| 1. |
- Ahrén, Bo, et al.
(författare)
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Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies.
- 2004
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 150:2, s. 97-104
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Forskningsöversikt (refereegranskat)abstract
- Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. A correct judgement of insulin secretion therefore requires validation in relation to the insulin sensitivity in the same subject. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant. This product is usually called the disposition index. Several techniques may be used for its estimation such as data derived from the frequently sampled i.v. glucose tolerance test, the oral glucose tolerance test or the glucose-dependent arginine stimulation test or the euglycemic hyperinsulinemic clamp technique in combination with a test on insulin secretion. Using these techniques the compensatory increase in beta cell function in insulin resistance has been verified in obesity, in pregnancy and after glucocorticoid administration as has the defective beta cell function as the underlying cause of impaired glucose tolerance and type 2 diabetes. Similarly, combined analysis of insulin sensitivity and insulin secretion has shown a down-regulation of beta cell function in increased insulin sensitivity accompanying weight reduction in obesity and following exercise. Acknowledging this inverse relationship between insulin secretion and insulin sensitivity therefore requires estimation of both variables for correct assessment in any individual.
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| 2. |
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| 3. |
- Bennet, Anna M, et al.
(författare)
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The risk of myocardial infarction is enhanced by a synergistic interaction between serum insulin and smoking.
- 2002
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 147:5, s. 641-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate the relationship between levels of serum insulin, the homeostasis model assessment (HOMA) and IGF-binding protein-1 (IGFBP-1) as factors related to myocardial infarction (MI) risk, and their interaction with lifestyle-related risk factors. DESIGN: The Stockholm epidemiology programme (SHEEP), a case-control study, consisting of 749 first-time MI cases (510 men, 239 women) and 1101 healthy controls (705 men, 396 women) was used. METHODS: The risk of developing MI was assessed by calculating odds ratios (OR) and synergistic interactions (SI) between serum insulin, IGFBP-1, HOMA and other variables related to MI risk (including smoking) in men and women. RESULTS: Subjects with elevated levels of insulin and HOMA (>75th percentile) had increased MI risks when compared with individuals with low levels. ORs for elevated insulin and HOMA (adjusted for age and residential area) for men: insulin 1.6 (95% confidence interval (CI) 1.3-2.1) and HOMA 1.5 (95% CI 1.1-1.9) and for women: insulin 2.1 (95% CI 1.5-2.9) and HOMA 1.9 (95% CI 1.3-2.8). Women with low levels of IGFBP-1 (<10th percentile) showed a tendency towards elevated MI risk even if this was not statistically significant (OR 1.5 (95% CI 0.9-2.6)). Smokers with high levels of serum insulin had greatly increased MI risk (OR for men: 4.7 (95% CI 3.0-7.2) and OR for women: 8.1 (95% CI 4.5-14.8)). SI scores based upon these interactions were statistically significant. CONCLUSIONS: These results might have preventive cardiovascular implications as they clearly suggest that subjects with insulin resistance are particularly susceptible to the hazards of smoking.
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| 4. |
- Boe, Anette S., et al.
(författare)
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Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G1
- 2004
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 150:1, s. 49-56
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVE: Immunoglobulin G (IgG) antibodies to the steroidogenic enzymes 21-hydroxylase (21OH) and side-chain cleavage enzyme (SCC) are important diagnostic markers for autoimmune Addison's disease and autoimmune polyendocrine syndromes (APS) types I and II. The characterization of autoantibody (IgG) subclasses may reveal information on how tIssue destruction takes place; therefore, IgG subtypes of anti-21OH and anti-SCC antibodies from sera of patients with Addison's disease, APS I and APS II were determined using recombinant 21OH and SCC. METHODS: SCC(51-521) and his-SCC(51-521) were expressed by pET-scc in the Escherichia coli strain BL21 Star (DE3) and inclusion bodies were purified. Full-length, human 21OH fused to an N-terminal 6x histidine affinity tag was expressed in insect cells by using the baculovirus expression system bac-to-bac. Western blots were used to investigate the IgG subtype(s) of the autoantibodies against 21OH and SCC in patients and healthy blood donors. RESULTS: All anti-SCC positive sera (n=10) contained autoantibodies of the IgG1 subclass, while four out of ten also contained IgG3. All anti-21OH positive sera (n=16) had autoantibodies exclusively against IgG1. Sera from 20 healthy subjects did not show any reactivity against 21OH or SCC. CONCLUSIONS: The finding of a predominating IgG1 response against 21OH and SCC may suggest that T helper (Th) cells of the Th1 subclass are involved in destruction of the adrenal cortex in patients with autoimmune Addison's disease.
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| 5. |
- Bulow, B., et al.
(författare)
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Increased leptin and tumour necrosis factor alpha per unit fat mass in hypopituitary women without growth hormone treatment
- 2001
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 145:6, s. 737-742
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Tidskriftsartikel (refereegranskat)abstract
- Background: The adipocyte products, leptin and tumour necrosis factor (TNF)alpha are associated with atherosclerotic diseases and may be factors contributing to the enhanced cardiovascular risk in hypopituitary patients with growth hormone (GH) deficiency. Objective: To investigate whether leptin and TNF alpha are increased in a group of hypopituitary women previously found to have increased cardiovascular morbidity, and to compare them with matched individuals of the same sex and age and with similar body composition. Design and Patients: Thirty-three GH-deficient women with a median age of 64 years (range 39-77 years) were investigated cross-sectionally. The patients were compared with 33 controls matched for sex, age, smoking habits, educational level and residence. Methods: Body composition was measured by bioimpedance analysis. Fasting concentrations of leptin, TNF alpha and insulin were analysed in patients and controls. Results: There was no significant difference in body mass index or fat mass between patients and controls (both P greater than or equal to 0.4). Serum leptin did not differ significantly between patients and controls. However, when serum leptin concentrations were expressed per kilogram fat mass, the patients had significantly greater concentrations (P = 0.01). Serum TNF alpha and TNF alpha per kilogram fat mass were also significantly greater in the patients (both P = 0.001). In contrast, serum insulin did not differ significantly between patients and controls. In the patients, serum leptin concentrations correlated positively with kilogram fat mass (r = 0.54, P = 0.002). Leptin concentration per kilogram fat mass was positively correlated with insulin (r = 0.40. P = 0.03). Conclusions: In contrast to serum concentrations of TNF alpha. serum leptin did not differ from that in controls, implying that leptin is not a major contributor to the previously found increase in cardiovascular morbidity in the hypopituitary women investigated. However, the patients had increased leptin concentrations per unit fat mass, indicating an altered adipocyte secretory function in this group.
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| 6. |
- Burén, Jonas, et al.
(författare)
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Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes.
- 2002
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Ingår i: European Journal of Endocrinology. - : European Society of Endocrinology. - 0804-4643 .- 1479-683X. ; 146:3, s. 419-29
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Glucocorticoid excess leads to insulin resistance. This study explores the effects of glucocorticoids on the glucose transport system and insulin signalling in rat adipocytes. The interaction between glucocorticoids and high levels of insulin and glucose is also addressed.DESIGN AND METHODS: Isolated rat adipocytes were cultured for 24 h at different glucose concentrations (5 and 15 mmol/l) with or without the glucocorticoid analogue dexamethasone (0.3 micromol/l) and insulin (10(4) microU/ml). After the culture period, the cells were washed and then basal and insulin-stimulated glucose uptake, insulin binding and lipolysis as well as cellular content of insulin signalling proteins (insulin receptor substrate-1 (IRS-1), IRS-2, phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)) and glucose transporter isoform GLUT4 were measured.RESULTS: Dexamethasone in the medium markedly decreased both basal and insulin-stimulated glucose uptake at both 5 and 15 mmol/l glucose (by approximately 40-50%, P<0.001 and P<0.05 respectively). Combined long-term treatment with insulin and dexamethasone exerted additive effects in decreasing basal, and to a lesser extent insulin-stimulated, glucose uptake capacity (P<0.05) compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by approximately 40%, P<0.05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a approximately 75% decrease (P<0.001) in IRS-1 expression and an increase in IRS-2 (by approximately 150%, P<0.001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by approximately 20%, P<0.01) and a substantial decrease in PKB content (by approximately 45%, P<0.001). Insulin-stimulated PKB phosphorylation was decreased (by approximately 40%, P<0.01) in dexamethasone-treated cells. Dexamethasone did not alter the amount of total cellular membrane-associated GLUT4 protein. The effects of dexamethasone per se on glucose transport and insulin signalling proteins were mainly unaffected by the surrounding glucose and insulin levels. Dexamethasone increased the basal lipolytic rate (approximately 4-fold, P<0.05), but did not alter the antilipolytic effect of insulin.CONCLUSIONS: These results suggest that glucocorticoids, independently of the surrounding glucose and insulin concentration, impair glucose transport capacity in fat cells. This is not due to alterations in GLUT4 abundance. Instead dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 and PKB accompanied by a parallel reduction in insulin-stimulated activation of PKB.
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| 7. |
- Burén, Jonas, et al.
(författare)
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High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes : possible implications for insulin resistance in type 2 diabetes.
- 2003
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Ingår i: European Journal of Endocrinology. - : European Society of Endocrinology. - 0804-4643 .- 1479-683X. ; 148:1, s. 157-67
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins.DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed.RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration.CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.
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| 8. |
- Carlsson, PO, et al.
(författare)
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Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice
- 2002
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 146:1, s. 107-112
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP Design: Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. Methods: Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. Results: No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPP-deficient mice when compared with control mice; neither did IAPP deficiency affect the glucose-induced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPP-deficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. Conclusions: The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.
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| 9. |
- Dwight, T, et al.
(författare)
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Genetic analysis of lithium-associated parathyroid tumors
- 2002
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Ingår i: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 146:5, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to determine the primary genetic events that may underlie the formation of parathyroid tumors in patients with lithium-associated hyperparathyroidism (HPT). METHODS: Comparative genomic hybridization (CGH), loss of heterozygosity (LOH) and multiple endocrine neoplasia type 1 gene (MEN1) mutation analysis were used to analyze twelve parathyroid tumors from nine patients with lithium-associated HPT. For comparison, CGH was also carried out in a non-lithium-associated group of thirteen sporadic parathyroid tumors. RESULTS: A higher prevalence of multiglandular disease in the lithium-associated HPT patients compared with the idiopathic sporadic patients was observed (Fisher's exact test, P=0.02). CGH alterations were detected in four lithium-associated parathyroid tumors, involving loss at 1p, 11, 15q, 22q and gain of the X chromosome. In addition, one of these four cases exhibited LOH at 11q13 and was found to contain a novel somatic MEN1 mutation (c.1193insTAC). Although fewer lithium-associated parathyroid tumors were shown to contain genetic alterations compared with the sporadic parathyroid tumors, the changes detected were those frequently associated with both familial and sporadic parathyroid tumorigenesis. CONCLUSION: This is, to our knowledge, the first genetic analysis of parathyroid tumors in lithium-associated HPT patients. Our data indicated that the majority of lithium-associated parathyroid tumors do not contain gross chromosomal alterations and suggest that in most cases the tumorigenic pathway is independent of MEN1 and genes at 1p34.3-pter and 1q21-q32. It is possible that other discrete genetic alterations or epigenetic changes, not screened for in this study, could also be responsible for parathyroid tumorigenesis in lithium-associated HPT.
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| 10. |
- Ekman, Bertil, et al.
(författare)
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A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
- 2002
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 147:1, s. 49-57
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.
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