Nanna B. Johansen

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16–21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

Determinants of Aortic Stiffness: 16-Year Follow-Up of the Whitehall II Study

Background Aortic stiffness is a strong predictor of cardiovascular disease endpoints. Cross-sectional studies have shown associations of various cardiovascular risk factors with aortic pulse wave velocity, a measure of aortic stiffness, but the long-term impact of these factors on aortic stiffness is unknown. Methods In 3,769 men and women from the Whitehall II cohort, a wide range of traditional and novel cardiovascular risk factors were determined at baseline (1991–1993) and aortic pulse wave velocity was measured at follow-up (2007–2009). The prospective associations between each baseline risk factor and aortic pulse wave velocity at follow-up were assessed through sex stratified linear regression analysis adjusted for relevant confounders. Missing data on baseline determinants were imputed using the Multivariate Imputation by Chained Equations. Results Among men, the strongest predictors were waist circumference, waist-hip ratio, heart rate and interleukin 1 receptor antagonist, and among women, adiponectin, triglycerides, pulse pressure and waist-hip ratio. The impact of 10 centimeter increase in waist circumference on aortic pulse wave velocity was twice as large for men compared with women (men: 0.40 m/s (95%-CI: 0.24;0.56); women: 0.17 m/s (95%-CI: −0.01;0.35)), whereas the opposite was true for the impact of a two-fold increase in adiponectin (men: −0.30 m/s (95%-CI: −0.51;−0.10); women: 0.61 m/s (95%-CI: −0.86;−0.35)). Conclusion In this large prospective study, central obesity was a strong predictor of aortic stiffness. Additionally, heart rate in men and adiponectin in women predicted aortic pulse wave velocity suggesting that strategies to prevent aortic stiffening should be focused differently by sex.

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care

BackgroundScreening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to quantify diabetes progression rates and to examine the development of early markers of cardiovascular disease and microvascular diabetic complications. We also require a better understanding of the mechanisms that underlie and drive early changes in cardiometabolic physiology. The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.Methods/DesignADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006. All individuals with impaired glucose regulation at screening, those who developed diabetes following screening, and a random sub-sample of those at lower levels of diabetes risk were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included detailed measurement of anthropometry, body composition, biochemistry, physical activity and cardiovascular risk factors including aortic stiffness and central blood pressure. All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.DiscussionThe ADDITION-PRO study is designed to increase understanding of cardiovascular risk and its underlying mechanisms among individuals at high risk of diabetes. Key features of this study include (i) a carefully characterised cohort at different levels of diabetes risk; (ii) detailed measurement of cardiovascular and metabolic risk factors; (iii) objective measurement of physical activity behaviour; and (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease. Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.

Combined heart rate- and accelerometer-assessed physical activity energy expenditure and associations with glucose homeostasis markers in a population at high risk of developing diabetes: the ADDITION-PRO study.

OBJECTIVE Regular physical activity (PA) reduces the risk of developing type 2 diabetes, and different subtypes of dysglycemia have shown different associations with PA. To better understand the associations of PA and glucose homeostasis, we examined the association of objectively measured PA energy expenditure (PAEE) with detailed measures of glucose homeostasis. RESEARCH DESIGN AND METHODS In 1,531 men and women, with low to high risk of developing type 2 diabetes, we measured 7 days of PAEE using a combined accelerometry and heart rate monitor (ActiHeart). Measures and indices of glucose homeostasis were derived from a 3-point oral glucose tolerance test in addition to measures of long-term glycemia (glycated hemoglobin A1c and advanced glycation end products). Associations of PAEE with glucose homeostasis markers were examined using linear regression models. RESULTS Median age (IQR) was 66.6 years (62.1–71.6) (54% men) with a median ActiHeart wear time of 6.9 days (6.0–7.1) and PAEE level of 33.0 kJ/kg/day (23.5–46.1). In fully adjusted models, we found higher levels of PAEE to be positively associated with insulin sensitivity and negatively with insulin 2 h after glucose load (P < 0.05). CONCLUSIONS Even in an elderly population with low levels of PA, we found higher objectively measured PAEE levels to be associated with a more beneficial glucose metabolic profile. Although our findings are cross-sectional, they indicate that even without high-intensity exercise, increasing the overall level of PAEE slightly in an entire population at risk for developing type 2 diabetes may be a realistic and worthwhile goal to reach in order to achieve beneficial effect in terms of glucose metabolism.

Insulin Resistance Is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation

Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P ≤ 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.

Effect of Intensive Multifactorial Treatment Compared With Routine Care on Aortic Stiffness and Central Blood Pressure Among Individuals With Screen-Detected Type 2 Diabetes: The ADDITION-Denmark study

OBJECTIVE Diabetes is associated with increased brachial and central blood pressure and aortic stiffness. We examined the effect of intensive multifactorial treatment in general practice on indices of peripheral and central hemodynamics among patients with screen-detected diabetes. RESEARCH DESIGN AND METHODS As part of a population-based screening and intervention study in general practice, 1,533 Danes aged 40–69 years were clinically diagnosed with screen-detected diabetes. General practitioners were randomized to provide intensive multifactorial treatment or routine care. After a mean follow-up of 6.2 years, an unselected subsample of 456 patients underwent central hemodynamic assessments by applanation tonometry. Central pressure was derived from the radial pulse wave. Aortic stiffness was assessed as carotid-femoral pulse wave velocity (aPWV). The intervention effect on each index of central hemodynamics was analyzed by mixed-effects models adjusted for heart rate, cluster randomization, age, and sex. RESULTS At screening, median age was 59.2 years (interquartile range 55.2–64.6); 289 patients (63%) were in the intensive treatment group, and 278 patients (61%) were men. Patients in the intensive treatment group had a 0.51 m/s (95% CI −0.96 to −0.05, P = 0.03) lower aPWV compared with routine care. Respective differences for central augmentation index (−0.84% [−2.54 to 0.86]), pulse pressure (0.28 mmHg [−1.75 to 2.32]), and systolic (−1.42 mmHg [−4.47 to 1.64]) and diastolic (−1.79 mmHg [−3.72 to 0.14]) blood pressure were not statistically significant. CONCLUSIONS Intensive multifactorial treatment of screen-detected diabetes during 6 years in general practice has a significant impact on aortic stiffness, whereas the effects on other hemodynamic measures are smaller and not statistically significant.

Relationship Between Insulin Resistance and β-Cell Dysfunction in Subphenotypes of Prediabetes and Type 2 Diabetes

CONTEXT There is little overlap between diabetes diagnosed by glycated hemoglobin (HbA1c) and blood glucose, and it is unclear which pathophysiological defects are captured when using HbA1c for diagnosis. OBJECTIVE We examined and compared the relationship between insulin sensitivity and β-cell function in different subphenotypes of prediabetes and type 2 diabetes (T2D). DESIGN, SETTING, AND PARTICIPANTS A cross-sectional analysis of the Danish ADDITION-PRO study was performed (n = 1713). Participants without known diabetes were classified into subgroups of prediabetes and T2D based on fasting or 2-hour glucose criteria or HbA1c. Insulin sensitivity and insulin release were determined from glucose and insulin concentrations during the oral glucose tolerance test, and disposition indices were calculated. RESULTS Individuals with prediabetes or T2D diagnosed by fasting glucose had lower absolute insulin release (P ≤ .01) and higher insulin sensitivity in response to glucose intake (P ≤ .01) but a similar disposition index (P ≥ .36), compared with individuals with elevated 2-hour glucose concentrations. Individuals with HbA1c-defined T2D or prediabetes had a mixture of the pathophysiological defects observed in the glucose-defined subgroups, and individuals with normoglycemia by HbA1c had worse pathophysiological abnormalities than individuals with normoglycemia by the glucose criteria. CONCLUSIONS On average, the diagnostic HbA1c criteria for diabetes and prediabetes identified individuals with a mixture of the pathophysiological characteristics found when using the glucose criteria, but the diversity and pathophysiology captured by the oral glucose tolerance test cannot be captured when applying the more simple HbA1c criteria. Whether the disease progression and prognosis will differ in individuals diagnosed by fasting glucose, 2-hour glucose, or HbA1c should be examined in longitudinal studies.

Glucose-Dependent Insulinotropic Polypeptide Is Associated With Lower Low-Density Lipoprotein But Unhealthy Fat Distribution, Independent of Insulin: The ADDITION-PRO Study

CONTEXT Glucose-dependent insulinotropic polypeptide (GIP) may increase lipid clearance by stimulating lipid uptake. However, given that GIP promotes release of insulin by the pancreas and insulin is anti-lipolytic, the effect may be indirect. OBJECTIVE In this study we examined the association between GIP and lipid metabolism in individuals with low to high risk of type 2 diabetes and assessed whether the associations were modified by or mediated through insulin. DESIGN, SETTING, AND PARTICIPANTS Analyses were based on the Danish cross-sectional ADDITION-PRO study (n = 1405). Lipid metabolism was measured by fasting plasma lipids and obesity including abdominal fat distribution assessed by ultrasonography. GIP and insulin were measured during an oral glucose tolerance test (0, 30 and 120 min). Linear regression analysis was used to study the associations between GIP, plasma lipids, and obesity measures. RESULTS A doubling in fasting GIP levels was associated with lower low-density lipoprotein in both men (mean [95% CI] -0.10 mmol/l [-0.18--0.03]) and women (-0.14 mmol/l [-0.23--0.04]) and with higher high-density lipoprotein in women (0.06 mmol/l [-0.02-0.10]). In men, a doubling in stimulated GIP was associated with 0.13 cm less 0.01-0.25 sc fat but with more visceral abdominal fat (0.45 cm [0.12-0.78]) and higher waist-hip ratio (0.011 [0.004-0.019]). CONCLUSIONS Contrary to what was previously thought, GIP may be associated with improved low-density lipoprotein clearance but with an unhealthy fat distribution independent of insulin. The effect of GIP on obesity measures was substantially different between men and women. The potential effect of GIP on visceral and sc adipose tissue physiology warrants further examination.

Higher Physical Activity Is Associated With Lower Aortic Stiffness but Not With Central Blood Pressure: The ADDITION-Pro Study

AbstractPhysical activity is associated with reduced cardiovascular disease risk. However, improvements in conventional risk factors due to physical activity do not explain its full benefit. Therefore, we examined associations of objectively measured physical activity energy expenditure and intensity with central hemodynamics to provide new insight into the link between physical activity and cardiovascular disease.We analyzed data from 1816 Danes (median age: 66 years) without cardiovascular disease. Physical activity was estimated using combined accelerometry and heart rate monitoring. Aortic stiffness was assessed by applanation tonometry, as aortic pulse wave velocity, and central blood pressure was estimated from radial waveforms. Associations between physical activity energy expenditure and central hemodynamics were examined by linear regression. Furthermore, the consequence of substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity on central hemodynamics was examined.Median physical activity energy expenditure was 28.0 kJ/kg/d (IQR: 19.8; 38.7). A 10 kJ/kg/d higher energy expenditure was associated with 0.75% lower aortic pulse wave velocity (CI: −1.47; −0.03). Associations with central systolic blood pressure and central pulse pressure were not statistically significant. We observed no difference in central hemodynamics when substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity.In this relatively inactive population, higher physical activity energy expenditure was associated with lower aortic stiffness, while there was no statistically significant association between substitution of activity intensity and central hemodynamics. This suggests that lower aortic stiffness is one of a number of health benefits attributed to higher habitual physical activity.

Metabolically Healthy Obesity and Ischemic Heart Disease: A 10-Year Follow-Up of the Inter99 Study

Context Recent studies have suggested that a subgroup of obese individuals is not at increased risk of obesity-related complications. This subgroup has been referred to as metabolically healthy obese. Objective To investigate whether obesity is a risk factor for development of ischemic heart disease (IHD) irrespective of metabolic health. Design In all, 6238 men and women from the Danish prospective Inter99 study were followed during 10.6 (standard deviation = 1.7) years. Setting General community. Participants Participants were classified according to body mass index and four metabolic risk factors (low high-density lipoprotein cholesterol, elevated blood pressure, triglycerides, and fasting plasma glucose). Metabolically healthy individuals were defined as having no metabolic risk factors, and metabolically unhealthy individuals were defined as having a minimum of one. Main Outcome Measures IHD. Results During follow-up, 323 participants developed IHD. Metabolically healthy obese men had increased risk of IHD compared with metabolically healthy normal-weight men [hazard ratio (HR), 3.1; 95% confidence interval (CI), 1.1 to 8.2)]. The corresponding results for women were less pronounced (HR, 1.8; 95% CI, 0.7 to 4.8). Being metabolically healthy but overweight was not associated with higher risk of IHD in men (HR, 1.1; 95% CI, 0.5 to 2.4), and in women the risk was only slightly increased and insignificant (HR, 1.5; 95% CI, 0.8 to 3.0). A substantial proportion of metabolically healthy individuals became metabolically unhealthy after 5 years of follow-up. When these changes in exposure status were taken into account, slightly higher risk estimates were found. Conclusions Being obese is associated with higher incidence of IHD irrespective of metabolic status, and we question the feasibility of denoting a subgroup of obese individuals as metabolically healthy.