[Diabetic nephropathy: the role of blood pressure and extra-cellular volume in its pathogenesis and treatment].
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Diabetic Nephropathies↗
Biomedical subjects
R P Dullaart
Publications and source records attributed to R P Dullaart.
[Diagnostic image (50) Positive Pemberton's sign].
A 32-year-old woman had a progressive euthyroid goitre and dyspnoea. Pemberton's sign was found to be positive: elevation of both arms resulted in an inspiratory stridor and venous congestion. Symptoms and signs resolved after total thyroidectomy.
Adult↗
[Elevated hormone levels without endocrinopathy: hypercortisoluria and hypoglycemia as facticious disorders].
A 29-year-old female patient with weight gain and intermittent hypertension was suspected of having Cushing's syndrome due to conspicuous hypercortisoluria. Specific laboratory tests demonstrated that the urine samples contained prednisolone, which had resulted in a false positive elevation of urine-free cortisol measurements. The patient admitted to having taken prednisolone tablets and also to having added them to several urine collections. In a 21-year-old male patient with unexplained hypoglycaemia, hypoglycaemia was recorded during a 72-hour fast together with an elevated level of plasma insulin and a low level of plasma C-peptide. The presence of insulin autoantibodies could be excluded, making a diagnosis of factitious hypoglycaemia highly likely. Both patients were confronted with the factitious disorder and received psychiatric counselling, after which no further problems arose. Where excessive hormone levels occur, the possibility of a factitious disorder needs to be considered. In such cases, specific supplementary laboratory tests may prove helpful.
Adrenocortical Hyperfunction↗
Redistribution of blood volume in type I diabetes.
AIMS/HYPOTHESIS: Impaired activity of endothelium-derived nitric oxide in Type I (insulin-dependent) diabetes mellitus will cause an increased vascular tone. Considering the lower production of nitric oxide in veins than in arteries, an impaired activity would have less vasoconstrictive effect in veins. The reported minimally changed total plasma volume in diabetes might, therefore, indicate a redistribution of blood volumes from the arterial to the venous side of the circulation. This could be more pronounced in patients with microalbuminuria. METHODS: In 16 normoalbuminuric and 16 microalbuminuric Type I diabetic patients and 16 individually matched healthy control subjects, venous and arterial blood volumes, venous myogenic response and arterial distensibilities were assessed in the upper arm using an electrical bio-impedance method. RESULTS: In diabetic patients, the venous blood volume and venous myogenic response were increased (p < 0.02 and p < 0.05, respectively), whereas the arterial blood volume did not change. Moreover, in diabetic patients the distensibility of the large arteries was decreased (p < 0.05) but increased in the total arterial bed (p < 0.05). Therefore, the distensibility of the small arteries must have been increased. No differences were found between normoalbuminuric and microalbuminuric diabetic patients. CONCLUSION/INTERPRETATION: The increase in venous blood volume and myogenic response and the decrease in distensibility of the large arteries in the upper arm are in agreement with the expected shift towards venous blood volume distribution in Type I diabetes with and without microalbuminuria. Furthermore, they support the haemodynamic hypothesis of the pathogenesis of diabetic microangiopathy.
Adult↗
Twenty four hour insulin infusion impairs the ability of plasma from healthy subjects and Type 2 diabetic patients to promote cellular cholesterol efflux.
Removal of cholesterol from peripheral cells by high density lipoproteins (HDL) is regarded as an important defence mechanism against atherosclerosis development. PLTP is involved in the generation of pre beta-HDL that can act as initial acceptors of cellular cholesterol. Exogenous hyperinsulinaemia may not only decrease HDL cholesterol, but also plasma phospholipid transfer protein (PLTP) activity. The effect of 24-h insulin infusion (30 mU/kg/h) on the ability of plasma to promote cholesterol efflux from Fu5AH cells was examined in eight healthy men and eight male Type 2 diabetic patients, matched for HDL cholesterol. Baseline HDL cholesterol and phospholipids, pre beta-HDL in incubated plasma, plasma apolipoprotein (apo) AI, PLTP activity and cholesterol efflux to plasma were not different between the groups. In both groups, HDL lipids, as well as plasma apo AI and PLTP activity decreased after 24 h of insulin (P<0.05 to P<0.01) compared to baseline and recovery, i.e. 1 week after insulin. Pre beta-HDL in incubated plasma did not significantly change. Cholesterol efflux to plasma from both groups decreased after insulin (P<0.05). Using plasma from healthy subjects, cholesterol efflux was correlated positively with HDL cholesterol, HDL phospholipids, pre beta-HDL in incubated plasma, plasma apo AI and PLTP activity (P<0.05 to P<0.001). Using plasma from diabetic patients, cholesterol efflux was not significantly correlated with any of these parameters. In conclusion, 24-h moderate hyperinsulinaemia impairs the ability of plasma to promote cholesterol efflux from Fu5AH cells. It is suggested that, apart from HDL, plasma PLTP activity is a determinant of cholesterol efflux via stimulation of pre beta-HDL formation. Cellular cholesterol efflux to plasma from selected Type 2 diabetic patients is maintained, but the interaction of Fu5AH cells with HDL may be altered.
Adult↗
Differentiated thyroid carcinoma in the elderly.
The overall prognosis of patients with differentiated thyroid cancer is excellent, but the prognosis is rapidly worsening, when the disease is diagnosed in elderly patients. Old patients more often present with poor prognostic features, such as large tumors, follicular or Hürthle cell subtypes, extrathyroidal growth and distant metastases. Therefore, an optimal therapeutic approach is recommended. Current therapy includes a total thyroidectomy, if necessary combined with a lymph node dissection and followed by high dose radioiodine ablation. Radioiodine therapy in elderly patients meets specific problems, concerning thyroid hormone withdrawal, side effects of 131I and nursing problems. Additional treatment of residual, recurrent or metastatic disease must be tailored, according to the stage of the disease, and should not be denied on the basis of chronological age. Lifelong treatment with suppressive thyroid hormone therapy does not lead to important long-term side effects at old age.
Aged↗
Short-term Acipimox decreases the ability of plasma from Type 2 diabetic patients and healthy subjects to stimulate cellular cholesterol efflux: a potentially adverse effect on reverse cholesterol transport.
AIMS: To evaluate the effect of short-term administration of the anti-lipolytic agent, Acipimox, on the ability of plasma to stimulate cellular cholesterol removal, which represents one of the first steps in the anti-atherogenic process of reverse cholesterol transport. METHODS: Eight male Type 2 diabetic patients and eight healthy subjects were studied after a 12-h fast at baseline, after 24 h of Acipimox administration, 250 mg every 4 h, and again after 1 week (recovery). Plasma lipids, apolipoprotein AI, phospholipid transfer protein (PLTP) activity, pre-beta high-density lipoproteins (HDL) in incubated plasma and efflux of radiolabelled cholesterol from Fu5AH rat hepatoma cells to plasma were measured at each time point. RESULTS: Acipimox lowered plasma triglycerides in diabetic patients (P = 0.001) and healthy subjects (P = 0.002), whereas plasma non-esterified fatty acids were decreased in diabetic patients (P = 0.001) compared with the averaged values at baseline and recovery. Acipimox decreased HDL cholesterol in healthy subjects (P = 0.007) and plasma apolipoprotein AI in both groups (P = 0.001 for diabetic patients; P = 0.008 for healthy subjects). Not only plasma PLTP activity (P = 0.001 for diabetic patients; P = 0.01 for healthy subjects), but also pre-beta HDL in incubated plasma (P = 0.001 for diabetic patients; P = 0.03 for healthy subjects) and cellular cholesterol efflux to plasma (P = 0.04 for diabetic patients; P = 0.005 for healthy subjects) were lowered by Acipimox in both groups. CONCLUSIONS: Short-term Acipimox administration impairs the ability of plasma from Type 2 diabetic patients and healthy subjects to stimulate cellular cholesterol efflux, in conjunction with alterations in HDL parameters and in PLTP activity. If the impairment of cellular cholesterol efflux to plasma is sustained with long-term treatment, this potentially adverse effect should be considered when treating diabetic dyslipidaemia with Acipimox. Diabet. Med. 18, 509-513 (2001)
Animals↗
Plasma cholesteryl ester transfer and hepatic lipase activity are related to high-density lipoprotein cholesterol in association with insulin resistance in type 2 diabetic and non-diabetic subjects.
We evaluated the hypothesis that plasma cholesteryl ester transfer (CET) and lipase activities are influenced by insulin sensitivity and contribute to the low high-density lipoprotein (HDL) cholesterol observed in type 2 diabetic patients and insulin-resistant non-diabetic subjects. Sixteen type 2 diabetic and 16 non-diabetic subjects participated. Diabetic and non-diabetic subjects were divided in equal groups of eight subjects with low or high insulin sensitivity, which was documented as the glucose infusion rate (M-value) during the last hour of a 3-h euglycaemic hyperinsulinaemic clamp (150 mU kg(-1) h(-1), blood glucose target 4.6 mmol L(-1)). Post-heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities were measured in samples obtained 1-2 weeks before the clamp. Plasma CET was measured by a radioisotope method. Compared to non-diabetic men with high insulin sensitivity (n = 8) HDL cholesterol was lower in type 2 diabetic men (n=8, p<0.01) and non-diabetic men (n=8, p <0.05) with low insulin sensitivity, and the HDL cholesterylester content was lower in type 2 diabetic men with high insulin sensitivity (n=8, p<0.05). In non-diabetic subjects with high insulin sensitivity, plasma CET was lower than in the other groups (p<0.05 for all). Multiple regression analysis showed that plasma CET (p=0.001) and HL activity (p=0.02) were independently and negatively associated with the M-value. No association between the M-value and LPL activity was observed. Independent negative relationships of HDL cholesterol with plasma CET (p = 0.04) and HL activity (p=0.03) were observed. This study supports the hypothesis that a low HDL cholesterol associated with insulin resistance in type 2 diabetic and non-diabetic subjects is related to a high plasma CET and a high HL activity.
Adult↗
Role of phospholipid transfer protein and prebeta-high density lipoproteins in maintaining cholesterol efflux from Fu5AH cells to plasma from insulin-resistant subjects.
Plasma phospholipid transfer protein (PLTP) enhances the generation of prebeta-high density lipoproteins (HDL) that may act as initial acceptors of cellular cholesterol, and are likely to play an important role in the antiatherogenic process of reverse cholesterol transport. We examined the interrelationships between insulin resistance, the ability of plasma to stimulate cellular cholesterol efflux, HDL cholesterol, plasma PLTP activity and prebeta-HDL in 12 non-diabetic, non-smoking, normotriglyceridaemic men. Cholesterol efflux from Fu5AH cells to plasma, plasma lipoproteins, PLTP activity and prebeta-HDL formation as measured in incubated plasma were determined after a 12-h fast. Insulin sensitivity was assessed by a euglycaemic, hyperinsulinaemic clamp (M-value). HDL cholesterol was positively correlated with the M-value (r=0.65, p< 0.05), whereas plasma PLTP activity (r= -0.59, p <0.05) and prebeta-HDL in incubated plasma (r= -0.66, p<0.05) were negatively correlated with the M-value. Thus, the lower the insulin sensitivity, the lower was HDL cholesterol and the higher were plasma PLTP activity and prebeta-HDL. Cellular cholesterol efflux tended to be correlated with HDL cholesterol (r=0.55, p < 0.10) as well as with plasma PLTP activity (r=0.56, p<0.10) and was positively correlated with prebeta-HDL in incubated plasma (r=0.74, p<0.01). No positive correlation between the M-value and cellular cholesterol efflux was found (r= -0.34, ns). These preliminary results support the hypothesis that, despite a lower HDL cholesterol, the ability of plasma from insulin-resistant subjects to promote cellular cholesterol efflux is not impaired, as a consequence of a higher plasma PLTP activity and enhanced prebeta-HDL formation.
Adult↗
Effects of growth hormone replacement on cortisol metabolism in hypopituitary patients treated with cortisone acetate.
Growth hormone (GH) replacement may inhibit 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) activity, resulting in diminished conversion of cortisone to cortisol. Moreover, GH replacement may lower bioavailability of hydrocortisone tablets. Therefore, substitution therapy with cortisone acetate could be disadvantageous during GH replacement. We conducted a randomized, placebo-controlled GH replacement (1 to 2 U GH/day) study during 6 months, followed by a 6-month open extension study (2U GH/day). Twelve men and 12 women with GH deficiency, of whom 17 received cortisone acetate (25 to 37.5 mg/day), participated. Eight patients were randomized to placebo initially. At baseline, after 6 and 12 months, urinary cortisol and cortisone metabolites were measured. No changes in urinary cortisol metabolites were observed after 6 months placebo (n=8). After 6 months GH the urinary (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortison ratio ((THF+alloTHF)/THE ratio) was unaltered in cortisone acetate treated patients (n = 17) and in patients with intact adrenal function (n = 7), whereas after 12 months GH the (THF + alloTHF)/THE ratio decreased only in cortisone acetate treated patients (1 dropout, n=9). Urinary THF and alloTHF were higher in cortisone acetate treated patients than in patients with intact adrenal function before GH and remained so after 12 months GH (p < 0.05 to p < 0.01). The sum of cortisol + cortisone metabolites did not change after GH in either group. The urinary free cortisol/free cortisone ratio, presumably reflecting renal 11betaHSD2 activity, tended to decrease in cortisone acetate treated patients (p<0.07 and p<0.05 after 6 and 12 months GH, respectively), as well as in patients with intact adrenal function (p<0.05 and a decrease in five/six patients after 6 and 12 months GH, respectively). In conclusion, these results suggest that GH replacement decreases 11betaHSD1 activity, which becomes manifest in patients receiving cortisone acetate substitution therapy. 11betaHSD2 activity is unaltered or may even be increased. It is unlikely that the bioavailability of conventional doses of cortisone acetate is impaired after GH replacement.
11-beta-Hydroxysteroid Dehydrogenase Type 1↗
Time course of the antiproteinuric and renal haemodynamic responses to losartan in microalbuminuric IDDM.
BACKGROUND: Interference in the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors has proven to be effective in lowering albuminuria in patients with insulin-dependent diabetes mellitus (IDDM). We studied whether angiotensin II receptor antagonism reduces urinary albumin excretion (UAE) in IDDM patients, and the relationship between the antiproteinuric effect and changes in systemic and renal haemodynamics. METHODS: Nine IDDM patients with microalbuminuria (30-300 mg/24 h) were studied. Patients were studied after a 4 week placebo period, on days 3, 7 and 28 of treatment with losartan 50 mg once daily, and after a 4 week placebo-controlled recovery period. RESULTS: Mean arterial pressure (MAP) was only slightly lowered during losartan treatment. Effective renal plasma flow (ERPF) was significantly increased on the third day of treatment and remained stable throughout the treatment period. Glomerular filtration rate (GFR) did not change throughout the study. Filtration fraction (FF) was maximally lowered on the third day of treatment and remained stable during treatment. UAE was already significantly lowered after 2 days of treatment, during both the day and night, and remained stable throughout the treatment period. The time course of the changes in UAE paralleled that of the changes in MAP, ERPF and FF. CONCLUSIONS: The angiotensin receptor antagonist losartan effectively lowers UAE in microalbuminuric IDDM patients. The changes observed in renal haemodynamics and UAE are concordant in time and maximal within only a few days of treatment. These results support the importance of the specific effects of interference in the renin angiotensin system (RAS) in microalbuminuric IDDM on blood pressure and renal haemodynamics in reducing urinary protein leakage, rather than non-haemodynamic, structural changes of the glomerular basement membrane.
Albuminuria↗
Enhanced escape of non-esterified fatty acids from tissue uptake: its role in impaired insulin-induced lowering of total rate of appearance in obesity and Type II diabetes mellitus.
AIMS/HYPOTHESIS: To estimate non-esterified fatty acids kinetics in patients with Type II (non-insulin-dependent) diabetes mellitus and obese subjects in the postabsorptive state and during hyperinsulinaemia using non-equilibrium tracer conditions. METHODS: We evaluated the effect of hyperinsulinaemia [euglycaemic clamp with insulin infused at 30 mU x kg(-1) x h(-1) (3-4 h) and 150 mU x kg(-1) x h(-1) (3 h)] on non-esterified fatty acid kinetics, traced with [14C]-palmitate using non-equilibrium tracer conditions in non-obese and obese healthy subjects and Type II diabetic patients (10 per group). Michaelis-Menten kinetics were applied for total non-esterified fatty acid disposal, which was assumed to be composed of total arterial plasma non-esterified fatty acid rate of appearance (equalling the rate of disappearance) and tissue uptake of non-esterified fatty acids derived from intravascular triglyceride hydrolysis. A model was developed to calculate the rate of escape of non-esterified fatty acids from tissue uptake and the net rate of tissue lipolysis. RESULTS: Total arterial plasma non-esterified fatty acid rate of appearance was lower in non-obese healthy subjects than in the other groups at low insulin infusion (p < 0.05) and in obese Type II diabetic patients at high insulin infusion (p < 0.05). Plasma triglycerides were also lowest in non-obese healthy subjects during hyperinsulinaemia (p <0.05 from other groups). The rate of escape from tissue uptake decreased during hyperinsulinaemia (p < 0.05 for each group) but remained higher in obese Type II diabetic patients (p < 0.05 from non-obese healthy subjects). In contrast, net rate of tissue lipolysis was not different between the groups at baseline and its decline during hyperinsulinaemia (p < 0.05 for each group) was similar in all groups. CONCLUSION/INTERPRETATION: This study challenges the view that the antilipolytic effect of insulin is impaired in Type II diabetes and obesity. We suggest that a high plasma triglyceride concentration causes a higher escape of non-esterified fatty acids from tissue uptake, leading to an impaired suppression of total arterial plasma rate of appearance during a low degree of hyperinsulinaemia in obese subjects and Type II diabetic patients and during a high degree of hyperinsulinaemia in obese Type II diabetic patients.
Adult↗
Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins.
Growth hormone (GH) deficiency and acromegaly may be associated with increased cardiovascular risk. Little is known about alterations in high density lipoproteins (HDL) in these conditions. Lecithin:cholesterol acyl transferase (LCAT) has the ability to esterify free cholesterol (FC) in HDL. Cholesteryl ester transfer protein (CETP) is able to transfer cholesteryl esters (CE) from HDL to very low and low density lipoproteins (VLDL and LDL). During phospholipid transfer protein (PLTP)-mediated HDL remodelling, small pre beta-HDL particles are generated which serve as acceptors for cellular cholesterol and provide the initial LCAT-substrate. We documented plasma lipids, LCAT, CETP and PLTP activity levels as well as plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) in 12 adult men with acquired GH deficiency, 12 acromegalic men and 24 healthy male subjects. All GH deficient and acromegalic patients received conventional hormonal replacement therapy if necessary. VLDL + LDL cholesterol and plasma triglycerides were higher in GH deficient (P < 0.01 and P < 0.05) and acromegalic patients (P < 0.05 and P < 0.01) than in healthy subjects. HDL cholesterol and HDL CE were lower (P < 0.05 for both) and the HDL FC/CE ratio was higher (P < 0.01) in these patient groups compared to healthy subjects. Plasma LCAT, CETP and PLTP activity levels were lower in acromegalic patients (P < 0.01 for all) and CETP activity was lower in GH deficient patients (P < 0.01) compared to healthy subjects. Plasma EST and CET were decreased in both acromegalic (P < 0.01 for both) and GH deficient patients (P < 0.05 for both). Multiple regression analysis demonstrated independent negative relationships of plasma insulin-like growth factor I with plasma LCAT (P = 0.0001), CETP (P = 0.009) and PLTP activity levels (P = 0.021). Plasma LCAT (P = 0.0001) and CETP activity (P = 0.0001) were also negatively associated with (substitution therapy for) adrenal insufficiency. In conclusion, GH deficient and acromegalic patients show abnormalities in HDL, consistent with impaired LCAT action. Decreases in plasma EST and CET in such patients, as well as a low PLTP activity in acromegaly suggest that reverse cholesterol transport may be impaired, contributing to increased cardiovascular risk.
Acromegaly↗
Microdialysis measurement of glucose in subcutaneous adipose tissue up to three weeks in type 1 diabetic patients.
BACKGROUND: Microdialysis of subcutaneous adipose tissue may provide an opportunity to monitor glucose continuously, when the device is connected to an extracorporal glucose sensor. We assessed whether our microdialysis probes are capable of measuring adipose tissue glucose over a prolonged period in Type 1 diabetic patients. Furthermore, the relationship between abdominal skinfold thickness and glucose recovery and the effect of spontaneous glucose excursions on its recovery were evaluated. METHODS: Microdialysis probes were pairwise inserted subcutaneously into the abdominal fat and remained in situ for 3 weeks in eight Type 1 diabetic patients. At days 1, 3, 4, 8, 11, 16, and 18 of probe retention, glucose, as measured by microdialysis, was compared to capillary blood glucose concentrations during a 4 h period. The recovery of glucose obtained by microdialysis was expressed as a percentage of the capillary blood glucose concentration. RESULTS: Eleven of the 16 inserted probes (69%) were evaluable during the complete study. Recovery of glucose was lower at day 1 and 3 (51+/-23% and 56+/-18%, respectively, mean+/-S.D.) compared to values found afterwards (67+/-19%, 72+/-13%, 76+/-14%, 71+/-16%, and 76+/-18%, for day 4, 8, 11, 16, and 18, respectively, for all P<0.05 vs. day 1 and 3). Skinfold thickness was inversely related to the overall 3 week glucose recovery (r=-0.76; P<0.03). Recovery was similar over a wide range of capillary blood glucose concentrations. CONCLUSIONS: Prolonged in vivo retention of microdialysis probes improves the recovery and lowers the variability of adipose tissue-sampled glucose in Type 1 diabetic patients. These findings show that microdialysis-based glucose measurements offer an opportunity for prolonged glucose monitoring.
Adipose Tissue↗
Effects of glucose and insulin levels on adipose tissue glucose measurement by microdialysis probes retained for three weeks in Type 1 diabetic patients.
BACKGROUND: To evaluate the effects of acute hyperglycaemia and hyperinsulinaemia on adipose tissue glucose measurements by microdialysis probes inserted for a 3-week period. METHODS: Microdialysis probes were implanted pairwise in abdominal adipose tissue in seven Type 1 diabetic patients and remained in situ during the complete study. Stepped hyperglycaemic hyperinsulinaemic clamps were performed at weekly intervals at which the probes were prepared for microdialysis. Adipose tissue glucose by microdialysis was compared to venous and capillary blood glucose concentrations. RESULTS: The mean time after which the acute rise in blood glucose was first detected was 11.3 min, which corresponds to the system delay of the microdialysis probe. The increase of the glucose concentration in dialysate was completed during the following 16 min. Hyperglycaemia and hyperinsulinaemia did not influence recovery compared to venous blood glucose concentrations, while recovery values compared to capillary blood glucose levels increased slightly under hyperinsulinaemic conditions (P<0.01). CONCLUSIONS: In Type 1 diabetic patients, recovery of glucose in adipose tissue compared to venous and capillary blood does not decrease during acute hyperglycaemia and hyperinsulinaemia. Although there is still a relevant time-delay to monitor a rise in blood glucose, these results show that microdialysis may offer an opportunity for future glucose monitoring over a prolonged time-period.
Adipose Tissue↗
Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients.
OBJECTIVES: To test whether insulin resistance in type 2 diabetes mellitus is associated with an altered overall setpoint of the 11beta-hydroxysteroid dehydrogenase (11betaHSD) mediated cortisol to cortisone interconversion towards cortisol, and to evaluate whether changes in insulin sensitivity induced by antecedent hyperinsulinaemia are related to changes in the 11betaHSD setpoint. PATIENTS AND MEASUREMENTS: The urinary ratio of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ((THF + allo-THF)/THE) and of free cortisol/free cortisone (UFF/UFE), as well as the plasma cortisol/cortisone ratio were measured in 8 male type 2 diabetic patients and 8 healthy male subjects without and after 24 h of insulin infusion. Insulin was infused at a rate of 30 mU/kg/h with blood glucose being clamped at euglycaemic levels in healthy subjects and at isoglycaemic levels in diabetic patients. Insulin sensitivity was assessed by measurement of whole body glucose uptake (M-value) during a 3-4 h euglycaemic clamp, directly after the 24 h insulin infusion and compared to the M-value on a control day, at least 1 week apart from the 24 h insulin infusion. RESULTS: Despite impaired insulin sensitivity (M-value, 11.6 +/- 7.7 vs. 28.5 +/- 11.6 micromol/kg/minutes, in type 2 diabetic and healthy subjects, respectively, P < 0.05), urinary (THF + allo-THF)/THE ratio and baseline plasma cortisol/cortisone ratio at 0800 h were similar in type 2 diabetic patients (0.82 +/- 0.07 and 3. 77 +/- 0.70, respectively) and healthy subjects (0.76 +/- 0.14 and 3. 81 +/- 0.88, respectively, ns). Insulin sensitivity was not correlated with urinary (THF + allo-THF)/THE ratio nor with baseline plasma cortisol/ cortisone. In type 2 diabetic patients, insulin sensitivity was further impaired by antecedent hyperinsulinaemia (P < 0.05), but the urinary (THF + allo-THF)/THE ratio (0.80 +/- 0.14, ns) and the plasma cortisol/cortisone at 0800 h (3.66 +/- 0.72, ns) did not change. In healthy subjects, insulin sensitivity did not change significantly (M-value, 22.5 +/- 9.7 micromol/kg/minutes, ns), although the urinary (THF + allo-THF)/THE ratio (0.92 +/- 0.25, P < 0.05) and the plasma cortisol/cortisone (4.59 +/- 0.63, P < 0.05) increased. Insulin did not affect the UFF/UFE ratio in either group. CONCLUSION: The present study does not support the hypothesis that insulin resistance in type 2 diabetes mellitus is associated with an overall change in the 11betaHSD set point towards cortisol. In view of the stimulatory effects of insulin and cortisol on adipogenesis, long-term stimulation of 11betaHSD reductase activity by insulin could aggravate visceral obesity.
11-beta-Hydroxysteroid Dehydrogenases↗
One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults.
OBJECTIVE: Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN: Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS: Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS: IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P < 0.01 from baseline; P < 0.01 from change with placebo). In the extension study, plasma IGF-I was also increased in the patients who previously received placebo (P < 0.02, n = 5). LI was evaluable in 14 biopsies at baseline, in 16 after 6 months and in 14 after 12 months. Overall crypt LI did not change in 8 GH treated patients after 6 months (P > 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS: Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.
Adult↗
Embolization in combination with radioiodine therapy for bone metastases from differentiated thyroid carcinoma.
BACKGROUND: The outcome for patients with bone metastases from differentiated thyroid carcinoma is worse compared to the overall prognosis of patients with differentiated thyroid carcinoma. The aim of this study is to evaluate the effect of embolization with concomitant radioiodine treatment on the serum thyroglobulin (Tg) level, pain and neurological symptoms in patients with large bone metastases from differentiated thyroid carcinoma. PATIENTS AND METHODS: Five symptomatic patients, who presented with a large unresectable bone metastasis of differentiated thyroid carcinoma were treated with radioiodine and embolization. The effect of this combined treatment was compared to the effect of radioiodine without embolization in a previously treated control group of 6 patients. Serum Tg levels, pain and neurological symptoms were scored. Both groups were treated similarly with total thyroidectomy followed by ablation with 5.55 GBq 131I and a second dose of 5.55 GBq 131I three months later, except for embolization in the embolization group, which took place between the 2 radioiodine treatments. RESULTS: In the embolization group, serum Tg at the second 131I therapy had decreased by 88.7% (median, range: 77.1-99.3%), which was significantly more compared to the decrease of serum Tg in the control group (18.6%, range: -4.7-95%, P < 0.05). CT-scanning showed a median volume reduction of the metastasis after radioiodine treatment combined with embolization of 52.5% (range: 39-80%). Both strategies resulted in a rapid relief of pain and neurological symptoms. Embolization was not accompanied with severe complications. CONCLUSIONS: This preliminary study suggests that embolization of bone metastases of differentiated thyroid carcinoma in combination with radioiodine treatment results in a significant initial reduction of serum Tg level compared to radioiodine treatment alone. This suggests a beneficial reduction in tumour burden. In this patient category, embolization appears to be a safe and well tolerated procedure.
Adult↗