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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance and hyperinsulinemia have been reported in homozygous beta-thalassemia before the development of diabetes. However, insulin sensitivity (SI) has never been studied in normoinsulinemic patients. Furthermore, whether hyperinsulinemia is due to increased beta-cell secretion or to decreased hepatic insulin extraction is poorly understood. We estimated SI, beta-cell secretion, and hepatic insulin extraction using the minimal model analysis of a frequently sampled intravenous glucose tolerance test (2.8 g/m2) in two groups of nondiabetic pubertal patients with homozygous beta-thalassemia (seven hyperinsulinemic and seven normoinsulinemic patients) and seven control subjects matched for age, body mass index, and pubertal stage. In both thalassemic groups, SI was reduced by approximately 40% (3.52 +/- 0.57 and 3.74 +/- 0.66 v 6.89 +/- 1.02 10(-4).min-1 [microU/mL], P = .011) and was inversely correlated with iron overload (r = -.707, P = .006). All parameters of beta-cell secretion were not significantly different in patients and controls. On the other hand, basal posthepatic insulin delivery (BDR) was more than doubled in hyperinsulinemic patients with respect to normoinsulinemic patients or controls (15.1 +/- 2.4 v 6.1 +/- 1.1 and 7.5 +/- 2.3 pmol/L.min-1, P = .012), and the same was true for total posthepatic insulin delivery ([TID] 6.3 +/- 1.0 v 2.9 +/- 0.5 and 2.9 +/- 0.7 pmol/L.240 min-1, P = .015). Hepatic insulin extraction was significantly lower in hyperinsulinemic patients than in normoinsulinemic patients or controls (49.3% +/- 9.4% v 73.0% +/- 3.7% and 77.4% +/- 3.9%, P = .011), and in patients it was inversely correlated with iron overload (r = -.829, P = .0001). In conclusion, insulin resistance is present even in normoinsulinemic patients, beta-cell responsiveness to glucose is normal, and hyperinsulinemia is mainly due to decreased hepatic insulin extraction. In nondiabetic thalassemic patients, these defects are possibly related to iron overload.
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PMID:Insulin resistance and hyperinsulinemia in homozygous beta-thalassemia. 788 70

Puberty is normally associated with a decline in tissue sensitivity to insulin. However, normal glucose homoeostasis is maintained by compensatory increases in glucose-stimulated insulin secretion. Here we describe studies performed in healthy children which have determined the site of insulin resistance (hepatic vs. peripheral) and whether this resistance extends to other substrates such as amino acid and free fatty acid metabolism. The changes in insulin action and secretion that are normally seen during puberty lead us to question the role of insulin resistance in other childhood conditions that are complicated by the later development of type I or type II diabetes, namely thalassaemia major and Turner's syndrome. These studies showed that in patients with thalassaemia and Turner's syndrome, insulin resistance and increased insulin secretion are very early metabolic defects that appear before the development of diabetes.
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PMID:Insulin-resistant syndromes in children. 826 87

To better understand the pathophysiology of glucose intolerance secondary to iron overload in patients with thalassemia major, we performed tolbutamide-modified frequently sampled iv glucose tolerance tests (FSIGTs) in 10 thalassemic patients (6 males and 4 females; 21.7 +/- 1.2 yr old; body mass index, 19.7 +/- 0.6 kg/m2) and 10 healthy controls (5 males and 5 females; 22.4 +/- 1.3 yr; body mass index, 20.6 +/- 0.5 kg/m2). Insulin secretion and action were quantified by application of the minimal model of glucose kinetics and the combined model of insulin and C-peptide kinetics to the FSIGT data. The insulin sensitivity index was significantly lower in thalassemia patients [72 +/- 12 min-1(nmol/mL)] compared to controls [158 +/- 21 min-1(nmol/mL); P = 0.0026]. The integrated insulin response during the FSIGT was significantly greater in thalassemia patients than in controls after tolbutamide injection (P = 0.042). The difference in insulin levels was apparently due to reduced hepatic insulin extraction in thalassemia (78 +/- 2% vs. 68 +/- 3%; P = 0.0251). Seven of the 10 thalassemia patients were studied prospectively at 6-month intervals for 6-12 months. Repeated measures analysis of variance indicated that across a 6-month interval, there was a decrease in the total integrated insulin response (P = 0.002), with no change in insulin sensitivity (P = 0.86). In conclusion, patients with thalassemia major have significant insulin resistance, which may be compensated for by an elevated circulating insulin level. The elevated insulin level in response to tolbutamide appears to be due to reduced hepatic extraction of insulin and not to an enhanced insulin secretory response. Over time, patients with thalassemia experience a reduction in their circulating insulin levels. Persistent insulin resistance along with a progressive reduction in circulating insulin levels may lead to glucose intolerance and diabetes mellitus, which have a high prevalence in patients with thalassemia major.
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PMID:Factors determining glucose tolerance in patients with thalassemia major. 834 55

Hyperinsulinemia and insulin resistance precede the development of diabetes in patients with thalassemia major on hypertransfusion/desferoxamine therapy. To examine whether these early metabolic defects could be reversed, seven nondiabetic patients with thalassemia (17 +/- 4 y) were studied for 12 mo before and during 12 mo of low-dose treatment with glyburide (1.25 to 3.75 mg/d), a second-generation oral hypoglycemic agent. Plasma glucose responses to oral glucose (1.75 g/kg body weight) were normal before and after glyburide. Plasma insulin responses were markedly increased before glyburide therapy (area under insulin response curve 86 +/- 15 and 96 +/- 15 versus 40 +/- 5 nmol/min/L in normal controls, p < 0.001). However, insulin responses to glucose fell significantly after 3 mo of glyburide (to 52 +/- 7 nmol/min/L, p < 0.05 versus pretreatment) and were normalized after 12 mo (42 +/- 7 nmol/min/L, p = NS versus controls). The rate of insulin-stimulated glucose metabolism during euglycemic insulin clamps (40 mU/m2/min) was low in the patients before treatment (163 +/- 10 versus 215 +/- 17 mg/m2/min in controls, p < 0.05) and increased to 205 +/- 30 mg/m2/min after 3 mo of glyburide. The treatment was well tolerated. In conclusion, in nondiabetic, hyperinsulinemic, thalassemic patients, chronic glyburide therapy normalizes insulin responses to oral glucose. To the extent that insulin hypersecretion contributes to the development of diabetes in thalassemia, glyburide therapy may provide a means of postponing this complication of the disease.
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PMID:Correction of hyperinsulinemia by glyburide treatment in nondiabetic patients with thalassemia major. 851 Oct 23

A Bangladeshi family is described in which the genes for both hemoglobin E (Hb E) and pyrimidine 5' nucleotidase deficiency are segregating. An individual homozygous for both these conditions has a severe hemolytic anemia, whereas family members who are homozygous for Hb E are asymptomatic and those homozygous for pyrimidine 5' nucleotidase deficiency have the mild hemolytic anemia that is characteristic of this disorder. Globin-chain synthesis experiments have shown that the mechanism underlying the interaction between these two genotypes is a marked decrease in the stability of Hb E in pyrimidine 5' nucleotidase-deficient red blood cells (RBCs). It has also been found that in the enzyme-deficient RBCs in which Hb E is highly unstable, free alpha-chains, though not beta E-chains, acoumulate on the membrane. In view of the increasing evidence that the hemolysis associated with pyrimidine 5' nucleotidase deficiency results not only from an increase in the level of erythrocyte pyrimidines, but also from inhibition of the hexose monophosphate shunt activity in young erythrocytes, it is likely that the marked instability of Hb E in the enzyme-deficient cells results from oxidant damage acting on a mildly unstable Hb variant. These observations may have important implications for the better understanding of the pathophysiology of Hb E/beta-thalassemia, globally the commonest important form of thalassemia.
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PMID:Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency. 926 98

In vitro, cytokines like interleukin-1-beta (IL-1-B) and tumour necrosis factor-alpha (TNF-A) inhibit insulin release and can destroy islet B-cells. We measured blood levels of IL-1-B, TNF-A, and islet cell antibody (ICA) in 20 children with IDDM, 20 of their non-diabetic siblings, 20 children with thalassemia major on long-term hypertransfusion therapy and iron chelation, and 10 normal age-matched children. In the non-diabetic and thalassemic children we investigated the early phase of insulin release after i.v. glucose (0.5 g/kg, 30 per cent solution) and evaluated tolerance to oral glucose (1.75 g/ kg). Circulating IL-1-B and TNF-A concentrations were significantly higher in IDDM-siblings (33.7 +/- 12.7 pg/ml and 655 +/- 165 pg/ml, respectively) v. normal children (21.1 +/- 6.4 pg/ml and 383 +/- 122 pg/ml, respectively). Thalassemic children had no detectable circulating ICA. The prevalence of ICA was 30 per cent in children with IDDM and 60 per cent of their siblings. Impaired oral glucose tolerance was detected in five children with thalassemia (25 per cent), but in none of the IDDM-siblings. The early phase of insulin release was significantly depressed in thalassemic children (peak insulin = 29.2 +/- 5.1 mIU/ml) v. normal children (52.3 +/- 9.5 mIU/ml) and IDDM-siblings (45.3 +/- 12.4 mIU/ml). It appears that thalassemic children had significantly decreased insulin secretion and impaired glucose tolerance, however, the mechanism of B-cell dysfunction is not mediated by ICA nor by cytokines.
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PMID:Interleukin-1-beta, tumour necrosis factor-alpha, islet-cell antibody, and insulin secretion in children with thalassemia major on long-term blood transfusion. 900 65

Patients with beta-thalassemia major (beta-thalassemia) frequently have bone disorders of multifactorial etiology. We attempted to analyze the relationship between the bone mineral density ([BMD] measured by dual-photon absorptiometry) and auxanologic parameters, degree of siderosis, function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein-3 (IGFBP3) axis, calcium-phosphate balance, parathyroid hormone (PTH), and cytokines (interleukin-1beta [IL-1] and tumor necrosis factor-alpha [TNF-alpha]) in 30 prepubertal children with beta-thalassemia major and 15 age-matched children with constitutional short stature (CSS), who have normal glucose tolerance and thyroid function. Children with beta-thalassemia had a significantly decreased BMD and mean BMD% for age and sex (0.75+/-0.24 g/cm2 and 71%+/-10%, respectively) versus children with CSS (1.06+/-0.3 g/cm2 and 92%+/-7%, respectively). Thalassemic patients had significantly lower circulating concentrations of IGF-I and IGFBP3 (49+/-21 ng/mL and 1.2+/-0.25 mg/L, respectively) compared with control children (153+/-42 ng/mL and 2.1+/-0.37 mg/L, respectively). The GH response to provocation by clonidine and glucagon was defective (peak GH < 7 microg/L) in 12 of the 30 thalassemic children. Serum concentrations of IL-1beta and TNF-alpha did not differ among the two study groups. Hypocalcemia was detected in five of the 30 thalassemic patients: hypoparathyroidism was diagnosed in two of the five and rickets in the other three. BMD was highly correlated with the circulating concentrations of IGF-I and IGFBP3, as well as with the auxanologic parameters (age, weight, height, height standard deviation score [HSDS], and body mass index [BMI]). It is suggested that increasing the circulating IGF-I concentration through aggressive nutritional therapy and/or GH/IGF-I therapy with supplementation with vitamin D and/or calcium might improve bone growth and mineralization and prevent the development of osteoporosis and consequent fractures in these patients. Such therapy requires blinded controlled trials.
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PMID:Bone mineral density in prepubertal children with beta-thalassemia: correlation with growth and hormonal data. 959 44

Cooley's original description of beta-thalassaemia major included marked bone deformities as a characteristic feature. These were thought to be due to expansion of haemopoiesis attempting to compensate for the congenital anaemia. Regular blood transfusions from infancy prevents these skeletal problems. Nevertheless, symptoms due to bone disease frequently occur in adult patients. Osteoporosis has not previously been reported as a cause of severe morbidity in thalassaemia major. The present study shows a high prevalence of low bone mass among thalassaemia major patients and analyses the predisposing causes. Bone density scans were performed in 82 patients with transfusion-dependent beta thalassaemia. Factors known to be associated with low bone mass such as gender, endocrine disorders and lifestyle activities, together with factors specific to the thalassaemia and its management, were included in a series of univariate analyses to ascertain any significant associations. 42 (51%) of the patients had severely low bone mass and a further 37 (45%) had low bone mass. The three factors showing a statistically significant association with severely low bone mass were male sex, 24/38 (63%) males had severely low bone mass, compared with 18/44 (41%) females, the lack of spontaneous puberty, 22/32 (69%) who required therapeutic induction of pubertal development had severely low bone mass, compared with 19/47 (40%) with spontaneous puberty and diabetes, 8/10 (80%) diabetic patients had severely low bone mass, compared with 23/56 (41%) with normal glucose tolerance. There was no association between the bone mineral density measurements and the haematological characteristics or treatment details of these patients. Severely low and low bone mass are common findings in patients with beta-thalassaemia major despite optimal transfusion and iron chelation. The associated features suggest that the severely low bone mass is due to endocrine abnormalities, in contrast to the haematological causes of bone disease characteristically seen in untreated thalassaemics.
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PMID:High prevalence of low bone mass in thalassaemia major. 988

Haematological data, genotype, transfusion requirements, metabolic indicators of oxidative stress (flux via hexose-monophosphate shunt (HMPS); steady state level of GSH and GSSG, NADPH and NADP; activity of anti-oxidant enzymes), parameters of membrane damage (aggregated band 3; membrane-bound haemichromes, autologous immunoglobulins (Igs) and C3 complement fragments) and erythrophagocytosis were measured in erythrocytes (RBC) of 15 beta-thalassaemia intermedia patients (nine splenectomized) with low, if any, transfusion requirements. Patients presented increased aggregated band 3, bound haemichromes, Igs and C3 complement fragments, and increased erythrophagocytosis. Bound haemichromes strongly correlated with aggregated band 3. Anti-band 3 Igs were predominantly associated with aggregated band 3. Erythrophagocytosis positively correlated with aggregated band 3, haemichromes and Igs, suggesting the involvement of haemichrome-induced band 3 aggregation in phagocytic removal of beta-thalassaemic RBC. Splenectomized patients showed higher degrees of membrane damage and phagocytosis, significantly higher numbers of circulating RBC precursors, and tendentially higher numbers of reticulocytes. Basal flux via HMPS was increased twofold, but HMPS stimulation by methylene blue was decreased, as was the glucose flux via HMPS. GSH was remarkably decreased, whereas NADPH was increased. Except for unchanged catalase and glutathione reductase, anti-oxidant enzymes had increased activity. Negative correlation between HMPS stimulation by methylene blue and bound haemichromes indicated that the ability to enhance HMPS may counteract haemichrome precipitation and limit consequent membrane damage leading to erythrophagocytosis.
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PMID:Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia. 1008 87

Glyco-metabolic status was evaluated in 29 pubertal homozygous thalassaemics aged from 17 to 42 years and in 12 age-matched healthy subjects. Diagnosis of diabetes mellitus was assessed in 4 patients (13.8%), who became diabetic after the age of 18 years. With respect to controls non-diabetic patients exhibited significantly higher fasting plasma glucose levels and more sustained glycemic responses to oral glucose tolerance test, whereas their overall insulin output was significantly lower. Moreover non-diabetic thalassaemic patients showed a clear reduction of both beta-cell function and insulin resistance indices (HOMA model). In conclusion our data show a high prevalence of diabetes but do not support the existence of an insulin resistant status in thalassaemia major, at least in adulthood.
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PMID:Glucose tolerance, insulin secretion and peripheral sensitivity in thalassaemia major. 1009 Nov 58


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