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Biomedical subjects

H Yki-Järvinen

Publications and source records attributed to H Yki-Järvinen.

At least 19 recordsLinked to original sources
PubMed2006

Overproduction of large VLDL particles is driven by increased liver fat content in man.

AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

Adipose Tissue↗
PubMed2006

Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study.

AIMS/HYPOTHESIS: In type 2 diabetic patients we compared 9 months of combination therapy with insulin glargine and metformin with 9 months of NPH insulin combined with metformin. The primary focus was changes in HbA(1c); secondary focus was diurnal glucose profiles and symptomatic hypoglycaemia. METHODS: In this investigator-initiated open, parallel-group clinical trial involving seven centres, 110 insulin-naive type 2 diabetic patients with poor glycaemic control (HbA(1c) >or=8.0%) on oral hypoglycaemic agents (90% using sulfonylurea plus metformin) were randomised to receive bedtime insulin glargine with metformin (G+MET) or bedtime NPH with metformin (NPH+MET) for 36 weeks. The patients were taught how to self-adjust their insulin dose and use a modem to send the results of home glucose monitoring to treatment centres. The goal was to achieve a fasting plasma glucose (FPG) of 4.0 to 5.5 mmol/l in both groups. RESULTS: During the last 12 weeks, FPGs averaged 5.75+/-0.02 and 5.96+/-0.03 mmol/l (p<0.001) and insulin doses were 68+/-5 and 70+/-6 IU/day (0.69+/-0.05 and 0.66+/-0.04 IU kg(-1) day(-1), NS) in the G+MET and NPH+MET groups, respectively. At 36 weeks, mean HbA(1c) was 7.14+/-0.12 and 7.16+/-0.14%, respectively (NS). Symptomatic, but not confirmed symptomatic, hypoglycaemia was significantly lower during the first 12 weeks in the G+MET group (4.1+/-0.8 episodes/patient-year) than in the NPH+MET group (9.0+/-2.3 episodes/patient-year, p<0.05), but not significantly different thereafter. Glucose levels before dinner were higher in the NPH+MET group (10.1+/-0.3 mmol/l) than in the G+MET group (8.6+/-0.3 mmol/l, p=0.002) throughout the 36-week study. With regard to baseline characteristics such as initial glycaemia or C-peptide, there was no difference between patients who achieved good glycaemic control (HbA(1c) <7.0%) and those who did not. Differences were seen in the following: between study centres, weight gain during the run-in period and insulin therapy, and FPG during the last 12 weeks (5.7+/-0.2 vs 6.7+/-0.3 mmol/l for patients reaching vs those not reaching target, p<0.01). CONCLUSIONS/INTERPRETATION: Good glycaemic control can be achieved with both G+MET and NPH+MET. Use of G+MET reduces symptomatic hypoglycaemia during the first 12 weeks and dinner time hyperglycaemia compared with NPH+MET.

Adult↗
PubMed2005

Acute in vivo effects of insulin on gene expression in adipose tissue in insulin-resistant and insulin-sensitive subjects.

AIMS/HYPOTHESIS: We determined the response of selected genes to in vivo insulin in adipose tissue in 21 non-diabetic women. MATERIALS AND METHODS: The women were divided into insulin-sensitive and -resistant groups based on their median whole-body insulin sensitivity (8.7+/-0.4 vs 4.2+/-0.3 mg kg(-1) min(-1) for insulin-sensitive vs -resistant group). Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 h of i.v. maintained euglycaemic hyperinsulinaemia. Adipose tissue mRNA concentrations of facilitated glucose transporter, member 1 (SLC2A1, previously known as GLUT1), facilitated glucose transporter, member 4 (SLC2A4, previously known as GLUT4), peroxisome proliferator-activated receptor gamma ( PPARG), peroxisome proliferator-activated receptor gamma co-activator 1alpha (PPARGC1A), 11beta-hydroxysteroid dehydrogenase-1 (HSD11B1), TNF, adiponectin (ADIPOQ), IL6 and the macrophage marker CD68 were measured using real-time PCR. RESULTS: Basal expression of 'insulin-sensitivity genes' SLC2A4 and ADIPOQ was lower while that of 'insulin-resistance genes', HSD11B1 and IL6 was significantly higher in the insulin-resistant than in the insulin-sensitive group. Insulin significantly increased expression of 'insulin-sensitivity genes' SLC2A4, PPARG, PPARGC1A and ADIPOQ in the insulin-sensitive group, while only expression of PPARG and PPARGC1A was increased in the insulin-resistant group. The expression of 'insulin-resistance genes' HSD11B1 and IL6 was increased by insulin in the insulin-resistant group, but insulin failed to increase HSD11B1 expression in the insulin-sensitive group. At 6 h, expression of HSD11B1, TNF and IL6 was significantly higher in the insulin-resistant than in the insulin-sensitive group. IL6 expression increased significantly more in response to insulin in the insulin-resistant than in the insulin-sensitive group. CD68 was overexpressed in the insulin-resistant as compared with the insulin-sensitive group at both 0 and 6 h. CONCLUSIONS/INTERPRETATION: These data suggest that genes adversely affecting insulin sensitivity hyperrespond to insulin, while genes enhancing insulin sensitivity hyporespond to insulin in insulin-resistant human adipose tissue in vivo.

Adipose Tissue↗
PubMed2005

Increased augmentation of central blood pressure is associated with increases in carotid intima-media thickness in type 2 diabetic patients.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with a two- to seven-fold increase in cardiovascular morbidity and mortality. The aim of this study was to determine the relationships between intima-media thickness (IMT), an established marker of atherosclerosis, large artery function and other determinants of cardiovascular risk in type 2 diabetic patients. METHODS: We studied 228 type 2 diabetic patients (75 women, aged 62+/-2 years [mean+/-SEM]). Carotid IMT was bilaterally measured using ultrasound technology. Applanation tonometry and pulse wave analysis were used to measure aortic systolic and diastolic blood pressures, central pressure augmentation (AG) and the augmentation index (AIx), a measure of systemic arterial stiffness. Conventional cardiovascular risk factors (lipids, HbA(1)c, smoking and diabetes duration) were also assessed. RESULTS: Women had higher AG and AIx (p<0.0001), despite comparable systolic BP and heart rate in women and men. In women, AG (r=0.39, p<0.001), age (r=0.32, p<0.01), brachial systolic BP (r=0.34, p<0.01) and aortic systolic BP (r=0.34, p<0.01) correlated with IMT. In men, age (r=0.41, p<0.001), diabetes duration (r=0.25, p<0.01), AG (r=0.22, p<0.01), aortic systolic BP (r=0.21, p<0.01), brachial systolic BP (r=0.21, p<0.01) and body weight (r=0.16, p<0.05) correlated with IMT. In multiple linear regression analyses, AG and aortic systolic BP, but not brachial systolic BP, were age-independent determinants of IMT in men and women. In all patients, increased AG (adjusted for sex, age and heart rate) correlated with longer duration of diabetes, urinary albumin excretion and IMT. CONCLUSIONS/INTERPRETATION: Measures of central systolic pressure correlate with carotid IMT, independently of age and other risk markers.

Aged↗
PubMed2005

The fatty liver and insulin resistance.

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.

Adiponectin↗
PubMed2004

In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue.

AIMS/HYPOTHESIS: Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). METHODS: In this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry. RESULTS: Patients with lipodystrophy had significantly higher 11beta-HSD1 mRNA concentrations (relative to beta2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29+/-0.20 vs 0.09+/-0.07, p=0.0004) and higher ratios of urinary cortisol : cortisone metabolites. Adipose tissue 11beta-HSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen. CONCLUSIONS/INTERPRETATION: In adipose tissue of patients with HAART-associated lipodystrophy, 11beta-HSD1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11beta-HSD1 may explain the pseudo-Cushing's features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk.

AIMS/HYPOTHESIS: Fat accumulation in the liver has been shown to be closely correlated with hepatic insulin resistance and features of insulin resistance, also independently of body weight. It remains to be established how fat in the liver correlates with that in other depots, and whether any association differs between men and women. METHODS: Liver fat (assessed using proton spectroscopy), intra-abdominal and subcutaneous fat (measured using magnetic resonance imaging) and markers of insulin resistance, including serum adiponectin, were determined in 132 non-diabetic subjects: 66 men (age 41+/-1 years) and 66 women (age 42+/-1 years). RESULTS: Although the women had almost twice as much subcutaneous fat as the men (5045+/-207 vs 2610+/-144 cm3, p<0.0001), amounts of intra-abdominal fat (1305+/-80 vs 1552+/-111 cm3, NS) and liver fat (6.7+/-0.8 vs 8.9+/-1.2%, NS) were similar. In this study, no sex differences were observed with respect to serum insulin, adiponectin, triglyceride and HDL cholesterol concentrations. Of all measures of body composition, liver fat was best correlated with serum insulin (r=0.58, p<0.001), with no difference observed between men and women. Serum adiponectin was inversely correlated with liver fat content (r=-0.21, p<0.05). Multiple linear regression analysis revealed that intra-abdominal fat was significantly associated with liver fat, independently of serum adiponectin and subcutaneous fat. Liver fat, but not intra-abdominal fat, significantly explained the variation in serum insulin concentrations. CONCLUSIONS/INTERPRETATION: Intra-abdominal fat is independently associated with liver fat, whereas subcutaneous fat is not. Liver fat, but not intra-abdominal fat, is independently associated with serum insulin. Men and women with similar amounts of intra-abdominal and liver fat do not exhibit sex differences in markers of insulin resistance (serum insulin, triglycerides, HDL cholesterol and adiponectin).

Abdomen↗
PubMed2004

Expression of fatty-acid-handling proteins in human adipose tissue in relation to obesity and insulin resistance.

AIMS/HYPOTHESIS: Protein-mediated trans-membrane and intracellular fatty acid trafficking are becoming increasingly recognised as biochemically and physiologically important concepts. Obesity and insulin resistance are polygenic disorders, heavily influenced by environmental and life-style factors, and are virtually always associated with disturbed fatty acid metabolism in adipose and other tissues. The aim of this study was to investigate mRNA expression levels of fatty-acid-handling proteins in adipose tissue in relation to markers of genetic and acquired obesity and insulin resistance. METHODS: We quantified mRNA expression of subcutaneous adipose tissue fatty-acid-handling proteins (ALBP, KLBP, FATP1, FATP4, CD36, ACS1) in 17 monozygotic twin-pairs with a range of intra-pair differences (Delta) in BMI and detailed measures of obesity and insulin resistance, allowing influences of genetic and non-genetic factors to be distinguished. RESULTS: In acquired obesity FATP4 expression was up-regulated independently of genetic background (DeltaFATP4 versus DeltaBMI; r=0.50, p=0.04; DeltaFATP4 versus Deltabody fat; r=0.59, p=0.01). Similarly, CD36 and FATP1 expression correlated with acquired differences in HDL cholesterol and non-esterified fatty acid concentrations respectively. Moreover, FATP4 and CD36 expression levels correlated with measures of obesity and insulin resistance that are influenced by both genetic and non-genetic factors (FATP4 versus BMI: r=0.53, p=0.0001; FATP4 versus body fat: r=0.51, p=0.002; FATP4 versus homeostasis model assessment [HOMA]: r=0.49, p=0.001; CD36 versus BMI: r=0.50, p=0.02; CD36 versus body fat: r=0.63, p=0.001; CD36 versus HOMA: r=0.34, p=0.06). CONCLUSIONS/INTERPRETATION: These findings indicate that expression of specific adipose tissue fatty-acid-handling proteins is related to obesity and insulin resistance, and that, in particular, FATP4 plays a role in acquired obesity. Our results suggest that facilitated fatty acid trafficking is a physiologically and pathologically relevant phenomenon in man.

Adipose Tissue↗
PubMed2004

Comparison of in vivo effects of nitroglycerin and insulin on the aortic pressure waveform.

BACKGROUND: Individuals whose platelets are resistant to the antiaggregatory effects of insulin in vitro are also resistant to the antiaggregatory effects of nitroglycerin (GTN). We have previously shown that insulin acutely diminishes central wave reflection in large arteries and that this action of insulin is blunted in insulin-resistant subjects. However, as yet, no studies have compared the haemodynamic effects of insulin and GTN on large arterial function in the same group of subjects. The aim of this study was to determine whether resistance to the haemodynamic effects of insulin is a defect specific to insulin or whether individuals resistant to the vascular actions of insulin are also resistant to GTN. DESIGN AND RESULTS: Dose-response characteristics of insulin and GTN on the aortic waveform were determined using applanation tonometry and pulse wave analysis (PWA) in seven healthy men (age 26 +/- 1 year, BMI 25 +/- 2 kg m(-2)). Three doses of sublingual GTN (500 microg for 1, 3 or 5 min) and insulin (0.5, 1 or 2 mU kg(-1) min(-1) for 120 min) were administered on three separate occasions. Both agents dose-dependently decreased central pulse pressure and the augmentation index (AIx) without changing brachial artery blood pressure. We next compared responses to insulin (2 mU kg(-1) min(-1) for 120 min) and sublingual GTN (500 microg for 5 min) in 20 nondiabetic subjects (age 50 +/- 2 year, BMI 21.0-36.3 kg m(-2)). Again, both agents significantly decreased AIx. Although the vascular effects of insulin and GTN vascular were positively correlated [Spearman's r=0.92 (95% confidence interval 0.81-0.97), P<0.0001], the time-course for the action GTN was faster than that of insulin. Brachial systolic blood pressure remained unchanged during the insulin infusion (122 +/- 3 vs. 121 +/- 3 mmHg, 0 vs. 120 min) but aortic systolic blood pressure decreased significantly by 30 min (111 +/- 3 vs. 107 +/- 3 mmHg, 0 vs. 30 min, P<0.01). Similarly, GTN decreased aortic systolic blood pressure from 119 +/- 4 to maximally 112 +/- 3 mmHg (P<0.001) without significantly decreasing systolic blood pressure in the brachial artery. CONCLUSIONS: The effects of insulin and GTN on large arterial haemodynamics are dose-dependent and significantly correlated. The exact mechanisms and sites of action of insulin and GTN in subjects with insulin resistance remain to be established.

Administration, Sublingual↗
PubMed2004

Insulin therapy in type 2 diabetes: role of the long-acting insulin glargine analogue.

Insulin glargine is a long-acting insulin analogue, with a longer duration of action and a flatter time-action profile compared with NPH insulin. These properties can be predicted to result in higher glucose levels during the night and lower glucose levels after dinner following bedtime injection of insulin glargine compared with an equal dose of NPH insulin injected at bedtime. In two large-scale clinical trials involving either insulin-naïve (426 patients treated for 1 year) or previously insulin-treated (518 patients treated for 28 weeks) patients with type 2 diabetes, comparing addition of once-daily insulin glargine or NPH insulin to oral agents, these predictions were proven to be correct. Nocturnal hypoglycaemia was reduced by 58% in insulin-naive patients and by 22% in previously insulin-treated patients, and dinner-time glucose control was significantly better with insulin glargine than with NPH insulin once daily in the study in insulin-naive patients. The 'treat-to-target study' (756 insulin-naive patients treated for 24 weeks) showed that good glycaemic control can be achieved with aggressive titration of the insulin dose with either once-daily insulin glargine or NPH insulin combined with oral agents (mean endpoint HbA(1c) was 6.96% with insulin glargine and 6.97% with NPH insulin); however, this was achieved with less variability and nocturnal hypoglycaemia with insulin glargine. These data support use of insulin glargine instead of NPH insulin for basal insulin replacement in patients with type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2003

Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects.

OBJECTIVE: Platelet aggregation responses to acetylsalicylic acid (ASA) show considerable interindividual variation, the causes of which are largely unknown. We determined whether variation in insulin action is associated with that of ASA on platelets. SUBJECTS: In all, 10 nonobese (age 50+/-3 y, BMI 25+/-1 kg/m(2)) and 11 obese (age 52+/-2 y, BMI 32+/-1 kg/m(2)) subjects. MEASUREMENTS: Insulin sensitivity of glucose uptake was determined by the euglycemic insulin clamp technique. Platelet aggregation responses to four doses of arachidonic acid (AA) and adenosine diphosphate (ADP) were assessed in platelet-rich plasma before and 1 h after ingestion of 50 mg ASA using Born's turbidometric aggregometer. RESULTS: Whole-body insulin sensitivity (M-value 0-180 min) was 36% lower in the obese (4.5+/-0.6) than the nonobese (7.1+/-0.6 mg/kg min, P<0.01) group. Before ASA, all doses of AA induced complete aggregation. After ASA ingestion, ASA inhibited maximal aggregation more in the nonobese than the obese group at AA concentrations of 0.75, 1 and 1.5 mmol/l (P=0.016 for ANOVA). ADP-induced aggregation at high doses (2 and 3 micromol/l) was also less inhibited in the obese group. In vivo insulin sensitivity (r=-0.68, P<0.001 for 1 mmol/l AA) and BMI (r=0.58, P<0.01 for 1 mmol/l AA) were closely correlated with residual aggregation after ASA administration. CONCLUSION: These data demonstrate that obese insulin-resistant subjects have a blunted response to platelet-inhibitory effect of ASA. If this blunted effect is of a single dose of ASA preserved in continuous use, it could contribute to the increased risk of atherothrombosis in insulin-resistant individuals.

Adenosine Diphosphate↗
PubMed2003

Low HDL cholesterol concentration is associated with increased intima-media thickness independent of arterial stiffness in healthy subjects from families with low HDL cholesterol.

BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) is associated with increased risk for developing coronary artery disease. Cardiovascular disease is characterized by increased intima-media thickness (IMT) and arterial stiffness, but the effect of low HDL on these measurements has not been reported. MATERIALS AND METHODS: We studied 18 apparently healthy subjects from families with low HDL-C and 18 control subjects, which were pair-matched to maximize statistical power. Intima-media thickness was assessed using ultrasound examination of the carotid arteries. Arterial stiffness was measured using applanation tonometry on the radial artery and pulse-wave analysis to obtain central aortic pulse-pressure waveform, from which the augmentation index, a measure of global large artery stiffness, was calculated. RESULTS: Low HDL subjects (age 41 +/- 3 years, BMI 26.6 +/- 1.0 kg m(-2) had significantly lower HDL-C than the control subjects (age 41 +/- 3 years, BMI 26.5 +/- 1.0 kg m-2; 1.00 +/- 0.05 vs. 1.49 +/- 0.09 mmol L-1, low HDL vs. control subjects, P < 0.0001). Subjects with low HDL-C had significantly thicker mean IMTs than the control subjects (0.77 +/- 0.03 vs. 0.70 +/- 0.02 mm, low HDL vs. control subjects, P < 0.01). The maximal (0.99 +/- 0.04 vs. 0.89 +/- 0.03 mm, P < 0.01), far wall (0.76 +/- 0.04 vs. 0.69 +/- 0.02 mm, P < 0.05) and carotid bulb (1.11 +/- 0.06 vs. 0.97 +/- 0.04 mm) IMTs were also significantly increased, whereas the mean common carotid and the internal artery IMT were not. The age-related increase in mean IMT was more pronounced in the low HDL subjects than the control subjects (P < 0.01 for difference between elevations of age vs. IMT slopes). There were no differences in central pressure augmentation, the augmentation index, peripheral or central blood pressures between the groups. CONCLUSIONS: A low HDL-C concentration is associated with thickening of carotid IMT independent of other risk factors in healthy affected members of low HDL families.

Adult↗
PubMed2003

Insulin therapy improves insulin actions on glucose metabolism and aortic wave reflection in type 2 diabetic patients.

BACKGROUND: Normal insulin action in vivo involves a decrease in aortic systolic blood pressure as a result of an insulin-induced decrease in the amplitude of the second systolic (reflected) pressure wave. This action of insulin and insulin action on glucose metabolism is impaired in insulin-resistant and type 2 diabetic subjects. We determined whether 6 months of insulin therapy affects insulin actions on glucose metabolism and vascular function. MATERIALS AND METHODS: Thirteen type 2 diabetic patients (age 53 +/- 2 years, body mass index 30.8 +/- 1.2 kg m(-2), HbA1C 8.8 +/- 0.2%) were studied before and after insulin therapy. Central aortic pressure waveforms were reconstructed from those recorded in the periphery using applanation tonometry every 30 min. This allowed determination of augmentation, i.e. the pressure difference between the second and first systolic pressure peaks and the augmentation index (AgI, augmentation divided by pulse pressure). The measurements were performed basally and during euglycaemic hyperinsulinaemic conditions. RESULTS: Insulin therapy increased whole body glucose disposal by 35% from 5.1 +/- 0.7 to 6.8 +/- 0.6 mg kg ffm(-1) min(-1) (P<0.001 for 0 vs. 60 months). 6 months of insulin therapy decreased basal AgI from 26.2 +/- 1.8 to 22.7 +/- 2.3% (P<0.05). The change in AgI by insulin infusion was similar before and after insulin therapy at all time points. Peripheral blood flow, heart rate and blood pressures remained unchanged. CONCLUSIONS: Insulin therapy improves insulin action on glucose metabolism and decreases basal AgI. These data support the idea that insulin therapy has beneficial effects on vascular function.

Adult↗
PubMed2003

Increased inflammatory activity parallels increased basal nitric oxide production and blunted response to nitric oxide in vivo in rheumatoid arthritis.

BACKGROUND: Endothelial dysfunction, defined as loss of bioactivity of NO in the vessel wall, is thought to precede atherosclerosis. OBJECTIVE: To determine whether endothelial dysfunction characterises patients with RA and whether these patients have increased inducible nitric oxide synthase (iNOS) dependent NO production in vivo. METHODS: and results: Twenty patients with RA and 33 normal subjects received intrabrachial artery infusions of endothelium dependent (acetylcholine (ACh)) and independent (sodium nitroprusside (SNP)) vasodilators to determine arterial responsiveness to NO. Basal flow and its percentage decrease by NG-monomethyl-L-arginine (L-NMMA), an inhibitor of both iNOS and endothelium dependent NOS (eNOS), was used to determine the contribution of iNOS and eNOS dependent NO to basal flow. Both SNP (p<0.01) and ACh (p<0.05) increased blood flow significantly less in patients with RA than normal subjects. Serum concentrations of TNFalpha were, within the RA group, inversely correlated with blood flow responses to both SNP (r=-0.67, p=0.002) and ACh (r=-0.64, p<0.005). Basal flow was significantly increased in RA and correlated within this group with serum CRP (r=0.48, p<0.05), TNFalpha (r=0.61, p<0.01) concentrations, and ESR (r=0.68, p<0.002). L-NMMA decreased basal flow significantly more (-34+/-2%) in the patients with RA than the normal subjects (-24+/-3%, p<0.02), suggesting in view of the blunted response to ACh, increased iNOS activity. CONCLUSIONS: Patients with RA have a dual abnormality in NO dependent vascular function. Basal blood flow is increased in proportion to inflammatory activity and more inhibited by L-NMMA, suggesting increased iNOS activity, and responsiveness to NO is reduced.

Acetylcholine↗
PubMed2002

Family histories of Type II diabetes and hypertension predict intima-media thickness in patients with Type I diabetes.

AIMS/HYPOTHESIS: Hyperglycaemia predicts microvascular complications but data on macrovascular disease are limited. We searched for predictors of carotid artery intima-media thickness in young adults with Type I (insulin-dependent) diabetes mellitus. METHODS: A total of 71 children (F/M = 34/37) were followed after their diagnosis until they reached 32 +/- 1 years of age, when duration of diabetes averaged 22 +/- 1 years. Cardiovascular risk markers [lipids, blood pressure, smoking, urinary albumin excretion rate, lifetime glycaemic exposure (A(1c) months), exercise habits, alcohol consumption, family history] were evaluated at age 21 +/- 1 for the baseline examination and at age 32 +/- 1 years for the follow-up examination years. During follow-up, intima-media thickness of common and internal carotid arteries and the carotid bulb were quantitated using a high-resolution B-mode ultrasound. RESULTS: In univariate analysis, age, BMI, blood pressure, lifetime glycaemic exposure, a positive family history of Type II (non-insulin-dependent) diabetes mellitus, hypertension and cardiovascular disease were predictors of carotid intima-media thickness. In multivariate analysis, a positive family history of Type II diabetes predicted maximal ( p< 0.05) and common ( p< 0.005) carotid artery intima-media thickness, family history of hypertension predicted increases in maximal ( p< 0.04), and far wall ( p< 0.006) carotid artery intima-media thickness, and lifetime glycaemic exposure was an independent predictor of increased carotid bulb thickness ( p< 0.03). CONCLUSION/INTERPRETATION: Positive family histories of Type II diabetes and hypertension are independent predictors of carotid intima-media thickness in patients with Type I diabetes, and could therefore predispose these patients to atherosclerosis

Adult↗
PubMed2001

In vivo glucose-stimulated amylin secretion is increased in nondiabetic patients with pancreatic cancer.

The incidence of diabetes is increased in patients with pancreatic cancer, but the mechanisms underlying this association are not clear. Alterations in beta-cell function, such as formation of amyloid from excessive production of amylin and reduced expression of GLUT2, have been suggested to be possible mechanisms. We compared in vivo secretory responses of amylin and insulin (n = 37) and expression of GLUT2 in pancreata (n = 10) obtained at surgery between diabetic and nondiabetic patients with and without pancreatic tumors. Fourteen had pancreatic adenocarcinoma, 7 had diabetes (duration 6 +/- 3 years) and a pancreatic tumor, 8 had type 2 diabetes (duration 6 +/- 2 years), and 8 were normal subjects. First (0 to 10 minutes) and second (10 to 120 minutes) phase insulin and amylin secretion were characterized using the hyperglycemic clamp technique. Both amylin and insulin concentrations followed a biphasic pattern in nondiabetic subjects. In nondiabetic patients with pancreatic cancer, total, as well as nonglycosylated amylin concentrations, were increased compared with nondiabetic subjects without pancreatic cancer. Both first- and second-phase plasma amylin and serum immunoreactive insulin concentrations were low in all patients with diabetes, ie, both in type 2 diabetes and in those patients with diabetes and pancreatic tumors. At surgery, specimens were obtained for characterization of GLUT2 expression in beta cells, which was unaltered in nondiabetic (n = 7) and diabetic (n = 3) patients. Amyloid staining was similarly negative in diabetic and nondiabetic pancreata independent of pancreatic carcinoma. In conclusion, plasma amylin, but not insulin concentrations, are increased in nondiabetic patients with pancreatic cancer, but low in all patients with diabetes. These data support the potential of using an increase in the ratio of circulating amylin to insulin as a marker for pancreatic cancer in nondiabetic patients.

Adenocarcinoma↗