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Biomedical subjects

C J Tack

Publications and source records attributed to C J Tack.

At least 37 records · Page 2Linked to original sources
PubMed2001

Short-term glucosamine infusion does not affect insulin sensitivity in humans.

Overactivity of the hexosamine biosynthetic pathway may underlie hyperglycemia-associated insulin resistance, but to date human studies are lacking. Hexosamine pathway activation can be mimicked by glucosamine (GlcN). In the present placebo-controlled study we determined whether GlcN infusion affects insulin resistance in vivo. In 18 healthy subjects, we applied the double forearm balance technique (infused arm vs. control arm) combined with the euglycemic hyperinsulinemic clamp (60 mU/m(2).min insulin) for at least 300 min. During the clamp, subjects received infusions in the brachial artery of 4 micromol/dL.min GlcN from 90-240 min (n = 6) or from 0-300 min (n = 6) or saline (placebo; n = 6). We studied the effects of GlcN on forearm glucose uptake (FGU; infused arm vs. control arm, and vs. placebo experiments) and on whole body glucose uptake. GlcN infusion raised the plasma GlcN concentration in the infusion arms to 0.42 +/- 0.14 and 0.81 +/- 0.46 mmol/L; plasma GlcN remained very low (< 0.07 mmol/L) in the control arms and in the placebo group. GlcN infusion did not change forearm blood flow. During insulin, FGU increased more than 10-fold. At all time points, FGU was similar in the GlcN-infused arm compared with the control arm and was not different from FGU in the placebo experiments. Similar results were obtained for forearm arteriovenous glucose differences or extraction and for whole body glucose uptake. Thus, despite relevant GlcN concentrations for 5 h in the infused forearm, GlcN had no effect on insulin-induced glucose uptake. These results do not support involvement of the hexosamine pathway in the regulation of insulin sensitivity in humans, at least not in the short-term setting.

Adult↗
PubMed2000

Myocardial perfusion and sympathetic innervation in patients with hypertrophic cardiomyopathy.

OBJECTIVES: This study assessed left ventricular myocardial perfusion and sympathetic innervation and function in hypertrophied and nonhypertrophied myocardial regions of patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Patients with HCM often have clinical findings consistent with increased cardiac sympathetic outflow. Little is known about the status of sympathetic innervation specifically in hypertrophic regions. METHODS: We conducted positron emission tomographic (PET) scanning using the perfusion imaging agent 13N-ammonia (13NH3) and the sympathoneuronal imaging agent 6-[18F]-fluorodopamine (18F-FDA) in 8 patients with HCM and 15 normal volunteers. Positron emission tomographic data corrected for attenuation and the partial volume effect were analyzed using the region-of-interest technique. RESULTS: Myocardial 13NH3-derived radioactivity was similar in hypertrophied and nonhypertrophied regions of patients with HCM and in normal volunteers. At all time points, the 18F:13N ratio was lower in hypertrophied than in nonhypertrophied regions of HCM patients and in the septum of normal volunteers (p = 0.001). Trends in 18F-FDA-derived radioactivity over time were normal in both hypertrophied and nonhypertrophied myocardium. CONCLUSIONS: The results are consistent with decreased neuronal uptake of catecholamines in hypertrophied but not in nonhypertrophied myocardium of patients with HCM. Other aspects of cardiac sympathoneural function seem normal. Decreased neuronal uptake could reflect local relative hypoinnervation, decreased numbers of neuronal uptake sites, or metabolic limitations on cell membrane transport. By enhancing norepinephrine delivery to adrenoceptors for a given amount of sympathetic nerve traffic, decreased neuronal uptake can explain major clinical features of HCM.

Adult↗
PubMed2000

Assessment of human muscle glycogen synthesis and total glucose content by in vivo 13C MRS.

BACKGROUND: Obesity is often accompanied by a decreased ability of insulin to stimulate glucose uptake and glycogenesis in skeletal muscle. The aim of this study was to investigate the rate of glycogen formation and of muscular glucose content in relation to insulin sensitivity under euglycemic conditions. MATERIALS AND METHODS: We applied a hyperinsulinemic (430 pmol m-2 min-1) euglycemic clamp with infusion of 20% glucose (30% enriched with 13C-1-glucose) to 8 subjects with a wide range of insulin sensitivities. Glycogen and glucose levels were monitored simultaneously by in vivo 13C MRS of the calf muscle on a clinical MR system at 1.5T field strength. RESULTS AND CONCLUSIONS: Glycogen synthesis rate showed a strong correlation with whole body glucose uptake during the clamp (r = 0.93, P < 0.01). With the use of 13C MRS, total muscular glucose content could be determined in vivo, and showed a positive, linear correlation with glycogen synthesis rate (r = 0.85, P < 0.01). 13C MRS provides important information regarding in vivo insulin action. Preliminary results indicate that the glycogen synthesis rate improves after treatment with troglitazone.

Adult↗
PubMed1999

The role of adenosine in insulin-induced vasodilation.

It was previously shown that systemic hyperinsulinemia induces vasodilation in human skeletal muscle. The mechanism mediating this vasodilation is not yet completely clarified. Based on data from animal experiments, we hypothesized that stimulation of the adenosine receptor is involved in insulin-induced vasodilation. To test this hypothesis, a 105-min hyperinsulinemic euglycemic clamp was performed in three groups of eight healthy volunteers. In group 1, placebo was infused into the left brachial artery (experimental forearm). In the second and third group, respectively, draflazine (an adenosine-uptake blocker) and theophylline (an adenosine-receptor antagonist) were administered by intrabrachial infusion. Forearm blood flow (FBF) was measured by venous-occlusion plethysmography, both at the experimental and the control forearms. The percentage decrease in flow ratio (FBF experimental arm/control arm) in the draflazine group was significantly less pronounced than that in the placebo group, whereas the percentage decrease in flow ratio was larger in the theophylline group. These results demonstrate that the insulin-induced increase in blood flow in the experimental arm was more pronounced at the site of adenosine-uptake blockade by draflazine, whereas this was reduced during adenosine-receptor antagonism by theophylline. Our observations are compatible with the hypothesis that insulin-induced vasodilation is mediated by the release of adenosine.

Adenosine↗
PubMed1998

[A Dutch family with an autosomal dominant form of diabetes mellitus as a result of a mutation in the HNF1 alpha-gene (MODY3)].

OBJECTIVE: To study the molecular genetic basis of an autosomal dominant form of diabetes mellitus in a Dutch family. DESIGN: Descriptive. SETTING: Academic Hospital Nijmegen, the Netherlands and Laboratories for Molecular Genetics, Birmingham and Exeter, Great Britain. METHODS: A large pedigree with maturity-onset diabetes of the young (MODY) was studied by taking a history and by performing laboratory analysis; DNA was isolated from peripheral blood lymphocytes and linkage analysis was carried out using genetic markers near known MODY loci. As linkage to the MODY3 gene (encoding for the transcription factor hepatocyte nuclear factor (HNF)1 alpha) was suggested, all exons of the gene were sequenced for mutation detection. RESULTS: Of the 27 family members 13 were affected by diabetes. Diabetes was diagnosed at a mean age of 36.7 years, with four family members diagnosed before the age of 25. Nearly all patients were treated with diet/oral antidiabetics. Diabetic family members had lower fasting (specific) insulin concentrations than normoglycaemic family members (53.8 (SD: 5.4) versus 90.4 (SD: 12.9) pmol/l; p < 0.05). Linkage to the MODY3 gene was established. Further investigation showed a mutation in exon 2 of the gene. CONCLUSION: This Dutch family suffered from an autosomal form of diabetes mellitus caused by a mutation in the HNFI alpha gene (MODY3). Phenotypically, the diabetes appeared to be relatively mild; it was characterised by impaired insulin secretion.

Adolescent↗
PubMed1998

Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone.

Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.

Acetylcholine↗
PubMed1998

Insulin stimulates epinephrine release under euglycemic conditions in humans.

In healthy subjects, acute physiological hyperinsulinemia induces activation of the sympathetic nervous system, but in the absence of hypoglycemia, plasma epinephrine levels have not been found to increase during insulin administration. However, the venous level of epinephrine reflects the net result of release, clearance, and uptake and therefore is not a good measure of adrenomedullary epinephrine secretion. The influence of 90 minutes of euglycemic physiological hyperinsulinemia (60 mU x m(-2) x min(-1); plasma insulin concentration, approximately 700 pmol x L[-1]) on epinephrine kinetics using the 3H-epinephrine tracer method was studied in 12 healthy normotensive, non-obese subjects. After bolus injection, [3H]-epinephrine was continuously infused with arterial and venous blood sampling at regular intervals, enabling calculation of total body (systemic) and forearm epinephrine release and clearance. Studies were performed in the basal state and during sympathetic stimulation by lower-body negative pressure (LBNP) of -15 mm Hg for 15 minutes. Control experiments ("sham" clamps, but with LBNP) were performed in four of the 12 individuals. Euglycemic hyperinsulinemia (all arterial glucose samples > or = 4.2 mmol x L[-1]) induced an increase of the arterial epinephrine concentration (P = .03), and tended to increase total body epinephrine release (P = .08). Total body epinephrine clearance did not change during hyperinsulinemia. The insulin-induced increase in forearm blood flow ([FBF] by plethysmography, from 3.0 +/- 0.4 to 3.8 +/- 0.6 mL x dL(-1) x min(-1), P = .01) was strongly correlated with the increase in arterial epinephrine (r = .78, P < .01). Plasma epinephrine concentrations did not change during control experiments (sham clamp). Sympathetic stimulation alone as induced by LBNP did not stimulate epinephrine release. However, the combination of insulin and LBNP significantly increased epinephrine release (from 0.37 +/- 0.06 to 0.56 +/- 0.12 nmol x m(-2) x min(-1), P = .03). We conclude that acute physiological hyperinsulinemia under euglycemic conditions induces epinephrine release. This effect is enhanced when hyperinsulinemia is combined with sympathetic stimulation by LBNP. Due to increased forearm removal, venous epinephrine concentrations hardly change. Epinephrine release was strongly correlated with the hemodynamic effects of insulin.

Adult↗
PubMed1998

The newly developed sulfonylurea glimepiride: a new ingredient, an old recipe.

Disturbances in insulin secretion and insulin action are both involved in the pathophysiology of type 2 (or non-insulin-dependent) diabetes mellitus. The newly developed sulfonylurea (SU) derivative glimepiride has a marked insulin secretory effect both in vitro and in vivo, and is capable of increasing plasma insulin levels with approximately 50% in type 2 diabetes subjects. Glimepiride improves metabolic control comparable but not superior to other (second generation) SU derivatives. Although it has been advocated for once-daily use, maximum effect is presumably achieved by twice-daily dosing. One of the most important side-effects of SU remains hypoglycemia in some patients, which may last for several hours. Although there is some indication that the use of glimepiride leads to fewer hypoglycemic episodes than glibenclamide, the differences reported sofar are not statistically significant.

Diabetes Mellitus, Type 2↗
PubMed1998

Haemodynamic actions of insulin.

Several lines of evidence indicate a significant association between insulin and cardiovascular disease. This association might be explained by direct (cardio) vascular effects of insulin. Two hemodynamic actions of insulin are discussed in this review; it induces direct vasodilation in skeletal muscle and stimulation of the sympathetic nervous system. These closely linked effects normally offset each other. Although more insight has been obtained into responses in insulin-resistant individuals and possible mechanisms, direct evidence to support a causative role for insulin is not yet available.

Animals↗
PubMed1998

Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects.

OBJECTIVE: Insulin resistance is associated with a predominance of small, atherogenic LDL particles that are more prone to oxidative modification. Treatment with the insulin-sensitizer troglitazone may improve LDL composition and resistance to oxidation. RESEARCH DESIGN AND METHODS: In a randomized double-blind crossover design, 15 obese subjects were treated with either 400 mg troglitazone daily or placebo for 8 weeks. Insulin sensitivity (clamp), (apo)lipoproteins, LDL subclass pattern, plasma TBARS, and ex vivo LDL oxidation were determined. RESULTS: Troglitazone treatment improved insulin sensitivity. LDL cholesterol increased from 2.58 +/- 0.18 to 2.77 +/- 0.20 mmol/l (P = 0.03) because of an increase in large (buoyant) LDL1 (from 0.45 +/- 0.04 to 0.62 +/- 0.09 mmol/l, P = 0.008). Because small (dense) LDL3 decreased, LDL1:LDL3 ratio increased (P = 0.02). Plasma TBARS concentration declined significantly, and the lag time of ex vivo LDL oxidation showed a small but significant increase. CONCLUSIONS: In obese subjects, treatment with troglitazone improves insulin sensitivity, increases the ratio of large buoyant to small dense LDL, and appears to enhance the resistance of the LDL particle to oxidation. These qualitative changes in lipoproteins may have a beneficial effect on cardiovascular risk profile and compensate for a small increase in LDL cholesterol.

Adult↗
PubMed1997

Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives.

Familial combined hyperlipidemia (FCH) is a heterogeneous lipid disorder, caused by overproduction of VLDL and characterized by the occurrence of small, dense LDL particles, all features that are also associated with insulin resistance. Therefore, insulin sensitivity was examined directly by means of the euglycemic hyperinsulinemic clamp technique in male nonobese, normotensive FCH patients and compared with that of their nonaffected relatives, matched for age and body mass index (BMI). In addition, an oral 75-g glucose tolerance test (OGTT) was performed and lipid values, including the LDL subfraction profile, were determined. During the clamp, forearm blood flow (FBF) was measured by venous occlusion plethysmography. All participants had a normal glucose response after the glucose load, whereas FCH patients showed hyperinsulinemia after OGTT and higher fasting C-peptide levels. During the clamp, insulin concentrations increased equally in both groups. Mean whole-body glucose uptake (M) (120 to 180 minutes) was lower in FCH patients than in nonaffected relatives (6.89 +/- 0.31 versus 8.94 +/- 0.76 mg.kg-1.min-1; P = .01). In addition, the glucose uptake per unit insulin (I) was lower in FCH patients (insulin sensitivity index [M/I], 7.46 +/- 0.50 versus 9.51 +/- 0.53; P = .009). M significantly correlated with BMI, plasma cholesterol and triglyceride concentrations, and the individual LDL density. The FBF correlated with insulin sensitivity and increased significantly in nonaffected relatives (1.9 +/- 0.12 to 2.5 +/- 0.4 mL.min-1.dL-1; P = .025) but not in patients. Thus, FCH patients characterized by a predominance of small, dense LDL are insulin resistant compared with their nonaffected relatives. This insulin resistance may partly be explained by a decreased insulin-induced vasodilation in skeletal muscle.

Adult↗