory impairment and susceptibility to schizophrenia. Our study supports the utility of parsing the broad phenotype of schizophrenia into component cognitive endophenotypes that reduce heterogeneity and enable the capture of potentially important genetic associations.

Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes

In a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25‐p24. The 6p region contains Dysbindin (DTNBP1), considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1 and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic re‐examination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1 and its association with schizophrenia, using a HapMap‐based gene‐tagging approach. We genotyped 39 tSNPs in a sample of 336 cases and 172 controls of Anglo‐Irish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control sample were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5′ region. Neither global haplotype tests, nor specific analysis of the “risk” haplotype previously reported in an ethnically related population, the Irish high‐density schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our sample. The framework and results of this study should facilitate further attempts at re‐analysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation.

The Relationship between Hypomagnesemia, Metformin Therapy and Cardiovascular Disease Complicating Type 2 Diabetes: The Fremantle Diabetes Study

Background Low serum magnesium concentrations have been associated with cardiovascular disease risk and outcomes in some general population studies but there are no equivalent studies in diabetes. Metformin may have cardiovascular benefits beyond blood glucose lowering in type 2 diabetes but its association with hypomagnesemia appears paradoxical. The aim of this study was to examine relationships between metformin therapy, magnesium homoeostasis and cardiovascular disease in well-characterized type 2 patients from the community. Methods and Findings We studied 940 non-insulin-treated patients (mean±SD age 63.4±11.6 years, 49.0% males) from the longitudinal observational Fremantle Diabetes Study Phase I (FDS1) who were followed for 12.3±5.3 years. Baseline serum magnesium was measured using stored sera. Multivariate methods were used to determine associates of prevalent and incident coronary heart disease (CHD) and cerebrovascular disease (CVD) as ascertained from self-report and linked morbidity/mortality databases. 19% of patients were hypomagnesemic (serum magnesium <0.70 mmol/L). Patients on metformin, alone or combined with a sulfonylurea, had lower serum magnesium concentrations than those on diet alone (P<0.05). There were no independent associations between serum magnesium or metformin therapy and either CHD or CVD at baseline. Incident CVD, but not CHD, was independently and inversely associated with serum magnesium (hazard ratio (95% CI) 0.28 (0.11–0.74); P = 0.010), but metformin therapy was not a significant variable in these models. Conclusions Since hypomagnesemia appears to be an independent risk factor for CVD complicating type 2 diabetes, the value of replacement therapy should be investigated further, especially in patients at high CVD risk.

Fear of falling is common in patients with type 2 diabetes and is associated with increased risk of falls

AIMS fear of falling is an important falls-related symptom that has received little attention in studies of falls risk in older adults with type 2 diabetes. METHODS matched pairs of participants with diabetes or with normoglycaemia (n = 186 per group) recruited from a community-based survey underwent an assessment of fear of falling and associated falls risk factors. Multivariate methods examined associations between fear of falling and risk factors for history of recent falls. RESULTS compared with the normoglycaemic participants, those with diabetes had worse mobility (slow timed Up and Go test times: 16.2 versus 4.9%, P < 0.01), more fear of falling (24.2 versus 15.1%, P < 0.05) and more activity restriction from fear of falling (indoors: 14.0 versus 4.8%, P = 0.006), but there was no increase in reported recent falls. In the combined sample, a history of recent falls was negatively associated with fear-related limitation of outdoor activities (odds ratio (95% confidence interval): 0.30 (0.15-0.58), P < 0.001) and positively associated with age (1.65 (1.20-2.28) per 10-year increase, P = 0.002) and use of antidepressants (2.14 (1.02-4.50, P = 0.044). The frequency of falls in those with recurrent falls was negatively associated with measures of balance. CONCLUSIONS type 2 diabetes is associated with increased fear of falling and fear-associated activity restriction, and this modifies the risk of falls even in the face of increased falls risk factors including worse mobility. Future studies of falls in diabetes need to consider that fear of falling is an important modifier of the relationship between risk factors and falls.

Effect of continuous positive airway pressure therapy on sexual function and serum testosterone in males with type 2 diabetes and obstructive sleep apnoea

There have been no studies of the effect of continuous positive airway pressure (CPAP) therapy on erectile dysfunction (ED) and serum testosterone in men with type 2 diabetes and obstructive sleep apnoea (OSA), a patient group at increased risk of ED and hypogonadism. The aim of this study was to determine whether CPAP improves sexual and gonadal function in males with type 2 diabetes and a pre‐CPAP apnoea–hypopnoea index >15/h.

Identification of Novel Circulating Biomarkers Predicting Rapid Decline in Renal Function in Type 2 Diabetes: The Fremantle Diabetes Study Phase II

OBJECTIVE To assess the ability of plasma apolipoprotein (apo) A-IV (apoA4), apo C-III, CD5 antigen-like (CD5L), complement C1q subcomponent subunit B (C1QB), complement factor H–related protein 2, and insulin-like growth factor binding protein 3 (IBP3) to predict rapid decline in estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS Mass spectrometry was used to measure baseline biomarkers in 345 community-based patients (mean age 67.0 years, 51.9% males) from the Fremantle Diabetes Study Phase II (FDS2). Multiple logistic regression was used to determine clinical predictors of rapid eGFR decline trajectory defined by semiparametric group-based modeling over a 4-year follow-up period. The incremental benefit of each biomarker was then assessed. Similar analyses were performed for a ≥30% eGFR fall, incident chronic kidney disease (eGFR <60 mL/min/1.73 m2), and eGFR decline of ≥5 mL/min/1.73 m2/year. RESULTS Based on eGFR trajectory analysis, 35 participants (10.1%) were defined as “rapid decliners” (mean decrease 2.9 mL/min/1.73 m2/year). After adjustment for clinical predictors, apoA4, CD5L, and C1QB independently predicted rapid decline (odds ratio 2.40 [95% CI 1.24–4.61], 0.52 [0.29–0.93], and 2.41 [1.14–5.11], respectively) and improved model performance and fit (P < 0.001), discrimination (area under the curve 0.75–0.82, P = 0.039), and reclassification (net reclassification index 0.76 [0.63–0.89]; integrated discrimination improvement 6.3% [2.1–10.4%]). These biomarkers and IBP3 contributed to improved model performance in predicting other indices of rapid eGFR decline. CONCLUSIONS The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes.

Prevalence, Incidence, and Prognosis of Hepatobiliary Disease in Community-Based Patients with Type 2 Diabetes: The Fremantle Diabetes Study

CONTEXT Few studies have examined morbidity and mortality associated with hepatobiliary disease in diabetes. Most have used administrative databases and/or have had limited/incomplete data including recognized risk factors for hepatobiliary disease. OBJECTIVE The objective of the study was to explore the relationship between type 2 diabetes and hepatobiliary disease in well-characterized patients with detailed risk factor data including viral hepatitis status and hemochromatosis genotype. DESIGN This was a community-based longitudinal observational study. SETTING The study was conducted in an urban Australian community. PATIENTS The study included 1294 patients of mean ± SD aged 64.1 ± 11.3 yr and 5156 age-, gender-, and ZIP code-matched nondiabetic controls. MAIN OUTCOME MEASURES Prevalent and incident hepatobiliary disease and hepatobiliary disease-related death were measured. Competing risks proportional hazard models provided independent associates of these end points. RESULTS During 13,705 patient-years (mean 11.5 yr), 144 patients had an initial hepatobiliary disease-related hospitalization/cancer registration vs. 403 controls during 63,937 person-years of follow-up, an incidence rate ratio of 1.66 (95% confidence interval 1.37-2.02). Incident hepatobiliary disease was associated with a lower glycosylated hemoglobin and higher urinary albumin to creatinine ratio. Nearly half of the patients (49.9%) died during follow-up [crude mortality ratio vs. nondiabetic controls 1.97 (1.16-3.32)], and 21 (3.3%) from hepatobiliary disease including two cases of cirrhosis attributable to nonalcoholic steatohepatitis. Hepatobiliary disease-related death was independently predicted by prior hepatobiliary disease, hepatitis C seropositivity, retinopathy, and peripheral neuropathy; higher educational level and higher fasting serum glucose were protective. CONCLUSIONS Hepatobiliary disease and associated mortality are increased in type 2 diabetes. Multiple factors including fatty infiltration, microangiopathy, and direct glucotoxicity are likely to contribute, but hospitalization and death due to cirrhosis from nonalcoholic steatohepatitis appear uncommon.

Lifetime depression history and depression risk in type 2 diabetes: A case-control study

AIMS To assess whether a personal history of depression assists in risk prediction for depression in type 2 diabetes. METHODS Age- and sex-matched participants with and without diabetes from the Busselton Health Survey were assessed for current and previous depression using the 9-item Patient Health Questionnaire and the Brief Lifetime Depression Scale (BLDS). In the diabetic participants, the temporal relationship between first depression episode and diabetes onset was also explored. RESULTS In 184 paired participants (age 70.2±10.1years, 50% female), those with diabetes had a higher prevalence of any current depression (12.5% vs 4.3%, P<0.01) and lifetime history of major depression (30.6% vs 21.1%, P=0.06) compared to those without diabetes. After adjustment, lifetime major depression history was independently associated with any current depression in the combined sample (odds ratio (95% CI): 5.55 (3.09-9.98), P<0.001), in those with diabetes (4.17 (2.00-8.71), P<0.001), in those without diabetes (8.29 (3.24-21.23), P<0.001) and in diabetes whether sub-divided by depression first occurring before or after diabetes onset (before: 3.16 (1.38-7.24), P=0.007; after: 2.77 (1.00-7.70), P=0.051). CONCLUSIONS Obtaining a lifetime history of major depression using the BLDS assists in depression risk prediction in type 2 diabetes regardless of whether depression preceded diabetes onset or not.