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Biomedical subjects

C J Tack

Publications and source records attributed to C J Tack.

At least 19 recordsLinked to original sources
PubMed2006

[Treatment of patients with diabetes mellitus by means of inhaled insulin].

Good glycaemic control of diabetes mellitus is still hampered by the fear of insulin injections. Particularly in patients with type 2 diabetes, inhaled insulin as a novel therapeutic option for glycaemic control could be an alternative to subcutaneous insulin. Phase III clinical studies have shown glycaemic equivalence between inhaled insulin and conventional subcutaneous insulin. However, no study comparing inhaled insulin with short-acting insulin analogues has yet been published. Thus, methodological problems preclude conclusive remarks concerning quality-of-life issues. Inhaled insulin should be reserved for selected patient groups only. Lengthier studies to evaluate the long-term (pulmonary) safety of inhaled insulin and a cost-effectiveness study are needed.

Administration, Inhalation↗
PubMed2006

Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus.

BACKGROUND: According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM). MATERIALS AND METHODS: In 15 DM patients (DM duration 6.3 +/- 3.8 year; HbA1c 7.9 +/- 1.3%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis. Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test. Forearm blood flow was measured during forearm vascular alpha- and beta-adrenergic receptor blockade. RESULTS: At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups. LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (DeltaFVR: 12 +/- 4 vs. 19 +/- 3 arbitrary units, P < 0.05). The responses of plasma NA and heart rate variability did not differ. CONCLUSIONS: Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes. However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness.

Adrenergic Antagonists↗
PubMed2006

Effects of pioglitazone in familial combined hyperlipidaemia.

OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.

Alanine Transaminase↗
PubMed2006

Student evaluation of a problem-oriented module of clinical medicine within a revised dental curriculum.

As part of a revised dental curriculum, a 3(rd) year module on medical subjects was developed based on a mixture of self-study and problem-oriented approach using cases. Pairs of students had to select a specific medical problem and solve a paper patient case using a problem-solving cycle. Results were presented in working groups and by writing an essay. The quality of the presentations was assessed by colleague students and by the teacher supervisor; the expert teacher in the field graded the essay. The results contributed for 40% to the overall grade of the module. A questionnaire filled out by 94% of the participating students showed that 85% of the students agreed in preferring this way of handling medical problems as compared with conventional, lecture-based education. Almost all of them enjoyed the provided opportunity to give a case presentation. The problem-oriented model was assessed as useful by 73% of the students. Knowledge concerning the topic chosen turned out to be higher than knowledge of other topics. Although this study cannot prove that this mode of education actually results in a better ability to cope with medical problems, it may contribute in several ways to the final competences in the area of general medicine in the undergraduate dental curriculum.

Attitude of Health Personnel↗
PubMed2006

Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.e. the inability to perceive symptoms of hypoglycaemia) is the clinical representative. The underlying mechanism of hypoglycaemia-induced counterregulatory failure has not yet been disclosed. Patients with clinical hypoglycaemia unawareness are at high risk of severe hypoglycaemia that requires third-party assistance. Management options include avoidance of hypoglycaemic events and optimisation of insulin therapy to limit deterioration of glycaemic control associated with hypoglycaemia avoidance. Several counterregulatory-stimulating agents have been found to improve hypoglycaemic awareness in small clinical trials, but none have been tested in sufficiently large randomised studies to justify their use in daily practice. More research is required to elucidate the pathogenesis of counterregulatory failure and to develop adequate treatment strategies.

Adult↗
PubMed2006

Efficacy and safety of inhaled insulin in the treatment of diabetes mellitus.

Many patients with diabetes mellitus view subcutaneous injections of insulin as a daily burden. Pulmonary delivery of insulin offers an alternative route of administration and may as such improve diabetes treatment. Inhaled insulin provides a rapid absorption of insulin, but with low bioavailability. Phase III clinical trials in type 1 and type 2 diabetes have disclosed clinical equivalence between three inhaled insulin products (Exubera, AErx idMs, and hIIp) and regular human insulin, both in terms of glycaemic control and hypoglycaemic risk. Inhaled insulin cannot be used to replace basal insulin requirements. The most commonly reported adverse effects of inhaled insulin are cough and insulin antibody formation, the clinical significance of which is uncertain. No or minimal deterioration in pulmonary function parameters have been recorded, although studies were typically of short duration. Patients participating in inhaled insulin trials generally expressed satisfaction with the product and chose to remain on it. The availability of inhaled insulin may increase willingness in type 2 diabetic patients to consider insulin therapy. More studies of longer duration are required to determine (pulmonary) safety and cost-effectiveness of inhaled insulin, and to disclose which patients may benefit the most.

Administration, Inhalation↗
PubMed2005

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection. METHODS: HNF-4alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1alpha MODY but negative for HNF-1alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. RESULTS: Mutations in HNF-4alpha were found in 14/48 (29%) probands negative for HNF-1alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4alpha mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal. CONCLUSIONS/INTERPRETATION: HNF-4alpha mutations are common when no HNF-1alpha mutation is found in strictly defined MODY families. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4alpha should be performed in patients with clinical characteristics of HNF-1alpha MODY in whom mutations in HNF-1alpha are not found.

Adolescent↗
PubMed2005

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.

BACKGROUND: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. METHODS: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. RESULTS: Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). CONCLUSION: Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Blood Glucose↗
PubMed2004

Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans.

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l(-1) for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl(-1).min(-1) ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.

Adult↗
PubMed2004

F-18-fluorodeoxyglucose positron emission tomography leading to a diagnosis of septic thrombophlebitis of the portal vein: description of a case history and review of the literature.

Pylephlebitis or septic thrombophlebitis of the portal vein is a serious infectious disorder. Early diagnosis is difficult, due to nonspecific symptoms and signs, limitations of diagnostic modalities and the lack of familiarity of physicians with this entity. We report the history of a 73-year-old man with fever of unknown origin (FUO) in whom laboratory tests, blood and urine cultures, chest X-ray, abdominal ultrasound, and Indium-111-leucocyte scintigraphy did not reveal the cause of the fever. F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) subsequently pointed to the diagnosis of pylephlebitis, which was confirmed by computed tomography (CT) and percutaneous puncture. We conclude that FDG PET allows detecting inflammatory foci in patients with FUO and offers to make the diagnosis of pylephlebitis at an early stage.

Aged↗
PubMed2003

Optimized detection of changes in glucose-6-phosphate levels in human skeletal muscle by 31P MR spectroscopy.

As glucose-6-phosphate (G6P) plays a central role in muscle energy metabolism, the possibility to observe changes in the tissue level of this compound in vivo is very relevant. G6P can be detected noninvasively by (31)P MR spectroscopy, but its visibility in vivo is severely hampered due to low tissue levels and spectral overlap with other, stronger phosphomonoester signals. To optimize the observation of changes in G6P levels in human calf muscle by (31)P MR spectroscopy at 1.5 T, we implemented an approach involving a new RF probe and a postacquisition correction method. An anatomically shaped circularly polarized (31)P coil was designed for high intrinsic sensitivity. Together with an additional (1)H coil and (1)H blocking circuits this allowed the application of NOE and (1)H decoupling to further enhance sensitivity. A hyperglycemic hyperinsulinemic clamp was used to increase G6P levels. The spectra were corrected for frequency and phase drift due to scanner instability and leg movements using an automated phase and frequency correction method. Difference (31)P spectroscopy was applied to detect changes of the G6P signal. The result, in five healthy subjects, demonstrated that the combination of sensitivity optimization with automated drift correction enabled a robust detection of G6P changes in time series experiments down to a resolution of 10 min.

Adult↗
PubMed2003

Treatment with intravenous insulin followed by continuous subcutaneous insulin infusion improves glycaemic control in severely resistant Type 2 diabetic patients.

AIMS: Despite high-dose s.c. insulin therapy, some Type 2 diabetes mellitus (DM) patients remain in poor metabolic control. We investigated whether a period of euglycaemia using i.v. insulin, followed by continuous subcutaneous insulin infusion (CSII), would ameliorate the deleterious effects of hyperglycaemia on insulin sensitivity and result in sustained, improved metabolic control. METHODS: In a prospective observational study, eight Type 2 DM patients with severe insulin resistance (insulin dose 1.92 +/- 0.66 U/kg per day (mean +/-sd)), in poor metabolic control (HbA(1c) 12.0 +/- 1.7%), were treated with i.v. insulin for 31 +/- 10 days aimed at euglycaemia, followed by CSII therapy for 12 months, using insulin lispro. Before and after 28 +/- 6 days of i.v. insulin treatment, insulin sensitivity was measured by a hyperinsulinaemic euglycaemic clamp. RESULTS: Euglycaemia was reached after 12 +/- 6 days of i.v. insulin treatment. Subsequently, the i.v. insulin dose required to maintain euglycaemia decreased from 1.7 +/- 0.9 to 1.1 +/- 0.6 U/kg per day (P < 0.005). Whole body glucose uptake increased from 12.7 +/- 5.7 to 22.4 +/- 8.8 micromol/kg per min (P < 0.0005). HbA(1c) decreased to 8.9 +/- 1.2% after 28 +/- 6 days, to 7.1 +/- 0.6% after 6 months and to 8.3 +/- 1.4% after 12 months (P < 0.001 vs. pretreatment, for all). Lipid profile improved and plasminogen activator inhibitor type 1 levels decreased significantly. Mean body weight did not change. CONCLUSIONS: In Type 2 diabetic patients, who are poorly controlled despite high-dose s.c. insulin treatment, a period of 2 weeks of euglycaemia achieved by i.v. insulin reverses hyperglycaemia-induced insulin resistance and substantially improves metabolic control. Subsequent CSII treatment, using insulin analogues, appears to maintain improved metabolic control for at least 1 year. This approach is promising but needs further evaluation.

Aged↗
PubMed2002

Vascular effects of glibenclamide vs. glimepiride and metformin in Type 2 diabetic patients.

AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.

Acetylcholine↗
PubMed2002

Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes.

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation.

Acarbose↗
PubMed2001

A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.

Adult↗
PubMed2001

Vascular effects of metabolic inhibition by 2-deoxy-D-glucose in humans.

2-Deoxy-D-glucose (2DG) is a structural analogue of glucose that inhibits the glycolytic pathway. In vitro 2DG induced vasodilation, which was inhibited by glibenclamide (blocker of ATP-dependent potassium channels). The vasodilation induced by 2DG may be an interesting model for metabolic vasodilation. In this study, we investigated whether 2DG induces vasodilation in the human skeletal muscle vascular bed and whether this vasodilation was inhibited by glibenclamide. We measured forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial 2DG (0.4 and 0.8 mg/min x dl of forearm volume, each dose for 30 min), either alone or with co-infusion of insulin to increase the cellular 2DG uptake, and compared the results with insulin infusion alone. Glibenclamide infusion (1.0 microg/min x dl) was added in a subgroup. 2DG alone did not change FBF ratio (experimental/control arm, 11 +/- 9%, p = 0.34), but 2DG with insulin significantly increased FBF ratio (32 +/- 17%, p = 0.04). The increase in FBF by 2DG and insulin was significantly more pronounced than the vasodilation induced by insulin alone (p = 0.03). Co-infusion of glibenclamide had no effect on the vasodilation induced by 2DG and insulin (percentage increase in FBF ratio 11 +/- 18% without and 17 +/- 12% with glibenclamide, p = 0.85). In conclusion, 2DG induces manifest vasodilation in humans when infused in combination with insulin. This vasodilation is not mediated by ATP-dependent potassium channels.

Adolescent↗