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.

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.

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.

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.

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.

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.

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.

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.

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.

Effects of exercise on VLDL-triglyceride oxidation and turnover.

Lipids are important substrates for oxidation at rest and during exercise. Aerobic exercise mediates a delayed onset decrease in total and VLDL-triglyceride (TG) plasma concentration. However, the acute effects of exercise on VLDL-TG oxidation and turnover remain unclear. Here, we studied the acute effects of 90 min of moderate-intensity exercise in healthy women and men. VLDL-TG kinetics were assessed using a primed constant infusion of ex vivo labeled [1-(14)C]triolein VLDL-TG. Fractional VLDL-TG-derived fatty acid oxidation was measured from (14)CO(2) specific activity in expired air. VLDL-TG concentration was unaltered during exercise and early recovery, whereas non-VLDL-TG concentration decreased significantly.VLDL-TG secretion rate decreased significantly during exercise and remained suppressed during recovery. Total VLDL-TG oxidation rate was unaffected by exercise. However, the contribution of VLDL-TG oxidation to total energy expenditure fell from 14 ± 9% at rest to 3 ± 4% during exercise. We conclude that VLDL-TG fatty acids are quantitatively important oxidative substrates under basal postabsorptive conditions but remain unaffected during 90-min moderate-intensity exercise and, thus, become relatively less important during exercise. Lower VLDL secretion rate during exercise may contribute to the decrease in TG concentrations during and after exercise.

Normalisation of insulin-like growth factor-I does not improve insulin action in cirrhosis.

BACKGROUND & AIMS: Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis. METHODS: This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 µg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp. RESULTS: The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 µg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 µg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 µg/L; total IGF-I from 200 ± 19 to 500 ± 50 µg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis. CONCLUSIONS: Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.

Effects of insulin-like growth factor-I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis.

BACKGROUND: The anabolic effects of insulin-like growth factor-I (IGF-I) may involve a decrease of hepatic nitrogen (N) clearance, but this has never been studied in humans. Patients with cirrhosis have low levels of IGF-I and might benefit from IGF-I therapy. Conversely, a possible decrease in hepatic N clearance by IGF-I could increase the risk of hepatic encephalopathy. AIMS: To examine the effects of 1-week IGF-I administration on the functional hepatic N clearance (FHNC), viz. the linear slope of the relationship between blood-α-amino-N concentration and urea-N synthesis rate as controlled by an infusion of alanine. METHODS: A randomized sequence-crossover placebo-controlled study. Eight healthy volunteers and eight patients with alcoholic cirrhosis received injections of saline or IGF-I twice daily (50 µg/kg) for 7 days. RESULTS: IGF-I levels at baseline were lower in the patients than those in the controls. The IGF-I treatment normalized patient levels and caused an increase in the controls to supra-physiological levels. FHNC was lower in patients compared with healthy subjects (23.0 vs 36.5 L/h, P=0.03). IGF-I treatment reduced FHNC by 30% in healthy subjects (from 36.5 to 25.7 L/h, P = 0.02), whereas no effect was found in the patients. CONCLUSION: IGF-I downregulates urea synthesis in normal subjects. This may be part of the explanation behind the anabolic effects of IGF-I. The normalization of IGF-I in cirrhosis patients without an effect on urea synthesis implies that the patients were resistant to IGF-I with regard to reduction of hepatic amino-N elimination. IGF-I treatment of cirrhosis patients evidently carries no risk of N accumulation.

Dilation of the ascending aorta in Turner syndrome - a prospective cardiovascular magnetic resonance study.

BACKGROUND: The risk of aortic dissection is 100-fold increased in Turner syndrome (TS). Unfortunately, risk stratification is inadequate due to a lack of insight into the natural course of the syndrome-associated aortopathy. Therefore, this study aimed to prospectively assess aortic dimensions in TS. METHODS: Eighty adult TS patients were examined twice with a mean follow-up of 2.4 ± 0.4 years, and 67 healthy age and gender-matched controls were examined once. Aortic dimensions were measured at nine predefined positions using 3D, non-contrast and free-breathing cardiovascular magnetic resonance. Transthoracic echocardiography and 24-hour ambulatory blood pressure were also performed. RESULTS: At baseline, aortic diameters (body surface area indexed) were larger at all positions in TS. Aortic dilation was more prevalent at all positions excluding the distal transverse aortic arch. Aortic diameter increased in the aortic sinus, at the sinotubular junction and in the mid-ascending aorta with growth rates of 0.1 - 0.4 mm/year. Aortic diameters at all other positions were unchanged. The bicuspid aortic valve conferred higher aortic sinus growth rates (p < 0.05). No other predictors of aortic growth were identified. CONCLUSION: A general aortopathy is present in TS with enlargement of the ascending aorta, which is accelerated in the presence of a bicuspid aortic valve.

Delayed ß-cell response and glucose intolerance in young women with Turner syndrome.

BACKGROUND: To investigate glucose homeostasis in detail in Turner syndrome (TS), where impaired glucose tolerance (IGT) and type 2 diabetes are frequent. METHODS: Cross sectional study of women with Turner syndrome (TS)(n = 13) and age and body mass index matched controls (C) (n = 13), evaluated by glucose tolerance (oral and intravenous glucose tolerance test (OGTT and IVGTT)), insulin sensitivity (hyperinsulinemic, euglycemic clamp), beta-cell function (hyperglycaemic clamp, arginine and GLP-1 stimulation) and insulin pulsatility. RESULTS: Fasting glucose and insulin levels were similar. Higher glucose responses was seen in TS during OGTT and IVGTT, persisting after correction for body weight or muscle mass, while insulin responses were similar in TS and C, despite the higher glucose level in TS, leading to an insufficient increase in insulin response during dynamic testing. Insulin sensitivity was comparable in the two groups (TS vs. control: 8.6 ± 1.8 vs. 8.9 ± 1.8 mg/kg*30 min; p = 0.6), and the insulin responses to dynamic ß-cell function tests were similar. Insulin secretion patterns examined by deconvolution analysis, approximate entropy, spectral analysis and autocorrelation analysis were similar. In addition we found low IGF-I, higher levels of cortisol and norepinephrine and an increased waist-hip ratio in TS. CONCLUSIONS: Young normal weight TS women show significant glucose intolerance in spite of normal insulin secretion during hyperglycaemic clamping and normal insulin sensitivity. We recommend regularly testing for diabetes in TS. TRIAL REGISTRATION: Registered with http://clinicaltrials.com, ID nr: NCT00419107.

Thoracic aortopathy in Turner syndrome and the influence of bicuspid aortic valves and blood pressure: a CMR study.

BACKGROUND: To investigate aortic dimensions in women with Turner syndrome (TS) in relation to aortic valve morphology, blood pressure, karyotype, and clinical characteristics. METHODS AND RESULTS: A cross sectional study of 102 women with TS (mean age 37.7; 18-62 years) examined by cardiovascular magnetic resonance (CMR- successful in 95), echocardiography, and 24-hour ambulatory blood pressure. Aortic diameters were measured by CMR at 8 positions along the thoracic aorta. Twenty-four healthy females were recruited as controls. In TS, aortic dilatation was present at one or more positions in 22 (23%). Aortic diameter in women with TS and bicuspid aortic valve was significantly larger than in TS with tricuspid valves in both the ascending (32.4 +/- 6.7 vs. 26.0 +/- 4.4 mm; p < 0.001) and descending (21.4 +/- 3.5 vs. 18.8 +/- 2.4 mm; p < 0.001) aorta. Aortic diameter correlated to age (R = 0.2 - 0.5; p < 0.01), blood pressure (R = 0.4; p < 0.05), a history of coarctation (R = 0.3; p = 0.01) and bicuspid aortic valve (R = 0.2-0.5; p < 0.05). Body surface area only correlated with descending aortic diameter (R = 0.23; p = 0.024). CONCLUSIONS: Aortic dilatation was present in 23% of adult TS women, where aortic valve morphology, age and blood pressure were major determinants of the aortic diameter.

Ambulatory arterial stiffness index in Turner syndrome: the impact of sex hormone replacement therapy.

BACKGROUND: Morbidity and mortality from congenital and acquired cardiovascular (CV) disease is increased in Turner syndrome (TS), where traditional indices of CV risk are widely present but the single most common feature remains estrogen deficiency. AIM: To investigate CV risk in TS as expressed by the widely available ambulatory arterial stiffness index (AASI) and the impact of female sex hormone replacement therapy (HRT) hereon. METHODS: TS women (n = 26) were examined following HRT washout and again during 6 months of HRT. Age-matched healthy female controls (n = 24) were examined once. 24-Hour ambulatory blood pressures, AASI in addition to metabolic and anthropometric indices of CV risk were measured. RESULTS: The relatively tachycardic TS women had higher systolic and diastolic blood pressures. HRT reduced diastolic blood pressures with an increase in physical fitness, worsening of glucose tolerance, and a reduction in high-density lipoprotein. AASI was significantly elevated in TS when compared to controls (0.36 (0.02) vs. 0.26 (0.03), p = 0.01) but unaffected by HRT. Major explanatory variables to AASI were status (being TS or not), age, and diurnal pulse variability. CONCLUSION: AASI was elevated in TS, possibly indicating elevated CV risk with no impact of short-term HRT.

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity.

CONTEXT: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance. OBJECTIVE: To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels. DESIGN: A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks. INTERVENTION: Patients received either pioglitazone 30 mg (N = 10) or placebo (N = 10) once daily for 12 weeks. RESULTS: Adiponectin levels almost doubled during pioglitazone treatment (P = 0.0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels (P = 0.02) and lipid oxidation (P = 0.02). Basal glucose oxidation rate (P = 0.004) and insulin sensitivity (P = 0.03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal (R = 0.69, P = 0.04). CONCLUSION: The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.

Effects of growth hormone on glucose and fat metabolism in human subjects.

This article focuses on in vivo data from tests performed in normal subjects and in patients who had abnormal growth hormone (GH) status. Experimental data in human subjects demonstrate that GH acutely inhibits glucose disposal in skeletal muscle. At the same time GH stimulates the turnover and oxidation of free fatty acid (FFA), and experimental evidence suggests a causal link between elevated FFA levels and insulin resistance in skeletal muscle. Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance, but it is recommended that overdosing be avoided and glycemic control be monitored.

The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism.

OBJECTIVE: Klinefelter's syndrome is associated with an increased prevalence of diabetes, but the pathogenesis is unknown. Accordingly, the aim of this study was to investigate measures of insulin sensitivity, the metabolic syndrome, and sex hormones in patients with Klinefelter's syndrome and an age-matched control group. RESEARCH DESIGN AN METHODS: In a cross-sectional study, we examined 71 patients with Klinefelter's syndrome, of whom 35 received testosterone treatment, and 71 control subjects. Body composition was evaluated using dual-energy X-ray absorptiometry scans. Fasting blood samples were analyzed for sex hormones, plasma glucose, insulin, C-reactive protein (CRP), and adipocytokines. We analyzed differences between patients with untreated Klinefelter's syndrome and control subjects and subsequently analyzed differences between testosterone-treated and untreated Klinefelter's syndrome patients. RESULTS: Of the patients with Klinefelter's syndrome, 44% had metabolic syndrome (according to National Cholesterol Education Program/Adult Treatment Panel III criteria) compared with 10% of control subjects. Insulin sensitivity (assessed by homeostasis model assessment 2 modeling), androgen, and HDL cholesterol levels were significantly decreased, whereas total fat mass and LDL cholesterol, triglyceride, CRP, leptin, and fructosamine levels were significantly increased in untreated Klinefelter's syndrome patients. In treated Klinefelter's syndrome patients, LDL cholesterol and adiponectin were significantly decreased, whereas no difference in body composition was found in comparison with untreated Klinefelter's syndrome patients. Multivariate analyses showed that truncal fat was the major determinant of metabolic syndrome and insulin sensitivity. CONCLUSIONS: The prevalence of metabolic syndrome was greatly increased, whereas insulin sensitivity was decreased in Klinefelter's syndrome. Both correlated with truncal obesity. Hypogonadism in Klinefelter's syndrome may cause an unfavorable change in body composition, primarily through increased truncal fat and decreased muscle mass. Testosterone treatment in Klinefelter's syndrome only partly corrected the unfavorable changes observed in untreated Klinefelter's syndrome, perhaps due to insufficient testosterone doses.