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| 2. |
- 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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| 3. |
- Ekman, Bertil, et al.
(författare)
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Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system
- 2002
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 57:4, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- objective To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin–angiotensin–aldosterone system (RAAS), natriuretic peptides and urine free cortisol.study design Open study with control group. The patients were titrated in dose steps of 0·17 mg GH/day every 6–8 weeks until an IGF-I level around the mean + 1 SD was attained (Tmax). After another month the dose was reduced by 0·17 mg (minimum dose 0·17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (Tend), and this maintenance dose was held constant for 6 months.subjects Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects.measurements Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels.results Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0·03). PRA was elevated on the highest GH dose (Tmax) compared to baseline (P < 0·01), but returned to baseline and levels of controls at Tend. Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0·09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0·01), but increased after GH substitution (P < 0·01) to levels found in with the controls.conclusions We found no major changes of the variables in the circulating renin–angiotensin–aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.
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| 5. |
- Hedman, Christina, 1964-, et al.
(författare)
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Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes
- 2004
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 89:12, s. 6305-6309
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Tidskriftsartikel (refereegranskat)abstract
- The GH-IGF-I axis is disturbed in patients with type 1 diabetes. Our aim was to investigate whether abnormalities are found in patients in very good glycemic control and, if so, to estimate the role of residual β-cell function. Patients with hemoglobin A 1c (HbA 1c) less than 6% (reference range, 3.6-5.4%) were selected for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± SD), with a diabetes duration of 17.8 ± 14.6 yr participated. Healthy controls (15 women and nine men), aged 41.3 ± 13.0 yr, were also studied. Overnight fasting serum samples were analyzed for HbA 1c, C peptide, free and total IGFs, IGF-binding proteins (IGFBPs), GH-binding protein, and IGFBP-3 proteolysis. HbA 1c was 5.6 ± 0.5% in patients and 4.4 ± 0.3% in controls. Total IGF-I was 148 ± 7 μg/liter in patients and 178 ± 9 μg/liter in controls (P < 0.001). Free IGF-I, total IGF-II, IGFBP-3, and GH-binding protein were lower, whereas IGFBP-1, IGFBP-1-bound IGF-I, and IGFBP-2 were elevated compared with control values. Patients with detectable C peptide (≥100 pmol/liter) had higher levels of total IGF-I, free IGF-I, and total IGF-II and lower levels of IGFBP-1 and IGFBP-2 than those with an undetectable C peptide level despite having identical average HbA 1c. IGFBP-3 proteolysis did not differ between patients and controls. Despite very good glycemic control, patients with type 1 diabetes and no endogenous insulin production have low free and total IGF-I. Residual β-cell function, therefore, seems more important for the disturbances in the IGF system than good metabolic control per se, suggesting that portal insulin delivery is needed to normalize the IGF system.
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| 6. |
- Hedman, Christina, 1964-, et al.
(författare)
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The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes
- 2005
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Ingår i: Growth Hormone & IGF Research. - : Elsevier BV. - 1096-6374 .- 1532-2238. ; 15:4, s. 304-310
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Tidskriftsartikel (refereegranskat)abstract
- Objective In type 1 diabetes the circulating IGF-system is altered with low IGF-I and changes in levels of IGF-binding proteins (IGFBPs) which may be of importance for the development of diabetes complications. Our aim was to study if IGF-I, as supported by experimental data in animals, can be affected by dietary protein intake.Design and methods Twelve patients with type 1 diabetes, age 37.5 ± 10.0 years (mean ± SD), diabetes duration 20.1 ± 9.3 years and HbA1c 6.3 ± 0.6% were allocated to isocaloric diets with either low normal protein content (LNP), (10 E%; 0.9 g protein/kg body weight) or high normal protein content (HNP) (20 E%; 1.8 g protein/kg body weight) in an open randomised cross-over study. Each diet was taken for 10 days with a wash-out period of 11 days in between. Circulating levels of total and free IGF-I and -II, IGFBP-1, -2 and -3 and GH-binding protein (GHBP) as well as ghrelin were measured with validated in-house immunoassays.Results At day 10, urinary urea excretion was 320 ± 75 mmol/24 h during LNP diet compared with 654 ± 159 mmol/24 h during HNP diet (p < 0.001). There were no changes in body weight or glycaemic control between the diets. Fasting levels of total IGF-I were 121 ± 33 μg/L after LNP and 117 ± 28 μg/L after HNP diet (ns) and the corresponding concentrations of IGFBP-1 were 142(141) and 132(157) μg/L [median (IQR)] (ns). There were no differences in plasma concentrations of total IGF-II, free IGF-I and -II, IGFBP-3, GHBP and ghrelin, whereas a small difference was found for IGFBP-2 (302 ± 97 vs. 263 ± 66 μg/L; LNP vs. HNP; p < 0.04).Conclusions A twofold change of the dietary protein intake does not influence the altered circulating IGF-system in type 1 diabetes. In order to affect the IGF-system other interventions must be used.
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| 7. |
- Hedman, Christina, 1964-, et al.
(författare)
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Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes
- 2001
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 55:1, s. 107-112
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE IGF-I levels in patients with type 1 diabetes without endogenous insulin production are low. Our aim was to examine whether the plasma insulin profile obtained by treatment with the insulin analogue lispro has a different effect on plasma concentrations of IGF-I and IGFBP-1 than that seen during treatment with conventional human insulin (regular insulin).DESIGN AND PATIENTS Twelve patients with type 1 diabetes, age 47·8 ± 2·4 years (mean ± SEM), body mass index 26·5 ± 1·0 kg/m2, diabetes duration 30·5 ± 3·2 years participated in this open label randomized cross-over study. IGF-I and IGFBP-1 levels were measured at the end of 6 weeks treatment with each insulin being administered by a continuous subcutaneous insulin infusion. IGF-I was measured fasting while IGFBP-1, free insulin and blood glucose were measured fasting and repeatedly after a morning meal preceded by an insulin bolus dose.RESULTS Lispro gave a marked insulin peak of 135 ± 20 pmol/l 50 minutes after injection. After an initial rapid rise, human regular insulin reached a plateau of approximately 50 pmol/l. The plasma free insulin area under the curve (AUC) from 0710 h to 0910 h was more than twice as large on lispro as on regular insulin (P = 0·01). Plasma IGF-I concentration was 78·8 ± 10·9 µg/l on lispro and 82·3 ± 10·5 µg/l on human regular insulin (not significant). AUC for IGFBP-1 did not show a significant difference even when divided from 0710 h to 0910 h and from 0930 h to 1430 h. Blood glucose AUC after administration of the bolus was significantly lower during treatment with lispro (P = 0·006) but glycosylated haemoglobin (HbA1c) was 6·4 ± 0·2% on both therapies.CONCLUSIONS Our results indicate that the effect of lispro on IGF-I and IGFBP-1 in patients with type 1 diabetes does not differ from that of human regular insulin.
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| 8. |
- Lindström, Torbjörn, 1952-, et al.
(författare)
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Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration
- 2006
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 65:6, s. 776-782
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes.Patients Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3·6–5·4%) were selected for the study. Twenty-two men and 24 women [age 41·3 ± 13·8 years (mean ± SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41·3 ± 13·0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins.Results Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9·7 ± 5·3 [median 8·1, interquartile range (IQR) 3·6] mg/l in patients with diabetes duration less than 10 years and 17·8 ± 10·7 (median 14·7, IQR 7·5) mg/l in patients with longer duration (P = 0·0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 ± 91 pmol/l). C-peptide levels in controls averaged 492 ± 177 pmol/l. HbA1c was 5·7 ± 0·6% in patients without detectable C-peptide and 5·6 ± 0·4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17·3 ± 11·1 vs. 10·6 ± 5·8 mg/l (P < 0·005)] and in the controls [10·1 ± 2·9 mg/l (P < 0·001 vs. patients without detectable C-peptide)].Conclusions The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual β-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.
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| 9. |
- Lindström, Torbjörn, 1952-
(författare)
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Insulin treatment of patients with type 2 diabetes : Risks and benefits
- 1993
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with Type 2 diabetes and secondary failure to oral hypoglycaemic agents were characterized before and during insulin treatment. During oral treatment the 24-h area under the curve for free insulin in blood was similar to that in healthy subjects. However, the insulin profile was abnormal, with normal fasting free insulin but insufficient prandial response. Plasma concentrations of triglyceride-rich lipoproteins were elevated, and the high density lipoprotein (HDL) cholesterol concentration was low.Insulin treatment caused hyperinsulinaemia, with a 2-3-fold increase in 24-h free insulin concentration. The mean blood glucose concentration and HbAlc were almost normalized, and glycaemic control remained improved even after 2-3 years of insulin treatment. A multi-injection regimen, based on preprandial regular insulin and intermediate-acting insulin at bedtime, gave slightly better prandial glycaemic control than a regimen based on twice-daily injections of mainly intermediate-acting insulin, but the overall glycaemic control was similar in both. Insulin treatment reduced the elevated proinsulin concentration that is present in Type 2 diabetes and also lowered the endogenous insulin secretion. The percentage change in blood C-peptide concentration was closely correlated with the percentage change in blood glucose concentration, but not with the percentage change in free insulin concentration. The lipid profile was improved, with marked reduction in the triglyceride-rich lipoprotein concentration and a small increase in HDL cholesterol. Microalbuminuria was reduced and there was no increase in PAI-l antigen concentration. Weight gain occurred during the first year of insulin treatment but not subsequently. Blood pressure was unchanged after 2-3 years of insulin treatment. Severe hypoglycaemic episodes were rare but such can cause cardiac arrhythmia. Patients reported that they felt better.Insulin treatment of patients with Type 2 diabetes and secondary failure to oral hypoglycaemic agents improves glycaemic control and improves or has no adverse effect on the major cardiovascular risk factors.
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