Diabetes-related risk factors and survival among individuals with type 2 diabetes and breast, lung, colorectal, or prostate cancer.

Premature death in diabetes is increasingly caused by cancer. The objectives were to estimate the excess mortality when individuals with type 2 diabetes(T2D) were diagnosed with cancer, and to examine the impact of modifiable diabetes-related risk factors. This longitudinal nationwide cohort study included individuals with T2D registered in the Swedish National Diabetes Register between 1998-2019. Poisson models were used to estimate mortality as a function of time-updated risk-factors, adjusted for sex, age, diabetes duration, marital status, country of birth, BMI, blood pressure, lipids, albuminuria, smoking, and physical activity. We included 690,539 individuals with T2D and during 4,787,326 person-years of follow-up 179,627 individuals died. Overall, the all-cause mortality rate ratio was 3.75 [95%confidence interval(CI):3.69-3.81] for individuals with T2D and cancer compared to those remaining free of cancer. The most marked risk factors associated to mortality among individuals with T2D and cancer were low physical activity, 1.59 (1.57-1.61) and smoking, 2.15 (2.08-2.22), whereas HbA1c, lipids, hypertension, and BMI had no/weak associations with survival. In a future with more patients with comorbid T2D and cancer diagnoses, these results suggest that smoking and physical activity might be the two most salient modifiable risk factors for mortality in people with type 2 diabetes and cancer.

Factors associated with attendance at clinical follow-up of a cohort with screen-detected type 2 diabetes: ADDITION-Denmark.

AIMS: To determine the association between concurrent overall burden of disease, cardiovascular disease, cancer, self-rated health, HbA1c levels, and attendance at clinical follow-up of the Danish arm of the ADDITION-study. METHODS: Logistic regression models were used to study factors proposed being associated with attendance in clinical follow-up. We used data from clinical examinations, questionnaires and national registers at a time-point near the follow-up examination. RESULTS: A total of 1119 participants were eligible for the follow-up conducted a median of 12.8 years (IQR 11.6; 13.4) after type 2 diabetes diagnosis by screening. Concurrent high burden of disease was associated with lower attendance (OR 0.6 (95% CI: 0.4; 0.9) for high-versus no burden of disease). Concurrent cardiovascular disease and cancer showed no statistically significant association with attendance (OR 1.0 (95% CI: 0.7; 1.4)) and (OR 0.8 (95% CI: 0.6; 1.1) for (disease versus no disease). Similarly, self-rated health (OR 0.7 (95% CI: 0.5; 1.0) poor-versus good self-rated health) and HbA1c levels (OR 1.0 (95% CI: 0.9; 1.2 unit=10mmol/mol)) were not statistically significant associated with attendance. CONCLUSIONS: This study showed a lower attendance in clinical follow-up after nearly 13years among individuals with concurrent high burden of disease. No associations were found between concurrent CVD, cancer, self-rated health and Hba1c levels and attendance.

Validity of Danish register diagnoses of myocardial infarction and stroke against experts in people with screen-detected diabetes.

BACKGROUND: Administrative patient registers are often used to estimate morbidity in epidemiological studies. The validity of register data is thus important. This study aims to assess the positive predictive value of myocardial infarction and stroke registered in the Danish National Patient Register, and to examine the association between cardiovascular risk factors and cardiovascular disease based on register data or validated diagnoses in a well-defined diabetes population. METHODS: We included 1533 individuals found with screen-detected type 2 diabetes in the ADDITION-Denmark study in 2001-2006. All individuals were followed for cardiovascular outcomes until the end of 2014. Hospital discharge codes for myocardial infarction and stroke were identified in the Danish National Patient Register. Hospital medical records and other clinically relevant information were collected and an independent adjudication committee evaluated all possible events. The positive predictive value for myocardial infarction and stroke were calculated as the proportion of cases recorded in the Danish National Patient Register confirmed by the adjudication committee. RESULTS: The positive predictive value was 75% (95% CI: 64;84) for MI and 70% (95% CI: 54;80) for stroke. The association between cardiovascular risk factors and incident cardiovascular disease did not depend on using register-based or verified diagnoses. However, a tendency was seen towards stronger associations when using verified diagnoses. CONCLUSIONS: Our results show that studies using only register-based diagnoses are likely to misclassify cardiovascular outcomes. Moreover, the results suggest that the magnitude of associations between cardiovascular risk factors and cardiovascular outcomes may be underestimated when using register-based diagnoses.

Clustering of microvascular complications in Type 1 diabetes mellitus.

AIMS: To describe to what extent microvascular complications exhibit clustering in persons with Type 1 diabetes, and to assess whether the presence of one complication modified the strength of the association between the other two. METHODS: We conducted a cross-sectional analysis of the electronic medical records of 2276 persons with Type 1 diabetes treated in a specialized care hospital in Denmark in 2013. We used log-linear analysis to describe associations between diabetic kidney disease, neuropathy and retinopathy and logistic regression models to quantify the magnitude of associations adjusting for potential confounders. RESULTS: The median duration of diabetes was 24 years and median HbA1c was 63 mmol/mol (7.9%). We found strong indication of clustering and found no evidence that presence of one complication modified the association between the other two. In models adjusted for diabetes duration and HbA1c, persons with neuropathy had an OR of 2.15 (95% CI: 1.73-2.66) for concurrent diabetic kidney disease. Those with retinopathy had an OR of 2.49 (1.92-3.24) for diabetic kidney disease and of 2.66 (1.94-3.64) for neuropathy. CONCLUSIONS: Microvascular complications in persons with Type 1 diabetes exhibit strong clustering. However, the association between any pair of complications is not modified by the presence of the third.

Physical Activity and Improvement of Glycemia in Prediabetes by Different Diagnostic Criteria.

Context: The effects of physical activity (PA) on improvement of glycemia may differ between prediabetic individuals defined by oral glucose tolerance test vs glycated hemoglobin (HbA1c). Objective: We studied the association between PA and improvement of glycemia in individuals with prediabetes defined by glucose vs HbA1c criteria. Design, Setting, and Participants: From the Whitehall II study, 957 participants with prediabetes defined by isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), or both and 457 with prediabetes defined by HbA1c were included. Main Outcome Measures: The associations of PA with concomitant changes in glucose-related outcomes during 5 years of follow-up were analyzed. A recursive partitioning analysis was performed to study heterogeneity in the association between baseline PA and the probability of reversion to normoglycemia. Results: After 5 years of follow-up, 405 (42%) individuals with glucose-defined prediabetes reverted to normal glucose tolerance (NGT). A 5-year increase in moderate-to-vigorous-intensity PA was associated with improvements in insulin sensitivity and ß-cell function, but PA was not generally associated with reversion to NGT. Only among women ≥50 years with i-IFG or i-IGT, higher amounts of PA were associated with higher probability of reversion to NGT. In HbA1c-defined prediabetes, only 20 individuals (4.4%) reverted to normoglycemia, and PA was not associated with improvement in glycemic markers. Conclusions: PA may be particularly important for reversion to normoglycemia among older women with i-IFG or i-IGT. Individuals with prediabetes identified by HbA1c have a low probability of reversion to normoglycemia, and their changes in glycemia are not related to PA.

Associations of objectively measured physical activity and abdominal fat distribution.

INTRODUCTION/PURPOSE: Visceral adipose tissue (VAT) and physical activity are both independent predictors of Type 2 diabetes. Physical activity and overall obesity are inversely associated with each other. Yet the nature of the association between objectively measured dimensions of physical activity and abdominal fat distribution has not been well characterized. We aimed to do so in a middle-age to elderly population at high risk of diabetes. METHODS: A cross-sectional analysis of 1134 participants of the ADDITION-PRO study. VAT and subcutaneous adipose tissue (SAT) were assessed one-dimensionally by ultrasonography and physical activity with combined accelerometry and HR monitoring. Linear regression of physical activity energy expenditure (PAEE) and time spent in different physical activity intensity levels on VAT and SAT was performed. RESULTS: Median body mass index (BMI) was 26.6 kg·m and PAEE was 28.1 kJ·kg·d, with 18.9 h·d spent sedentary, 4.5 h·d in light-intensity physical activity, and 0.4 h·d in moderate-intensity physical activity. PAEE was significantly negatively associated with VAT, and in women, PAEE was also significantly negatively associated with SAT. The difference in VAT was -1.1 mm (95% confidence interval [CI] = -1.8 to -0.3) per 10-kJ·kg·d increment, and the corresponding difference in SAT for women was -0.6 mm (95% CI = -1.2 to -0.04) in models adjusted for age, sex, and waist circumference. Exchanging 1 h of light physical activity with moderate physical activity was significantly associated with VAT (-4.5 mm, 95% CI = -7.6 to -1.5). Exchanging one sedentary hour with light physical activity was significantly associated with both VAT (-0.9 mm, 95% CI = -0.1 to -1.8) and SAT (-0.4 mm, 95% CI = -0.0 to -0.7). CONCLUSIONS: In this population with low physical activity levels, cross-sectional findings indicate that increasing overall physical activity and decreasing time spent sedentary is important to avoid the accumulation of metabolically deleterious VAT.

The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. METHODS: The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (n(total) = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). RESULTS: The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(ß) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10(-5)) and fasting total cholesterol (ß = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10(-4)). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. CONCLUSION: Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

The role of diabetes co-morbidity for tuberculosis treatment outcomes: a prospective cohort study from Mwanza, Tanzania.

BACKGROUND: Due to the association between diabetes and pulmonary tuberculosis (TB), diabetes may threaten the control of TB. In a prospective cohort study nested in a nutrition trial, we investigated the role of diabetes on changes in anthropometry, grip strength, and clinical parameters over a five months follow-up period. METHODS: Among pulmonary TB patients with known diabetes status, we assessed anthropometry and clinical parameters (e.g. haemoglobin) at baseline and after two and five months of TB treatment. A linear mixed-effects model (repeated measurements) was used to investigate the role of diabetes during recovery. RESULTS: Of 1205 TB patients, the mean (standard deviation) age was 36.6 (13.0) years, 40.9% were females, 48.9% were HIV co-infected, and 16.3% had diabetes. TB patients with diabetes co-morbidity experienced a lower weight gain at two (1.3 kg, CI95% 0.5; 2.0, p = 0.001) and five months (1.0 kg, CI95% 0.3; 1.7, p = 0.007). Similarly, the increase in the level of haemoglobin was lower among TB patients with diabetes co-morbidity after two (Δ 0.6 g/dL, CI95% 0.3; 0.9 p < 0.001) and five months (Δ 0.5 g/dL, CI95% 0.2; 0.9 p = 0.004) of TB treatment, respectively. CONCLUSION: TB patients initiating TB treatment with diabetes co-morbidity experience delayed recovery of body mass and haemoglobin, which are important for the functional recovery from disease.

Diabetes is a risk factor for pulmonary tuberculosis: a case-control study from Mwanza, Tanzania.

BACKGROUND: Diabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent. METHODS: A case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants. RESULTS: Among 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants. CONCLUSION: Diabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control.

Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans.

AIMS: A study of 222 candidate genes in type 2 diabetes reported association of variants in RAPGEF1, ENPP1, TP53, NRF1, SLC2A2, SLC2A4 and FOXC2 with type 2 diabetes in 4,805 Finnish individuals. We aimed to replicate these associations in a Danish case-control study and to substantiate any replicated associations in meta-analyses. Furthermore, we evaluated the impact on diabetes-related intermediate traits in a population-based sample of middle-aged Danes. METHODS: We genotyped nine lead variants in the seven genes in 4,973 glucose-tolerant and 3,612 type 2 diabetes Danish individuals. In meta-analyses we combined case-control data from the DIAGRAM+ Consortium (n = 47,117) and the present genotyping results. The quantitative trait studies involved 5,882 treatment-naive individuals from the Danish Inter99 study. RESULTS: None of the nine investigated variants were significantly associated with type 2 diabetes in the Danish samples. However, for all nine variants the estimate of increase in type 2 diabetes risk was observed for the same allele as previously reported. In a meta-analysis of published and online data including 55,521 Europeans the G-allele of rs1042522 in TP53 showed significant association with type 2 diabetes (OR = 1.06 95% CI 1.02-1.11, p = 0.0032). No substantial associations with diabetes-related intermediary phenotypes were found. CONCLUSION: The G-allele of TP53 rs1042522 is associated with an increased prevalence of type 2 diabetes in a combined analysis of 55,521 Europeans.