Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

The potential for improvement of outcomes by personalized insulin treatment of type 1 diabetes as assessed by analysis of single-patient data from a randomized controlled cross-over insulin trial.

AIMS: The evidence for optimal insulin treatment in type 1 diabetes is mainly based on randomised controlled trials applying a parallel-group design. Such trials yield robust general results but crucial individual treatment effects cannot be extracted. We aimed to assess the potential for further improvement of outcomes by personalized insulin therapy by analyzing data from a cross-over trial at individual level. METHODS: Post hoc analysis of data from a two-year multicentre, prospective, randomised, open, blinded endpoint (PROBE) trial (the HypoAna trial). In a cross-over design 114 patients with type 1 diabetes and recurrent severe hypoglycemia were treated with basal-bolus therapy based on analog (detemir/aspart) or human (NPH/regular) insulin aiming at maintenance of baseline HbA1c levels. For each patient a superior outcome was defined as fewer events of severe hypoglycemia defined by need for third party treatment assistance or a more than 0.4% (4.4mmol/mol) lower HbA1c. RESULTS: Only one quarter had comparable outcome of the two treatments in terms of rate of severe hypoglycemia or HbA1c. Twice as many patients had superior outcome of analog-based as compared to human insulin-based insulin treatment. The rate of severe hypoglycemia with the superior treatment was lower compared to the rates obtained with analog insulin and with human insulin (0.67, 1.09, and 1.57 episode per patient-year, respectively (p<0.0001)). CONCLUSIONS: Personalized insulin treatment of type 1 diabetes based on single-patient evidence may improve outcomes significantly compared to a general treatment approach.

Rates of Community-based Antibiotic Prescriptions and Hospital-treated Infections in Individuals With and Without Type 2 Diabetes: A Danish Nationwide Cohort Study, 2004-2012.

BACKGROUND: The excess risk of antibiotic use and hospital-treated infections in patients with type 2 diabetes (T2D) compared with general population is poorly understood. METHODS: In a nationwide cohort of patients with incident T2D (n = 155 158) and an age-, gender-, and residence-matched comparison cohort (n = 774 017), we used Cox regression to compute rates and confounder-adjusted rate ratios (aRRs) of community-based antibiotic prescription redemption and hospital-treated infections during 2004-2012. RESULTS: The rates of community-based antibiotic prescriptions in the T2D and comparison cohorts were 364 vs 275 per 1000 person-years after a median follow-up of 1.1 years (aRR = 1.24; 95% confidence interval [CI], 1.23 to 1.25). The corresponding rates for hospital-treated infection were 58 vs 39 per 1000 person-years after a median follow-up of 2.8 years (aRR = 1.49; 95% CI, 1.47 to 1.52). The aRRs were increased particularly for urinary tract infections (UTIs, 1.41; 95% CI, 1.35 to 1.45), skin infections (1.50; 95% CI, 1.45 to 1.55), septicemia (1.60; 95% CI, 1.53 to 1.67), and tuberculosis (1.61; 95% CI, 1.25 to 2.06) and of community-based antibiotics prescribed for UTIs (1.31; 95% CI, 1.29 to 1.33), Staphylococcus aureus infections (1.32; 95% CI, 1.30 to 1.34), and mycobacterial infections (1.69; 95% CI, 1.36 to 2.09). The 1-year aRR declined from 1.89 (95% CI, 1.75 to 2.04) in 2004 to 1.59 (95% CI, 1.45 to 1.74) in 2011 for hospital-treated infection (trend P = .007) and from 1.31 (95% CI, 1.27 to 1.36) in 2004 to 1.26 (95% CI, 1.22 to 1.30) in 2011 for community-based antibiotic prescriptions (trend P = .006). CONCLUSIONS: Patients with T2D have rates of community-based antibiotic prescriptions and hospital-treated infections that are higher than for the general population.

Low positive predictive value of midnight salivary cortisol measurement to detect hypercortisolism in type 2 diabetes.

BACKGROUND: Hypercortisolism is prevalent in type 2 diabetes (T2D), but analytical and functional uncertainties prevail. Measurement of salivary cortisol is considered an expedient screening method for hypercortisolism, but its usefulness in the context of T2D is uncertain. AIM: To compare late-night salivary cortisol (LNSC) with the 1 mg overnight dexamethasone suppression test (DST), which was considered 'reference standard', in T2D. PATIENTS AND METHODS: A total of 382 unselected and recently diagnosed patients with T2D underwent assessment of LNSC and DST, and the test outcome was related to age, gender, body mass index (BMI) and haemoglobin A1c levels. We used the following cut-off values: LNSC ≤ 3·6 nmol/l and DST ≤ 50 nmol/l. RESULTS: The median (range) levels of LNSC and DST were 6·1 (0·3-46·2) nmol/l and 34 (11-547) nmol/l, respectively. Hypercortisolism was present in 86% based on LNSC values and 22% based on DST. LNSC, as compared to DST, had the following test characteristics: sensitivity: 85% (95% CI: 7-92%), specificity: 14% (95% CI: 10-19%), positive predictive value: 22% (95% CI: 17-27%), negative predictive value: 76% (95% CI: 63-87%), and overall accuracy: 30% (95% CI: 25-34%). LNSC and DST values were not associated with haemoglobin A1c, BMI and age in this cohort of patients with T2D. CONCLUSION: The LNSC is characterized by very low specificity and poor positive predictive value as compared to the DST, resulting in an overall low accuracy. Further methodological and clinical studies are needed to substantiate the relevance of cortisol status in T2D.

Basal and insulin-regulated VLDL1 and VLDL2 kinetics in men with type 2 diabetes.

AIMS/HYPOTHESIS: Hypertriacylglycerolaemia is a hallmark of diabetic dyslipidaemia with increased concentrations of triacylglycerol (TG)-rich VLDL1 particles. However, whether VLDL1 secretion or removal is abnormal in type 2 diabetes remains unclear. The aim of this study was to compare basal and insulin-mediated VLDL1- and VLDL2-TG kinetics in men with type 2 diabetes and healthy men using a novel direct VLDL1- and VLDL2-TG labelling method. METHODS: Twelve men with type 2 diabetes and 12 healthy men matched for age and BMI were recruited. VLDL1- and VLDL2-TG turnover were measured during a 4 h basal period and a 3.5 h hyperinsulinaemic clamp period using a primed-constant infusion of ex vivo labelled VLDL1-TG and VLDL2-TG. RESULTS: Basal VLDL1-TG and VLDL2-TG secretion rates were similar in men with diabetes and healthy men. During hyperinsulinaemia, VLDL1-TG secretion rates were suppressed significantly in both groups, whereas no suppression of VLDL2-TG secretion rate was observed. VLDL1-TG to VLDL2-TG transfer rate was not significantly different from zero in both groups, while VLDL1-TG fatty acid oxidation rate was substantial, with a contribution to total energy expenditure of approximately 15% during postabsorptive conditions. VLDL1 and VLDL2 particle size (TG/apolipoprotein B [apoB] ratio) and apoB-100 concentration were unaltered by hyperinsulinaemia in men with type 2 diabetes, but significantly reduced in healthy men. CONCLUSIONS/INTERPRETATION: Insulin inhibits VLDL1-TG secretion rate similarly in age- and BMI-matched men with type 2 diabetes and healthy men, while VLDL2-TG secretion is unaltered by hyperinsulinaemia. However, VLDL1- and VLDL2-apoB levels are not lowered by hyperinsulinaemia in men with type 2 diabetes, which is indicative of a diminished hepatic response to insulin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01564550.

Low Physical Activity Is Associated With Increased Arterial Stiffness in Patients Recently Diagnosed With Type 2 Diabetes.

AIMS: Several studies have indicated that low physical activity is associated with increased risk of cardiovascular disease (CVD) and all-cause mortality among patients with diabetes. The association between physical activity and subclinical cardiovascular changes preceding clinical events remains to be elucidated. We investigated the relationship between physical activity and arterial stiffness, an independent predictor of CVD, in patients with type 2 diabetes and controls. METHODS: We included 100 patients with type 2 diabetes and 100 sex- and age-matched controls in a cross-sectional study. Arterial stiffness (carotid-femoral pulse wave velocity, cfPWV) was measured using the SphygmoCor device (AtCor Medical, Sydney, Australia). Physical activity was assessed by an accelerometer (counts per minute (cpm), Actiheart (CamNtech, Cambridge, UK)) worn by the participants for up to 6 days. High vs. low levels of physical activity was defined according to the median level of activity (cpm = 31). RESULTS: Sixty-five patients and 65 controls were included in the final analysis (median age 59 years, 55% men, median diabetes duration 1.9 years). Participants with low physical activity had higher cfPWV compared to participants with high physical activity: (i) Patients and controls combined: 9.3±1.7 m/s vs. 7.8±1.5 m/s, P < 0.001; (ii) Patients with diabetes: 9.5±1.8 m/s vs. 8.3±1.6 m/s, P = 0.02 and C) Controls: 9.0±1.4 m/s vs. 7.7±1.4 m/s, P < 0.01). The difference remained significant after adjustment for other determinants of cfPWV including whole body fat percentage (P < 0.01). No significant interaction between diabetes and the effect of low activity was seen. CONCLUSIONS: Low physical activity is associated with increased arterial stiffness in patients recently diagnosed with type 2 diabetes and in healthy controls. CLINICAL TRIALS REGISTRATION: Trial Number NCT00674271.

Morning blood pressure surge and target organ damage in newly diagnosed type 2 diabetic patients: a cross sectional study.

BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease. METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE). RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03). CONCLUSION: MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.

Associations between ultrasound measures of abdominal fat distribution and indices of glucose metabolism in a population at high risk of type 2 diabetes: the ADDITION-PRO study.

AIMS: Visceral adipose tissue measured by CT or MRI is strongly associated with an adverse metabolic risk profile. We assessed whether similar associations can be found with ultrasonography, by quantifying the strength of the relationship between different measures of obesity and indices of glucose metabolism in a population at high risk of type 2 diabetes. METHODS: A cross-sectional analysis of 1342 participants of the ADDITION-PRO study. We measured visceral adipose tissue and subcutaneous adipose tissue with ultrasonography, anthropometrics and body fat percentage by bioelectrical impedance. Indices of glucose metabolism were derived from a three point oral glucose tolerance test. Linear regression of obesity measures on indices of glucose metabolism was performed. RESULTS: Mean age was 66.2 years, BMI 26.9kg/m2, subcutaneous adipose tissue 2.5cm and visceral adipose tissue 8.0cm. All measures of obesity were positively associated with indicators of glycaemia and inversely associated with indicators of insulin sensitivity. Associations were of equivalent magnitude except for subcutaneous adipose tissue and the visceral/subcutaneous adipose tissue ratio, which showed weaker associations. One standard deviation difference in BMI, visceral adipose tissue, waist circumference, waist/height ratio and body fat percentage corresponded approximately to 0.2mmol/l higher fasting glucose, 0.7mmol/l higher 2-hr glucose, 0.06-0.1% higher HbA1c, 30 % lower HOMA index of insulin sensitivity, 20% lower Gutt's index of insulin sensitivity, and 100 unit higher Stumvoll's index of beta-cell function. After adjustment for waist circumference visceral adipose tissue was still significantly associated with glucose intolerance and insulin resistance, whereas there was a trend towards inverse or no associations with subcutaneous adipose tissue. After adjustment, a 1cm increase in visceral adipose tissue was associated with ~5% lower insulin sensitivity (p≤0.0004) and ~0.18mmol/l higher 2-hr glucose (p≤0.001). CONCLUSION: Visceral and subcutaneous adipose tissue assessed by ultrasonography are significantly associated with glucose metabolism, even after adjustment for other measures of obesity.

The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy.

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

Isolated hyperglycaemia does not increase VLDL-triacylglycerol secretion in type 1 diabetic men.

AIMS/HYPOTHESIS: In type 1 diabetes, abnormalities of both glucose and lipoprotein metabolism are seen. The relationship between these factors is not understood, but studies indicate that hyperglycaemia may increase hepatic VLDL-triacylglycerol (VLDL-TG) secretion and reduce VLDL-TG fatty acid oxidation, which could lead to the development of dyslipidaemia. The aim of this study was to determine the isolated effect of hyperglycaemia on VLDL-TG and NEFA kinetics in men with type 1 diabetes. METHODS: VLDL-TG and palmitate kinetics were measured in eight men with type 1 diabetes using ex vivo labelled VLDL-TG and palmitate tracers. A 2.5 h basal period (plasma glucose 5 mmol/l) was followed by a 4 h hyperglycaemic period (plasma glucose 16 mmol/l). Steady-state VLDL-TG kinetics (VLDL-TG secretion, clearance and oxidation rates) were assessed by an isotope dilution technique using an intravenous primed-constant infusion of ex vivo labelled [1-(14)C]VLDL-TG in combination with sampling of blood and expired air. Palmitate turnover was measured using [9,10-(3)H]palmitate. RESULTS: The VLDL-TG secretion rate (36.0 ± 9.6 vs 30.8 ± 6.1 µmol/min, NS) and clearance rate (209 ± 30.4 vs 197 ± 41.7 ml/min, NS) were unchanged during the basal and hyperglycaemic periods, resulting in unchanged VLDL-TG concentrations (0.25 ± 0.11 µmol/l vs 0.28 ± 0.10 µmol/l, NS). In addition, VLDL-TG fatty acid oxidation and palmitate flux were not changed during hyperglycaemia. CONCLUSIONS/INTERPRETATION: Four hours of acute hyperglycaemia (16 mmol/l) without a concomitant increase in insulin does not alter VLDL-TG and NEFA kinetics in men with type 1 diabetes. CLINICAL TRIAL REGISTRY NUMBER: NCT01178957.

Socioeconomic factors do not but GH treatment does affect mortality in adult-onset growth hormone deficiency.

CONTEXT: GH deficiency is associated with changes in body composition, increased cardiovascular risk markers, and reduced bone mineral density. There seem to be multiple causes of the reported increased morbidity and mortality. OBJECTIVE: The objective was to study the socioeconomic status in patients with adult-onset GH deficiency and its impact on mortality. DESIGN: This is a nationwide registry study in which the socioeconomic status in adult-onset GH deficient patients was identified in the Danish registries and compared with controls matched on age and gender. The socio-economic status included cohabitation, education, income, parenthood, convictions, and retirement. PATIENTS AND CONTROLS: All patients had adult-onset GH deficiency and were born between 1950 and 1980. Two-hundred seventy-six patients (53.6% men) and 25 717 controls were included. RESULTS: GH-treated patients had a reduced mortality in total and due to malignancy compared with untreated patients. This difference remained after adjustment for cohabitation and education. Compared with the background population, the incidence of cohabitation, parenthood, and convictions was significantly reduced in patients, whereas education was unaffected. Retirement was significantly increased. CONCLUSIONS: Mortality was increased in patients, especially among patients not treated with GH. In GH-treated patients, mortality was decreased in total and due to malignancy compared with untreated patients, even after adjustment for all possible measured confounders. The patients had an impaired socioeconomic profile on most parameters compared with controls. This study does not support the suggestion that GH replacement therapy causes increased mortality.

Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes.

OBJECTIVE: Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48-64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients. RESEARCH DESIGN AND METHODS: A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12. RESULTS: The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients (-0.20 vs. -0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/10(6) peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab. CONCLUSIONS: Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.

Acute and short-term chronic testosterone fluctuation effects on glucose homeostasis, insulin sensitivity, and adiponectin: a randomized, double-blind, placebo-controlled, crossover study.

CONTEXT: Low levels of adiponectin and T in men have been shown to predict development of the metabolic syndrome, but the effects of T on glucose metabolism are incompletely understood and may be influenced either directly or indirectly through changes in body composition or in levels of adiponectin. OBJECTIVE: The aim of the study was to test whether T exerts its effects on glucose metabolism directly or indirectly. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy young males were studied on four separate occasions. They received GnRH agonist treatment 1 month before 3 of 4 trial days to induce castrate levels of T. On trial days, T gel containing either high or low physiological T dose or placebo was applied to the body. On a fourth trial day, participants constituted their own eugonadal controls. INTERVENTION: Each study comprised a 5-hour basal period and a 3-hour hyperinsulinemic euglycemic clamp. MAIN OUTCOME MEASURES: We measured the effect of acute T on peripheral glucose disposal, total adiponectin and subforms, and other indices of glucose metabolism. RESULTS: Short-term hypogonadism was associated with increased high molecular weight adiponectin levels (P < .03) and increased oxidative glucose disposal (P = .03) but not total glucose disposal (P = .07). Acute T treatment was an independent suppressor of high molecular weight adiponectin levels (P = .04) but did not affect total glucose disposal (P = .17). CONCLUSIONS: These data show that T can act through putative fast nongenomic pathways to affect adiponectin levels in humans. The early hypogonadal state is characterized by a marked shift in fuel oxidation from lipids toward glucose, which may rely partly on buffering capabilities of adiponectin.

Impaired postprandial response of the insulin-like growth factor system in maintenance haemodialysis.

OBJECTIVE: Patients on maintenance haemodialysis (HD) have reduced circulating free and bioactive insulin-like growth factor I (IGF-I) due to increased IGF-binding proteins (IGFBPs). This study investigated the postprandial response of the IGF system in HD patients compared with matched healthy subjects. DESIGN AND PATIENTS: In a crossover study, twelve nondiabetic HD patients were assigned in a random order to three 10-h study days: (1) a non-HD day with one meal served at baseline (NHDM1), (2) an HD day with one meal served during HD (HDM1) and (3) an HD day with two meals served during and after HD, respectively (HDM2). Twelve healthy controls conducted session 1. RESULTS: After the baseline meal, insulin concentrations changed similarly in HD patients and controls, whereas hyperglycaemia was more prolonged in HD patients (P < 0·001). Postprandial IGFBP-1 showed greater reductions from baseline in controls (-76% [-81; -70%], mean [95% confidence intervals], P < 0·001) than in patients on non-HD days (-45% [-57; -30%], P < 0·001). In the latter group, the response was even more attenuated during HD (-22% [-38; -1%] and -24% [-40; -4%], P ≤ 0·041). After the second meal on HDM2 days, IGFBP-1 further decreased (-50% [-61; -37%], P < 0·001), whereas IGFBP-1 returned to baseline levels on the other study days. Consistently, at the end of the study days, bioactive IGF-I was significantly above baseline only on HDM2 days (+22% [+5; +43%], P = 0·012). CONCLUSIONS: HD patients were unable to suppress IGFBP-1 to the same extent as healthy controls, which may increase the risk of protein-energy wasting in maintenance HD. A second meal after HD, however, effectively suppressed IGFBP-1 and increased bioactive IGF-I.

Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults.

OBJECTIVE: Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay. DESIGN: We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured. RESULTS: Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (P<0.001 and P=0.005), and both increased with age. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders. Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1. CONCLUSIONS: Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.

Reproducibility of pulse wave analysis and pulse wave velocity in patients with type 2 diabetes.

AIMS: Patients with type 2 diabetes have increased arterial stiffness and a high incidence of cardiovascular disease compared with non-diabetics. Arterial stiffness and central waveforms can be assessed by carotid-femoral pulse wave velocity (PWV) and pulse wave analysis (PWA) using the SphygmoCor device. These methods can potentially improve cardiovascular risk stratification in the future. However, a prerequisite is acceptable reproducibility. The objective of this study was to assess the intra- and inter-observer reproducibility of PWV and PWA indices in patients with type 2 diabetes using the SphygmoCor device. METHODS: Two trained observers (A and B) each undertook two PWA and two carotid-femoral PWV recordings in random order in 20 patients with type 2 diabetes under standardized conditions on the right side of the patients. Observer A also made double recordings on the left side. The mean of the two recordings was used for inter-observer comparison. Data were analyzed by Bland-Altman plots. RESULTS: The mean intra-observer differences (± 2SD) on the right side for observer A and B, respectively, were 0.0 ± 2.8 mmHg and 0.3 ± 3.2 mmHg (aortic systolic blood pressue (BP)), 0.0 ± 1.2 mmHg and 0.1 ± 1.0 mmHg (aortic diastolic BP), - 1.1 ± 3.2% and 1.1 ± 9.6% (central augmentation index (Aix)), - 1.6 ± 6.6% and 0.1 ± 9.0% (Aix normalized to heart rate 75 beats/min (Aix@HR75)) and 0.1 ± 1.8 m/s and 0.0 ± 1.6 m/s (PWV). The mean inter-observer differences (± 2SD) were - 2.6 ± 13.0 mmHg (aortic systolic BP), - 2.1 ± 7.4 mmHg (aortic diastolic BP), - 0.8 ± 8.4% (Aix), - 1.5 ± 7.4% (Aix@HR75) and - 0.3 ± 1.6 m/s (PWV). Left-vs-right comparison showed comparable results (observer A). CONCLUSIONS: PWA and PWV assessed with the SphygmoCor device are characterized by good reproducibility in patients with type 2 diabetes.

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.

Effect of hyperinsulinemia during hemodialysis on the insulin-like growth factor system and inflammatory biomarkers: a randomized open-label crossover study.

BACKGROUND: A marked reduction in serum levels of bioactive insulin-like growth factor-I (IGF-I) has been observed in fasting hemodialysis (HD) patients during a 4-h HD session. The aim of the present study was to investigate the beneficial effect of hyperinsulinemia during HD on bioactive IGF-I and inflammatory biomarkers. METHODS: In a randomized cross-over study, 11 non-diabetic HD patients received a standardised HD session with either: 1) no treatment, 2) glucose infusion (10% glucose, 2.5 mL/kg/h), or 3) glucose-insulin infusion (10% glucose added 30 IU NovoRapid® per litre, 2.5 mL/kg/h). Each experiment consisted of three periods: pre-HD (-120 to 0 min), HD (0 to 240 min), and post-HD (240 to 360 min). A meal was served at baseline (-120 min); infusions were administered from baseline to 240 min. The primary outcome was change in bioactive IGF-I during the experiment. Secondary outcomes were changes in high-sensitivity C-reactive protein, interleukin-1ß, interleukin-6, and tumor necrosis factor α. Comparisons were performed using mixed-model analysis of variance for repeated measures. RESULTS: From baseline to the end of study, no significant differences were observed in the changes in either serum bioactive IGF-I or total IGF-I between study days. Overall, serum bioactive IGF-I levels rose above baseline at 120 to 300 min with a maximum increase of 20% at 120 min (95% confidence interval (CI), 9 to 31%; p < 0.001), whereas total IGF-I levels rose above baseline at 180 to 300 min with a maximum increase of 5% at 240 min (95% CI, 2 to 9%; p = 0.004). A significant difference was observed in the changes in serum IGF-binding protein-1 (IGFBP-1) between study days (p = 0.008), but differences were only significant in the post-HD period. From baseline to the end of HD, no significant difference was observed in the changes in serum IGFBP-1 levels between study days, and in this time period overall serum IGFBP-1 levels were below baseline at all time points with a maximum decrease of 51% at 180 min (95% CI, 45 to 57%; p < 0.001). None of the investigated inflammatory biomarkers showed any differences in the changes over time between study days. CONCLUSIONS: Postprandial insulin secretion stimulated the IGF-system during HD with no further effect of adding glucose or glucose-insulin infusion. Hyperinsulinemia during HD had no effect on biomarkers of inflammation. TRIAL REGISTRATION: ClinicalTrials.gov registry: NCT01209403.

Carotid-femoral pulse wave velocity is associated with cerebral white matter lesions in type 2 diabetes.

OBJECTIVE: Patients with type 2 diabetes have a high incidence of cardiovascular events including stroke. Increased arterial stiffness (AS) predicts cardiovascular events in the general population. Cerebral white matter lesions (WMLs) are associated with an increased risk of stroke. It is unknown whether AS in patients with type 2 diabetes is associated with WMLs. RESEARCH DESIGN AND METHODS: We examined 89 patients recently diagnosed with type 2 diabetes (<5 years) and 89 sex- and age-matched controls. AS was assessed with carotid-femoral pulse wave velocity (PWV). WMLs were identified using magnetic resonance imaging and graded qualitatively with the Breteler scale (no/slight changes = 0, moderate changes = 1, severe changes = 2) and semiquantitatively. RESULTS: The diabetic population had excellent glycemic control (HbA(1c), 6.5% [6.2-6.8]; median [interquartile range {IQR}]) and had, compared with the controls, lower office blood pressure (BP) (127 ± 12/79 ± 8 vs. 132 ± 14/84 ± 10 mmHg) and total cholesterol (4.3[3.9-4.7] vs. 5.6 [5.1-6.4]; mmol/L; median [IQR]), (P < 0.01 for all). Despite this, PWV was higher in the patients with diabetes compared with controls (9.3 ± 2.0 vs. 8.0 ± 1.6 m/s; P < 0.0001). PWV was associated with Breteler score (OR 1.36 [95% CI 1.17-1.58]; P < 0.001) and WML volume (OR 1.32 [95% CI 1.16-1.51]; P < 0.001) per 1 m/s increase in PWV. These associations remained significant when adjusted for age, sex, diabetes, 24-h mean arterial BP, BMI, heart rate, and use of antihypertensives and statins (Breteler score: OR 1.28 [95% CI 1.03-1.60]; P < 0.05 and WML volume: OR 1.30 [95% CI 1.06-1.58]; P < 0.05). CONCLUSIONS: PWV was higher among patients with well-controlled type 2 diabetes compared with controls and was independently associated with WMLs. PWV may represent a clinically relevant parameter in the evaluation of cerebrovascular disease risk in type 2 diabetes.

Independent effects of testosterone on lipid oxidation and VLDL-TG production: a randomized, double-blind, placebo-controlled, crossover study.

Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men.