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IGF-I in growth hormone deficiency and in type 1 diabetes
Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Both GH-deficiency and type 1 diabetes are associated with low IGF-I levels. The aim with our studies was to develop a dose titration model to obtain physiological IGF-I levels in growth hormone deficiency and to evaluate the relationship between glycaemic control and IGF-I in diabetes. First we established reference values for insulin like growth factor-I (IGF-I) and insulin like growth factor bindingprotein-1 (IGFBP-1) from 101 women and 101 men randomly selected from the population registry. No gender differences in IGF-I levels were fmmd. IGF-1 decreases with advancing age in both sexes, whereas IGFBP-1 increases with age.

Titrating the GH dose according to population based reference values of IGF-I might be a way to obtain a fairly physiological substitution dose of GH. We hypothesised that a safe and probably effective maintenance dose of GH should increase IGF-I to the mean or slightly below the mean according to age adjusted reference levels. Eighteen adult hypopituitary patients with severe GH deficiency were titrated in steps, according to age adjusted IGF-I levels, to an individual dose of recombinant GH. For comparison 17 untreated healthy control subjects were evaluated. Similar IGF-1 levels armmd the mean for corresponding age were obtained in both sexes, but the maintenance median GH dose was more than twice in the women compared to men. The :individual dose differed markedly and elderly patients needed lower GH doses due to unchanged GH-sensitivity. Six months on the maintenance GH dose induced changes in blood-glucose, lipids, and insulin sensitivity index, indicating increased insulin resistance, which compared with the controls, were a normalisation. No major changes were seen in the variables of the renin-angiotensin-system. A significant increase in atrial natriuretic peptide seems also to be a normalisation if compared with the controls. The patients had less muscle strength and endmance at baseline compared with the controls and increased the muscle strength and endmance about 10 % after GH-substitution, an effect associated with the increase in IGF-I.

Paradoxically circulating IGF-I is decreased in type 1 diabetes despite increased GH levels. We studied 134 adult patients with type I diabetes (aged 20-60 years), without endogenous insulin secretion, and found that circulating IGF-I were decreased to about 70 % of the values in the reference population. No con·elation between glycaemic control and IGF-I levels was found.

To conclude the GH dose obtained when normalising circulating IGF-I according to population-based IGF-I levels, depends on GH-sensitivity (gender) and the IGF-1 level aimed for (age). In comparison with matched controls several OR-dependent variables are improved. In type 1 diabetes, our results suggests that the low IGF-I levels are independent of glycaemic control, and can not be corrected with subcutaneous insulin substitution.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 757
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25640Local ID: 10015ISBN: 91-7373-485-3 (print)OAI: oai:DiVA.org:liu-25640DiVA: diva2:246188
Public defence
2002-12-05, Administrationsbyggnadens aula, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-19Bibliographically approved
List of papers
1. Population-based reference values for IGF-I and IGF-binding protein-1: Relations with metabolic and anthropometric variables
Open this publication in new window or tab >>Population-based reference values for IGF-I and IGF-binding protein-1: Relations with metabolic and anthropometric variables
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1997 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 136, no 2, 165-172 p.Article in journal (Refereed) Published
Abstract [en]

Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20–70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y=366–3·28×age (years), r =−0·61, P<0·0001; women: Y=386–3·49×age, r =−0·57, P<0·0001, P=0·4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r =0·21, P=0·01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5·9±4·8 μg/l and 4·0±3·3 μg/l respectively; Mann–Whitney, P=0·002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman): men: r=0·32, P=0·002; women: r=0·24, P=0·03). C-peptide correlated negatively (Spearman: men: r =−0·38, P=0·002; women: r =−0·49, P<0·000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r=0·50, P<0·0001; women: r =0·55, P<0·0001).

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81631 (URN)10.1530/eje.0.1360165 (DOI)
Available from: 2012-09-19 Created: 2012-09-19 Last updated: 2017-12-07Bibliographically approved
2. A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
Open this publication in new window or tab >>A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
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2002 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, 49-57 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24897 (URN)10.1530/eje.0.1470049 (DOI)9300 (Local ID)9300 (Archive number)9300 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system
Open this publication in new window or tab >>Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system
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2002 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 57, no 4, 473-479 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24919 (URN)10.1046/j.1365-2265.2002.01617.x (DOI)9323 (Local ID)9323 (Archive number)9323 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Improved muscle function in GH substituted adults is related to increase in circulating IGF-I
Open this publication in new window or tab >>Improved muscle function in GH substituted adults is related to increase in circulating IGF-I
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We studied the effects of individualized growth hormone substitution, aiming at normal IGF-I levels, on biomechanical output and EMG of isokinetic muscle strength and endurance performance in 18 hypopituitary adults compared with matched controls. The muscle function tests consisted of isokinetic contractions of the dght knee extensors, and torque and EMG were recorded. Plasma levels of IGF-I were normalized, and peak torque at 90° s-1, and peak torque endurance level increased after dose titration and 6 months constant GH-dose. The change in IGF-I correlated positively with the changes in biomechanical output and EMG variables and a negative correlation existed with the perception of fatigue. Despite improvement during GH-substitution the patients still had about 10-20 % less muscle strength and endurance compared with the controls at the study end. In summary we found that individualized GH substitution improves muscle function and that the net increase in IGF-I levels indicates generally increases in biomechanical output and EMG variables and a lower perception of fatigue.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81632 (URN)
Available from: 2012-09-19 Created: 2012-09-19 Last updated: 2012-09-19Bibliographically approved
5. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes
Open this publication in new window or tab >>Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes
2000 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 143, no 4, 505-510 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM.

DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction.

RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14).

CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26789 (URN)10.1530/eje.0.1430505 (DOI)11394 (Local ID)11394 (Archive number)11394 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved

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