Elevated fasting vs post-load glucose levels and pregnancy outcomes in gestational diabetes: a population-based study.

AIMS: To examine the relative association between fasting plasma glucose vs post-load (1-h and 2-h) glucose levels based on the oral glucose tolerance test in pregnancy and large-for-gestational-age and hypertensive disorders of pregnancy outcomes. METHODS: All live singleton births between October 2008 and December 2014 in Alberta, Canada were included. Gestational diabetes mellitus was diagnosed using Diabetes Canada criteria. Logistic regression models were used to examine the association between fasting plasma glucose vs post-load values and large-for-gestational-age infants and hypertensive disorders of pregnancy after adjusting for maternal characteristics and pharmaceutical intervention in gestational diabetes pregnancies. RESULTS: Among 257 547 pregnancies, 208 344 (80.9%) had negative 50-g glucose challenge tests, 36 261 (14.1%) had negative 75-g oral glucose tolerance tests, and 12 942 (5.0%) had gestational diabetes based on either elevated fasting plasma glucose (n=4130, 1.6%) or elevated 1-h and/or 2-h oral glucose tolerance test values (n=8812, 3.4%). Large-for-gestational-age and hypertensive disorders of pregnancy rates were 8.1% and 5.1% in negative glucose challenge test pregnancies, 11.0% and 7.0% in negative oral glucose tolerance test pregnancies, 22.4% and 11.9% in gestational diabetes pregnancies with elevated fasting plasma glucose, and 9.1% and 8% in gestational diabetes pregnancies with elevated post-load levels, respectively. Among gestational diabetes pregnancies, those with elevated fasting plasma glucose were at higher risk of large-for-gestational age (adjusted odds ratio 2.66, 95% CI 2.39-2.96) and hypertensive disorders of pregnancy (adjusted odds ratio 1.51, 95% CI 1.33-1.72) outcomes relative to pregnancies with post-load glucose elevations only. Fasting plasma glucose remained significantly associated with adverse outcomes in gestational diabetes pregnancies with and without pharmacological intervention. CONCLUSIONS: Elevated fasting plasma glucose in women with gestational diabetes is a stronger predictor of large-for-gestational-age and hypertensive disorders of pregnancy outcomes than elevated post-load glucose.

History of mood or anxiety disorders and risk of gestational diabetes mellitus in a population-based cohort.

AIM: To examine the association between mood and anxiety disorders and the development of gestational diabetes mellitus in a retrospective population-based cohort study. METHODS: Clinical data from a provincial perinatal health registry were linked to physician claims, hospitalization records and emergency visits to identify any diagnoses of mood or anxiety disorders in the 2 years prior to pregnancy and a subsequent diagnosis of gestational diabetes during pregnancy. The study population included all singleton pregnancies in the Canadian province of Alberta from 1 April 2000 to 31 March 2010. Generalized estimating equations were used to determine the adjusted odds ratio of gestational diabetes, comparing women with and without a history of mood or anxiety disorders. RESULTS: Among 373 674 pregnancies from 253 911 women, 25.7% had a history of mood or anxiety disorders, and 3.8% developed gestational diabetes. The multivariate-adjusted odds of developing gestational diabetes were higher among women with a history of mood or anxiety disorders (odds ratio 1.10, 95% CI 1.06-1.14). CONCLUSIONS: Women with a history of mood or anxiety disorders had a moderately increased risk of developing gestational diabetes.

Patterns of glucose-lowering therapies and neonatal outcomes in the treatment of gestational diabetes in Canada, 2009-2014.

AIM: To examine patterns of use of different glycaemic control agents for treating gestational diabetes mellitus. METHODS: This was a large, retrospective, population-based cohort study of pregnant women with gestational diabetes from Alberta, Canada. We linked data from the Alberta Vital Statistics - Birth database with administrative claims data. Alberta Vital Statistics - Birth data were used to identify births that occurred between 1 January 2009 and 31 December 2014. We used International Classification of Diseases version 9/10 codes to identify women with gestational diabetes, and we excluded women with pre-existing diabetes. RESULTS: Our cohort consisted of 16 857 women with gestational diabetes, with a total of 18 761 birth events between 2009 and 2014. Over the study period, the proportion of women with gestational diabetes who were treated with glycaemic control therapies increased from 25.0% to 31.4% (P<0.0001). The number of pregnancies treated with insulin only increased (from 23.6% to 28.3%; P<0.0001), as did the number treated with metformin, +/- insulin (from 1.4% to 3.2%; P<0.0001). Rates of large-for-gestational-age infants were significantly higher among pregnancies treated with insulin only (17%) or metformin (16.5%) than among pregnancies that did not receive any pharmacological treatment (12.8%). CONCLUSIONS: Our findings show increasing use of insulin and metformin in women with gestational diabetes. Rates of large-for-gestational-age infants were similar among pregnant women receiving either pharmacological treatment, and higher than among pregnant women who did not receive any pharmacological treatment. Future research should explore the long-term outcomes and safety of metformin as an alternative for treating gestational diabetes.

Validation of administrative and clinical case definitions for gestational diabetes mellitus against laboratory results.

AIM: To examine the validity of International Classification of Disease, version 10 (ICD-10) codes for gestational diabetes mellitus in administrative databases (outpatient and inpatient), and in a clinical perinatal database (Alberta Perinatal Health Program), using laboratory data as the 'gold standard'. METHODS: Women aged 12-54 years with in-hospital, singleton deliveries between 1 October 2008 and 31 March 2010 in Alberta, Canada were included in the study. A gestational diabetes diagnosis was defined in the laboratory data as ≥2 abnormal values on a 75-g oral glucose tolerance test or a 50-g glucose screen ≥10.3 mmol/l. RESULTS: Of 58 338 pregnancies, 2085 (3.6%) met gestational diabetes criteria based on laboratory data. The gestational diabetes rates in outpatient only, inpatient only, outpatient or inpatient combined, and Alberta Perinatal Health Program databases were 5.2% (3051), 4.8% (2791), 5.8% (3367) and 4.8% (2825), respectively. Although the outpatient or inpatient combined data achieved the highest sensitivity (92%) and specificity (97%), it was associated with a positive predictive value of only 57%. The majority of the false-positives (78%), however, had one abnormal value on oral glucose tolerance test, corresponding to a diagnosis of impaired glucose tolerance in pregnancy. CONCLUSIONS: The ICD-10 codes for gestational diabetes in administrative databases, especially when outpatient and inpatient databases are combined, can be used to reliably estimate the burden of the disease at the population level. Because impaired glucose tolerance in pregnancy and gestational diabetes may be managed similarly in clinical practice, impaired glucose tolerance in pregnancy is often coded as gestational diabetes.

Quantifying levels of function between different subgroups of chronic ankle instability.

The purpose of this original investigation was to determine if selected sensorimotor, mechanical, and self-reported measures are different among chronic ankle instability (CAI) subgroups, healthy control participants, and lateral ankle sprain copers (LAS-Copers). Ninety-four participants volunteered and were categorized into perceived ankle instability (PI) alone (n = 13), recurrent ankle sprains (RAS) alone (n = 12), PI in combination with RAS (PI-RAS; n = 25), LAS-Copers (n = 18), and controls (n = 26). Participants completed self-assessed global, regional, and psychological health-related quality-of-life (HRQOL) questionnaires and assessments of sensorimotor function and mechanical joint laxity. One-way ANOVAs were performed with the intention of reducing the number of original outcomes into a smaller number of predictor variables. Discriminant functional analysis was used to establish which specific measures best differentiate between groups. Eight outcome measures from neural excitability, postural control, static postural control, and HRQOL showed a significant differentiation between five groups (Wilk's λ = 0.26, χ232  = 114 45, P < 0.001, canonical correlation = 0.80) and correctly determined only 58.1% of group membership, and the PI-RAS and control groups were the only fit in the proposed model. A different model or other sensorimotor outcomes from more dynamic and complex tasks may be needed for the PI, RAS, and LAS-Coper groups.

Validation of administrative data case definitions for gestational diabetes mellitus.

AIM: To examine, using administrative data, the validity of two algorithms for identifying gestational diabetes mellitus: 1) the current National Diabetes Surveillance System algorithm for excluding gestational diabetes cases and 2) gestational diabetes-specific ICD codes in the delivery-related hospitalization. METHODS: This was a retrospective study of all women, aged 18-54 years, residing in Alberta, Canada, with singleton deliveries between 1 April 1999 and 31 March 2010. We linked Alberta Perinatal Health Program data on all deliveries to administrative claims data from Alberta Health using the mother's personal health number. For both gestational diabetes algorithms, we calculated the sensitivity, specificity, positive predictive value, negative predictive value and agreement, using gestational diabetes identified in the Alberta Perinatal Health Program as the 'gold standard'. RESULTS: Our study sample consisted of 411 390 deliveries for 273 152 women. The mean (sd) age was 29.1 (5.6) years and 82.3% of the women were white. Crude rates of gestational diabetes were 3.9% (16 215 cases), 1.3% (5189 cases) and 4.0% (16 440 cases) according to the Alberta Perinatal Health Program, National Diabetes Surveillance System and ICD code-based algorithms, respectively. Compared with the Alberta Perinatal Health Program database, the National Diabetes Surveillance System algorithm had a sensitivity of 25% and specificity of 100%, whereas the gestational diabetes-specific ICD code-based algorithm had a sensitivity of 86% and specificity of 99%. CONCLUSIONS: The National Diabetes Surveillance System algorithm underestimates the number of gestational diabetes cases. A more valid mechanism to identify gestational diabetes prevalence using health administrative data is the use of gestational diabetes-specific ICD-9/10 codes in the delivery hospitalization.

Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies.

AIMS: To determine whether data from observational studies supports the hypothesis of an increased risk of overall and site-specific cancer among individuals with diabetes using exogenous insulin therapies. METHODS: We conducted a comprehensive search of nine key biomedical databases for all years up to December 2011, restricted to the English language. Data from cohort and nested case-control studies were included in random effects meta-analyses of site-specific and overall cancer incidence comparing ever use and new use of: (1) insulin to no insulin and; (2) insulin glargine to other insulins. RESULTS: The search yielded 3052 unique citations, of which 19 were selected for inclusion, representing data for 1,332,120 people and 41,947 cancers. Pancreatic cancer risk was increased among new users of insulin (RR: 3.18, 95%CI: 3.27-3.71, I(2)=32%). New use of insulin glargine was associated with an increased risk of pancreatic cancer (RR: 1.63, 95%CI: 1.05-2.51, I(2)=0%) and prostate cancers (RR: 2.68, 95%CI: 1.50-4.79, I(2)=0%) but a decreased risk of colorectal cancer (RR: 0.78, 95%CI: 0.64-0.94, I(2)=15%). CONCLUSION: New use of insulin or insulin glargine was associated with an increased risk of pancreatic cancer, possibly due to reverse causality. New use of insulin glargine was associated with a decreased risk of colorectal cancer but an increased risk of prostate cancer. Our results should be interpreted with caution due to limitations of included studies.

Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis.

AIMS: Evidence suggests thiazolidinediones (TZDs) may modify the relationship between type 2 diabetes and cancer incidence. We aimed to summarize data from randomized controlled trials (RCTs) and observational studies to examine risk of overall and site-specific cancers with TZD use in individuals with type 2 diabetes. METHODS: We searched 12 key biomedical databases and seven grey literature sources up to June 2011, without language restrictions. We performed separate meta-analyses according to cancer site and study design, comparing ever-use to never-use of TZDs, and pioglitazone alone. RESULTS: The search yielded 1338 unique citations; we included four RCT, seven cohort and nine nested case-control studies, contributing data from 2.5 million people. Estimates from observational studies suggested any TZD use was associated with a decreased risk of colorectal (pooled RR: 0.93, 95%CI 0.87-1.00, P=0.04, I(2)=30%), lung (pooled RR: 0.91, 95%CI 0.84-0.98, P=0.02, heterogeneity (I(2))=35%) and breast (pooled RR: 0.89, 95%CI 0.81-0.98, P=0.02, I(2)=44%) cancer. Risk of overall cancer with TZD use was not significantly modified in RCTs (pooled RR: 0.92, 95%CI 0.79-1.07, P=0.26, I(2)=0%) or observational studies (pooled OR: 0.95, 95%CI 0.78-1.16, P=0.63, I(2)=70%). Pioglitazone use was, however, associated with a decreased risk of overall cancer (colorectal, lung, breast, prostate and renal sub-sites combined) in observational studies (pooled RR: 0.95, 95%CI 0.91-0.99, P=0.009, I(2)=0%). CONCLUSIONS: Our findings suggest that use of TZDs is associated with a modest but significantly decreased risk of lung, colorectal and breast cancers. Results were limited by the paucity of studies designed to answer our research question. Further evaluation of TZD use, cancer risk factors and potential confounders is required.

Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence.

Substantial evidence suggests that people with type 2 diabetes have an increased risk of developing several types of cancers. These associations may be due to a number of direct and indirect mechanisms. Observational studies of these associations, including the potential role for glucose-lowering therapy, are being increasingly reported, but face a number of methodological challenges. This paper is the first of two review papers addressing methodological aspects underpinning the interpretations of links between diabetes and cancer, and suggests potential approaches to study designs to be considered in observational studies. This paper reviews factors related to cancer incidence in the diabetic population; the second paper relates to studies of cancer mortality.

Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias.

AIMS/HYPOTHESIS: Despite the vast body of epidemiological literature on the risk of cancer in people with diabetes, few studies have examined the pattern of cancer risk during different time windows following diabetes onset. The objective of the study was to examine the risks of site-specific cancer in people with incident type 2 diabetes during different time windows following diabetes onset. METHODS: This was a population-based retrospective cohort study. The study period was 1 April 1994 to 31 March 2006; censoring occurred at 31 March 2006, at death or on departure from British Columbia, Canada. Using linked health databases, we identified incident cohorts with and without diabetes, who were matched by age, sex and index year. Following a minimum 2-year cancer washout period, first site-specific cancers were identified prospectively in both cohorts. RESULTS: Within 3 months following diabetes onset, participants with diabetes had significantly increased risks of colorectal, lung, liver, cervical, endometrial, ovarian, pancreatic and prostate cancers. After the initial 3-month period, the risks for colorectal (HR 1.15, 95% CI 1.05, 1.25), liver (HR 2.53, 95% CI 1.93, 3.31) and endometrial (HR 1.58, 95% CI 1.28, 1.94) cancers remained significantly elevated compared with those without diabetes. The diabetes cohort remained at increased risk of pancreatic cancer in later years, but followed a different pattern: HR 3.71 at 3 months-1 year, 2.94 at 1-2 years, 1.78 at 2-3 years and 1.65 at 3-10 years (p value for all <0.01). After an initial period of elevated risk, men with type 2 diabetes subsequently had a decreased risk of prostate cancer (HR 0.82, 95% CI 0.76, 0.88). CONCLUSIONS/INTERPRETATION: People with type 2 diabetes are at increased risk of select cancers; this risk is particularly elevated at the time of diabetes onset, which is likely to be due to increased ascertainment.

Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials.

AIMS/HYPOTHESIS: The purpose of this study was to explore the relationship between hyperglycaemia in type 2 diabetes and risk of cancer incidence or cancer mortality. We were interested to determine if data from major randomised controlled trials would support a hypothesis that improving glycaemic control may reduce the risk of cancer outcomes. METHODS: We included major randomised controlled trials conducted with an overall aim of intensified glycaemic control in type 2 diabetes. We abstracted data from published papers and supplemental material and conducted separate meta-analyses of cancer mortality and cancer incidence. RESULTS: Four trials reported cancer mortality for the intensive (222 events in 53,892 person-years) and standard control (155 events in 38,743 person-years) arms (UK Prospective Diabetes Study [UKPDS] 33, UKPDS 34, Action to Control Cardiovascular Risk in Diabetes [ACCORD] and Veterans Affairs Diabetes Trial [VADT]); the summary risk ratio for cancer mortality was 1.00 (95% CI 0.81-1.24; I² = 0%). Excluding the UKPDS metformin trial resulted in a pooled risk estimate of 1.03 (95% CI 0.83-1.29; I² = 0%). Three trials reported cancer incidence for the study arms (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], PROspective pioglitAzone Clinical Trial In macroVascular Events [PROactive], Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes [RECORD]) with 357 events in 47,974 person-years with improved glycaemic control and 380 events in 45,009 person-years in the control arms; the pooled risk ratio for cancer incidence was 0.91 (95% CI 0.79-1.05; I² = 0%). CONCLUSIONS/INTERPRETATION: Data from large randomised controlled trials of intensified glycaemic control suggest that cancer risk is not reduced by improving glycaemic control in type 2 diabetes. These data therefore do not support the hypothesis that hyperglycaemia is causally linked to increased cancer risk.

Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure.

AIMS/HYPOTHESIS: We explored the relationship between glucose-lowering agents and cancer mortality rates in type 2 diabetes patients, hypothesising a decreased risk of cancer mortality with metformin use and a dose-risk gradient for insulin therapy. METHODS: This was a population-based cohort study using administrative data from Saskatchewan Health, Canada. We identified new users of metformin or sulfonylureas from 1 January 1991 to 31 December 1996, with follow-up until death, departure from the province or 31 December 1999. Cox regression analyses were used to estimate the HR of death from cancer, accounting for time-varying exposure to metformin, sulfonylurea, and exogenous insulin therapy. RESULTS: We identified 10,309 new users of metformin or sulfonylurea. The average follow-up was 5.4 (1.9) years, during which 407 (4.0%) cancer deaths occurred. Adjusting for age, sex and chronic disease score, the adjusted HR for metformin use was 0.80 (95% CI 0.65-0.98) compared with sulfonylurea monotherapy users. Adjusted HRs for subsequent insulin use were 2.22 (0.99-5.00), 3.33 (2.26-4.89) and 6.40 (4.69-8.73) for <3, 3 to 11 and > or = 12 insulin dispensations/year, respectively, compared with patients not on insulin. We observed a similar risk gradient among the sub-cohort of new insulin users. CONCLUSIONS/INTERPRETATION: Our results support previous reports of a decreased risk of cancer outcomes associated with metformin use relative to sulfonylurea monotherapy. We also provide new evidence of a gradient of cumulative insulin dispensations and cancer mortality rates.

Self-monitoring in Type 2 diabetes: a randomized trial of reimbursement policy.

AIM: Self-monitoring of blood glucose is often considered a cornerstone of self-care for patients with diabetes. We assessed whether provision of free testing strips would improve glycaemic control in non-insulin-treated Type 2 diabetic patients. METHODS: Adults with Type 2 diabetes, excluding those with private insurance or using insulin, were recruited through community pharmacies and randomized to receive free testing strips for 6 months or not; all patients received similar baseline education and a glucose meter. Primary outcome was change in HbA(1c) over 6 months. RESULTS: We randomized 262 patients (131 intervention and 131 control subjects). Mean age was 68.4 years (sd 10.9), 48% were male, mean duration of diabetes was 8.2 years (sd 7.2), 97% used oral glucose-lowering agents and mean baseline HbA(1c) was 7.4% (sd 1.2). After 6 months, we observed no difference in HbA(1c) between intervention and control patients, after adjusting for baseline HbA(1c)[adjusted difference 0.03, 95% confidence interval (CI) -0.16, 0.22; P = 0.78]. A per protocol analysis of study completers (152/262; 60%) yielded similar results. Intervention patients reported testing 0.64 days per week more often than control subjects (95% CI 0.18, 1.10; P = 0.007), although testing was not associated with better glycaemic control (Pearson r = -0.10, P = 0.12). CONCLUSIONS: Reducing financial barriers by providing free testing strips did not improve glycaemic control in patients with Type 2 diabetes not using insulin. Our results question the value of policies that reduce financial barriers to testing supplies in this population.

A review of general hepatitis C virus lookbacks in Canada.

BACKGROUND AND OBJECTIVES: This article reviews the Canadian experience with general hepatitis C virus (HCV) lookback programmes. MATERIALS AND METHODS: Comprehensive literature searches were conducted in PubMed, Medline, HealthSTAR and EMBASE. In addition, bibliographic searches were performed on all retrieved articles, and provinces were contacted to determine whether they had performed general HCV lookbacks. RESULTS: Of the seven Canadian general HCV lookbacks identified, two focused specifically on the paediatric population. The proportion of transfused patients presumed to be alive varied from 48.9 to 97.5%. Between 55.3 and 99.1% of letters were successfully delivered. The proportion of patients tested for HCV and subsequently found to be HCV positive varied considerably (66.2-80.4% and 0.9-5.0%, respectively). Newly diagnosed patients represented 42-58% of cases identified. CONCLUSIONS: The Canadian general HCV lookback experience successfully identified previously undiagnosed HCV-positive patients, but the resources required to notify patients are high and the yield is relatively low. The effectiveness may be greatest in the paediatric population.

Enzyme studies on TPPase-reactive cytoplasmic structures observed in early meiotic prophase I of the hamster oocyte.

Ovaries of immature and adult hamsters were incubated in medium containing thiamine pyrophosphate (TPP) to determine the age at which TPPase-reactive cytoplasmic structures first appear in the germ cells, and at what age the structures cease to be present. The structures were found only in oocytes from animals 8-15 days of age. They occur in predictyate germ cells in polyovular follicles and in very early dictyate oocytes in unilaminar follicles. The TPPase-reactive structures were never observed in atretic oocytes, in unilaminar follicles of adult animals, nor in multilaminar follicles of animals at any age. Ovaries of 8-12-day-old animals and adults were then incubated in media in which one of the following substrates was substituted for TPP: uridine diphosphate (UDP), inosine diphosphate (IDP), and adenosine monophosphate (AMP). Half of the samples in each experiment were incubated in medium containing the inhibitor L-p-bromotetramisole. beta-Glycerophosphate was used in control incubations, or the substrate was omitted entirely. The cytoplasmic structures were found to be reactive after incubation in UDP-containing media, but not after incubation in media containing AMP. With IDP as substrate, reactions were atypical and confined to peripheral regions of the cytoplasm. Other sites of enzyme activity after incubation with the various substrates (cell membranes, zona pellucida, endoplasmic reticulum and Golgi apparatus) are also described and discussed.