An Interactive Web Application for the Statistical Analysis of Continuous Glucose Monitoring Data in Epidemiological Studies.

MOTIVATION: Continuous glucose monitoring (CGM) systems are an essential part of novel technology in diabetes management and care. CGM studies have become increasingly popular among researchers, healthcare professionals, and people with diabetes due to the large amount of useful information that can be collected using CGM systems. The analysis of the data from these studies for research purposes, however, remains a challenge due to the characteristics and large volume of the data. RESULTS: Currently, there are no publicly available interactive software applications that can perform statistical analyses and visualization of data from CGM studies. With the rapidly increasing popularity of CGM studies, such an application is becoming necessary for anyone who works with these large CGM datasets, in particular for those with little background in programming or statistics. CGMStatsAnalyser is a publicly available, user-friendly, web-based application, which can be used to interactively visualize, summarize, and statistically analyze voluminous and complex CGM datasets together with the subject characteristics with ease.

Evaluating the efficacy and safety of GKT137831 in adults with type 1 diabetes and persistently elevated urinary albumin excretion: a statistical analysis plan.

BACKGROUND: The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. METHODS/DESIGN: The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the "Guidelines for the content of statistical analysis plans in clinical trials" to support transparency and reproducibility of the trial findings. DISCUSSION: With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. TRIAL REGISTRATION: ANZCTR registry: ACTRN12617001187336. Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.

A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.

PURPOSE: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN: This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES: Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION: This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.

Acute metabolic and cardiovascular effects of mirabegron in healthy individuals.

AIMS: To quantify acute energy expenditure, supraclavicular skin temperature and cardiovascular responses to four doses of the ß3-adrenoceptor agonist, mirabegron. MATERIALS AND METHODS: A total of 17 individuals (11 men, six women) participated in this ascending-dose study, receiving single 50-, 100-, 150- and 200-mg doses of mirabegron on four separate days with 3 to 14 days wash-out between each dose. All variables were measured each visit from baseline to 180 minutes post mirabegron treatment. To determine brown adipose tissue (BAT) thermogenic efficacy at each dose, energy expenditure and supraclavicular skin temperature were compared from baseline to 180 minutes post mirabegron treatment. To examine safety, changes in cardiovascular variables at 100, 150 and 200 mg were compared with the standard clinical dose of 50 mg. RESULTS: Energy expenditure significantly increased after the 100- (35.6 ± 5.4 kJ/h) and 200-mg (35.6 ± 13.1 kJ/h) doses (P ≤ 0.05), and trended towards an increase after 150 mg (24.1 ± 13.6 kJ/h). Supraclavicular skin temperature increased after 50- (0.22 ± 0.1°C), 100- (0.30 ± 0.1°C) and 150-mg mirabegron doses (0.29 ± 0.1°C; P ≤ 0.05). The change in systolic blood pressure was greater after 150- (7.1 ± 1.3 mm Hg) and 200-mg doses (9.3 ± 1.9 mm Hg) than after the 50-mg dose (2.2 ± 1.3 mm Hg; P ≤ 0.05). The change in heart rate was greater after 200 mg (9.0 ± 2.2 bpm) compared with 50 mg (2.9 ± 1.4 bpm; P ≤ 0.05). CONCLUSIONS: A 100-mg dose of mirabegron increases energy expenditure and supraclavicular skin temperature in a ß3-adrenoceptor-specific manner, without the off-target elevations in blood pressure or heart rate observed at higher doses.

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans.

AIMS/HYPOTHESIS: Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans. METHODS: We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [18F]fluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention. RESULTS: Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (-57 ± 6% vs -12 ± 18%, respectively; p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (-50 ± 10% vs -6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected. CONCLUSIONS/INTERPRETATION: The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02236962 FUNDING: This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.

Correction to: Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans.

The baseline insulin data given in Table 1 for the placebo group were incorrectly reported as 51 ± 10 pmol/l instead of 48 ± 10 pmol/l. This mistake also impacts on data reported in Table 4.

Cystatin C estimated glomerular filtration rate and all-cause and cardiovascular disease mortality risk in the general population: AusDiab study.

AIMS: Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population. METHODS: Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFRcysC ) and serum creatinine (eGFRcr ) and albuminuria (uACR) to total and CVD mortality. RESULTS: After adjusting for age, sex, CVD risk factors and uACR, compared with an eGFRcysC >90 mL/min per 1.73 m2 , eGFRcysC <60 mL/min per 1.73 m2 was associated with 56% and 73% increases in the risks for all-cause and CVD mortality, respectively. The respective changes for the c-statistic when eGFRcysC was added to a risk prediction model were 0.003 (95% confidence interval: 0.001 to 0.005) and 0.002 (95% confidence interval: -0.001 to 0.006). The net proportion of non-events assigned a lower-risk category significantly improved with the addition of eGFR (non-event net reclassification index eGFRcr : 1.0% and eGFRcysC : 1.5%) for all-cause mortality, but for CVD mortality, improvements were only significant when eGFR was combined with uACR. The net proportion of events assigned a higher-risk category was not significantly improved. CONCLUSION: In our community-based cohort, reduced eGFRcysC was associated with all-cause and CVD mortality. The addition of chronic kidney disease measures to risk prediction models improved overall risk stratification among those at low risk as opposed to those at high baseline risk of mortality.

A pilot study to examine the tolerability and device preference in type 1 diabetes of insulin aspart administered by InsuJet compared with subcutaneous injection.

BACKGROUND: Jet injectors allow needle-free insulin delivery. The study objective was to compare the tolerability and device preference of subcutaneous insulin aspart delivery by jet injector (InsuJet™; European Pharma Group, Schiphol-Rijk, The Netherlands) with pen injection in an open-label, randomized, crossover pilot study. SUBJECTS AND METHODS: Ten participants with type 1 diabetes underwent two meal tolerance tests 1 week apart. Plasma glucose and serum insulin levels were sampled from 10 min preceding to 240 min after insulin aspart administration by InsuJet or FlexPen(®) (Novo Nordisk Pharmaceuticals Pty. Ltd., Baulkham Hills, NSW, Australia). Insulin dose was calculated using participants' insulin-to-carbohydrate ratios. Immediately after insulin administration, participants drank 500 mL of Ensure(®) (Abbott Australasia Pty. Ltd., Botany, NSW, Australia) (providing 2,240 kJ of energy, 18.6 g of protein, 96 g of carbohydrate, and 3 g of fat). RESULTS: In this small pilot study, the devices were similar in glucose excursion (median [quartile 1, quartile 3], InsuJet vs. FlexPen, 9.4 [4.8, 12.8] vs. 8.1 [5.4, 10.6] mmol/L; P=0.43), in the area under the glucose concentration-time curve for 0-240 min corrected for baseline glucose level (InsuJet vs. FlexPen, 1,230 [623, 2,012] vs. 1,175 [91, 1,774] mmol · min/L; P=0.4), and in insulin absorption over the 240-min period. Devices were similar for participant preference and relative injection pain. CONCLUSIONS: Subcutaneous jet injection of aspart insulin was well tolerated.

Residual proteinuria and eGFR predict progression of renal impairment within 2 years in type 2 diabetic patients with nephropathy who are receiving optimal treatment with angiotensin receptor blockers.

AIM: Proteinuria and estimated glomerular filtration rate (eGFR) predict progression of renal impairment in type 2 diabetic nephropathy (DN) but are they still predictive when these patients are treated with angiotensin receptor blockers (ARB)? We investigated whether residual (after ≥3 months of ARB treatment) urinary protein/creatinine ratio (rPCR) or urinary albumin/creatinine ratio (rACR) and residual eGFR (reGFR), predict subsequent progression. METHODS: One thousand, two hundred and forty-five patients with type 2 DN from two international multi-center studies were analysed. Cross classification of rPCR, rACR with reGFR (rPCR: <1000, 1000-<2000 and ≥2000 mg/g; rACR: <666.7, 666.7-<1333.3 and ≥1333.3 mg/g; reGFR: 15-29, 30-44 and 45-59 mL/min per 1.73 m2). Progression of renal disease exhibited as: end stage renal failure, doubling of serum creatinine, or serum creatinine ≥6 mg/dL. RESULTS: Increasing rPCR or rACR, and decreasing reGFR were strongly associated with increasing risk of renal disease progression, with no evidence of interaction between rPCR and reGFR, or rACR and reGFR. The estimated 24-month risk was low (<8%) for patients with rPCR <1000 mg/g regardless of reGFR, for patients with reGFR ≥45 mL/min per 1.73 m2 regardless of rPCR, or with rPCR between 1000-<2000 mg/g and reGFR ≥30 mL/min per 1.73 m2 . However, the risk rose steeply (to 39.4%) for reGFR <30 mL/min per 1.73 m2 and rPCR ≥2000 mg/g. CONCLUSION: Despite DN patients being treated with ARB, renal disease progression risk over 2 years increases with increasing proteinuria, albuminuria and decreasing eGFR. Recognition of these risk factors' impact is important in patient management and future clinical trial design.

The association between cystatin C and incident type 2 diabetes is related to central adiposity.

BACKGROUND: Cystatin C has recently been shown to be associated with incident type 2 diabetes. This study aims to validate this association and to study the impact of baseline adiposity. METHODS: We investigated the 3-year diabetes incidence in 2849 participants from the French Data of an Epidemiological Study on the Insulin Resistance syndrome study, without overt kidney disease. Odds ratios (ORs) associated with cystatin C were adjusted for classical diabetes risk factors and interactions between cystatin C and these risk factors were studied. RESULTS: Baseline serum cystatin C was significantly associated with incident diabetes on univariate analysis (OR/1 SD of log cystatin C: 1.74; 95% confidence interval [CI] 1.33-2.28; P=0.0001) and after adjustment for age and gender (OR 1.55; 95% CI 1.15-2.10; P=0.0039). This association was independent of serum creatinine-derived measures of baseline renal function and independent of fasting plasma glucose and HbA1c. When body mass index (BMI), waist circumference or baseline insulin resistance index were used as covariates, there was an interaction with cystatin C level. Cystatin C was associated only with incident diabetes for people with BMI, waist circumference or insulin resistance index≥median value with OR (95% CIs), respectively: 1.35 (0.98-1.84, P=0.0625); 1.39 (1.01-1.91, P=0.0441) and 1.41 (1.02-1.94, P=0.0398). CONCLUSIONS: Cystatin C was associated with 3-year incident diabetes but only in people with central adiposity or insulin resistance. This should be considered in further studies assessing the clinical relevance of its prognostic value.

Epidemiology of diabetic kidney disease.

The increasing prevalence of diabetes has led to DKD becoming the leading cause of ESRD in many regions. The economic cost of DKD will grow to prohibitive amounts unless strategies to prevent its onset or progression are urgently implemented. In type 1 and type 2 diabetes, the presence of microalbuminuria and macroalbuminuria confers increased risk of developing ESRD and of death. Comparison of recent studies with earlier historical studies shows that the incidence of ESRD and death has decreased in DKD. Increased risk of albuminuria has been identified in certain non-European ethnic groups. However, the initial concept of progression of DKD as an albuminuric phenotype involving development of microalbuminuria, macroalbuminuria, and then ESRD has had to be modified. Albumin excretion frequently regresses, and GFR can decline without abnormality in albumin excretion. There is emerging evidence that changes in renal function occurring early in the course of diabetes predict future outcomes. The major challenges are to prevent DKD onset, to detect it early, and to improve DKD outcomes globally.

The GIANT study, a cluster-randomised controlled trial of efficacy of education of doctors about type 2 diabetes mellitus management guidelines in primary care practice.

OBJECTIVES: Primary aim: does general practitioner (GP) education on type 2 diabetes treatment improve HbA1c? Secondary aim: cardiovascular risk factors, hypoglycaemia, treatment intensification, health service utilisation, treatment barriers. METHODS: 99 Asia-Pacific GPs were cluster-randomised to be educated on regional diabetes management guidelines (intervention) or continue standard care (control). The intervention employed meetings, reminders, medical record summary sheets and patient result cards. Each GP recruited four type 2 diabetic patients, assessed at baseline, 6 and 12 months. The primary outcome was mean change in HbA1c from 0 to 6 months in patients with baseline HbA1c≥6.5%. RESULTS: 361 patients (93%) completed 6 month follow-up. The primary HbA1c outcome was -0.11% (95% CI -0.27, 0.05) with intervention and -0.22% (95% CI -0.39, -0.05) in the control group (p=0.340). The groups did not differ in control of other glycaemic indices, blood pressure or lipids after 6 or 12 months. In those with HbA1c≥9.0%, approximately 50% received intensified treatment by 6 months, and 30% in the final 6 months. GPs identified treatment costs and patient reluctance to use insulin as management barriers. CONCLUSIONS/INTERPRETATION: A structured GP education programme did not improve HbA1c in patients with type 2 diabetes.

Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy.

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Pyridorin in type 2 diabetic nephropathy.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.

BACKGROUND: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. STUDY DESIGN: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. SETTING & PARTICIPANTS: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. INTERVENTION: The study drug was sulodexide, 200 mg/d. OUTCOME & MEASUREMENTS: The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR. RESULTS: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. LIMITATIONS: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. CONCLUSION: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Epidemiology of diabetic nephropathy.

Diabetic nephropathy affects approximately one third of people with type 1 or type 2 diabetes mellitus. Risk factors affecting progression of kidney disease include baseline albumin excretion, age, glycemic control, blood pressure, serum cholesterol and use of renin-angiotensin system blockers. As the total number of people with diabetes is projected to increase substantially to 2050, the prevalence of diabetic nephropathy will rise dramatically, with concomitant increase in associated cardiovascular mortality and endstage renal disease. This will produce significant social and economic ramifications, particularly in the developing world.

Proteinuria in type 2 diabetic patients with renal impairment: the changing face of diabetic nephropathy.

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of <500 mg/g. Therapy with ACEi and/or ARB at the time of screening was recorded in 94%, where prior medication data was available. In patients with type 2 DN and advanced renal impairment, levels of proteinuria below that which traditionally defines overt diabetic nephropathy, are found in more than one fifth of patients. We suggest that the high prevalence of ACEi and ARB usage in patients with type 2 DN may be effecting the traditional clinical paradigm of type 2 DN.

Type 2 diabetes strengthens the association between pulse pressure and chronic kidney disease: the AusDiab study.

OBJECTIVE: Chronic kidney disease (CKD) is a serious disorder with significant public health impact. Identification of factors associated with risk of progression of kidney disease may help in earlier intervention in high-risk groups. We investigated whether brachial pulse pressure (PP) was associated with 5-year changes in estimated glomerular filtration rate (eGFR) and incident CKD and whether type 2 diabetes modified these associations. METHODS: In the population-based Australian Diabetes, Obesity and Lifestyle Study (AusDiab) 5554 individuals (5.8% with type 2 diabetes) who took part in the 5-year follow-up and had no CKD or microalbuminuria at baseline were included. RESULTS: After adjusting for baseline age, sex, eGFR and use of blood pressure-lowering medication, each baseline SD higher PP was associated with a decline in eGFR of 0.32 ml/min (P=0.006) and an odds ratio (OR) for CKD of 1.29 [95% confidence interval (CI) 1.09-1.53] in individuals without type 2 diabetes. In individuals with type 2 diabetes, eGFR declined by 1.10 ml/min (P=0.011) and the OR for incident CKD was 1.94 (1.14-3.29). Similar associations with eGFR decline were observed with systolic blood pressure and incident CKD in individuals without type 2 diabetes. In individuals with type 2 diabetes, higher systolic blood pressure was only significantly associated with eGFR decline if the diastolic blood pressure was 70 mmHg or less (P for interaction between systolic and diastolic blood pressure: 0.033). CONCLUSIONS: PP is an important risk factor for eGFR decline and incident CKD over a 5-year period, especially in individuals with type 2 diabetes.

The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis.

Most human tumors display inactivation of the p53 and the p16(INK4)/pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16(INK4a) and p14(ARF) (murine p19(ARF)) proteins. p16(INK4a) is deleted in 40-60% of breast cancer cell lines, and p16(INK4a) inactivation by DNA methylation occurs in < or =30% of human breast cancers. In mice genetically heterozygous for p16(INK4a) or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf(+/-) mice have increased E micro -Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf(+/-) mice, mouse mammary tumor virus-ErbB2 Ink4a/Arf(wt) mammary tumors showed increased p16(INK4a), reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.