1619
blood glucose concentrations registered during the 24 h blood glucose profiles before the start of rhGH treatment (range 1-6-2-0 mmol/1), none of the four diabetics reported any autonomic or neuroglycopenic symptoms ofhypoglycaemia.4 On day 7 of rhGH treatment patients 1 and 2 noticed sweating at blood glucose concentrations of 2-2 and 2-5 mmol/1. Within the next 2-3 weeks all four reported sweating, hunger, general muscle weakness, and moderate occipital headache at blood glucose values of 2-2-35
mmol/1. It would be very difficult to speculate about the mechanism of action of rhGH on the reappearance of hypoglycaemia awareness in insulin-dependent diabetes mellitus. However Williams and Patrick’s endorsement encourages us in our future research. Department of Endocrinology, "Zvezdara" University Medical Centre, 11000 Belgrade, Yugoslavia
MIROSLAV I. WURZBURGER GORDANA M. PRELEVIĆ
Department of Endocrinolgy, St Thomas’ Hospital, London SE1 7EH, UK
PETER H. SÖNKSEN
59-year-old man with idiopathic osteoporosis. The baseline value of IGF-I was 159 µg/1 (IRMA-mat, Byk-Sangtec Diagnostica, Dietzenbach, Germany; normal 130-450 µg/1) and increased to a maximum of 920 gg/1 on the second day of treatment. No adverse effects
were
observed.
During the week of IGF-I treatment, markers for bone formation increased (figure). Bone-specific alkaline phosphatase (bALP), measured by wheat-germ lectin extraction (Boehringer Mannheim Diagnostica), increased by 40%. Osteocalcin, measured by radioimmunoassay (CEA, Oris, France), increased by 50%, and carboxyterminal pepetide of procollagen type I (PICP, Farmos Diagnostica, Turku) by 100%. Markers for bone resorption also increased. Urinary hydroxyproline to creatinine ratio (OHPr/Cr) and calcium to creatinine (Ca/Cr) increased by 110%, and carboxyterminal telopeptide of collagen type I (ICTP, Farmos) increased by 120%. The biomarkers were also measured over the subsequent 4 weeks, and the formative indices (osteocalcin, PICP, and bALP) remained elevated at 20-70% above baseline values, whereas the resorptive markers (ICTP and OHPr/Cr) were only slightly raised, and Ca/Cr was even 50% lower than before
MI, Prelevic GM, Wheeler M, Sonksen PH. The effect of human growth hormone on serum IGF-I concentration m type I diabetes. Diabetologia 1991; 34 (suppl 2): A13. 2. Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabetic Med 1990; 7: 711-17. 3. Hepburn DA, Patrick AW, Brash HM, Thomas I, Frier BM. Hypoglycaemia unawareness in type I diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation. Diabetic Med 1991; 8: 934-45. 4. Patrick AW, Bodmer CW, Tieszen KL, White MC, Williams G Human insulin and awareness of acute hypoglycaemia symptoms in insulin-dependent diabetes. Lancet 1991; 338: 528-32.
Supraphysiological concentrations of IGF-I after subcutaneous administration of recombinant hormone activated bone formation as well as resorption in this patient with idiopathic osteoporosis. This is suggestive of endocrine effects of circulating IGF-I on bone. The changes in biomarkers in our patient, with remaining anabolic activity and a decrease in urinary excretion of calcium during follow-up indicate that intermittent treatment with IGF-I might benefit patients with osteoporosis and low IGF-I.
Insulin-like growth factor I stimulates bone turnover in osteoporosis
Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden
1. Wurzburger
recombinant
SIR,-We have reported low plasma concentrations of insulinlike growth factor I (IFG-1) in young men with osteoporosis.1 This finding, with numerous studies in vitro in which IGF-I has been found to have anabolic effects on osteoblasts,2-4 suggests a causal role for IGF-I in the pathophysiology of osteoporosis in these patients and that IGF-I might be therapeutic. We have now assessed the effects of subcutaneous injections of 160 µg/kg per day of recombinant human IGF-I (Kabi Pharmacia) over 7 days on blood and urinary biochemical markers for bone metabolism in a
treatment.
Ljunghall S, Johansson AG, Burman P, Kampe O, Lindh E, Karlsson FA. Low plasma levels of insulin-like growth factor I (IGF-I) in male patients with idiopathic osteoporosis. J Int Med (in press). 2. Canalis E. Effect of insulinlike growth factor I on DNA and protein systhesis in cultured rat calvaria. J Clin Invest 1980; 66: 709-19. 3. Hock JM, Centrella M, Canalis E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication Endocrinology 1988; 122: 254-60. 4. Schmid C, Guler H-P, Rowe D, Froesch ER. Insulin-like growth factor I regulates type I procollagen messenger ribonucleic add steady state levels in bone of rats. Endocrinology 1989; 125: 1575-80. 1.
Insulin resistance and
Biochemical markers in patient with osteoporosis during 7 days of IGF-I treatment and 4 weeks thereafter. Left= bone formation, in and in urine.
serum
and right= bone resorption, in
serum
ANNA G. JOHANSSON ERIK LINDH SVERKER LJUNGHALL
cigarette smoking
SIR,-Dr Facchini and colleagues (May 9, p 1128) report the characteristic lower high-density lipoprotein (HDL) cholesterol concentrations and higher fasting serum triglyceride values in smokers than in non-smokers, but, additionally, report the novel fmding that smokers have reduced insulin sensitivity. Reaven1 has suggested that reduced HDL cholesterol, raised triglyceride and insulin concentrations, and insulin resistance are elements in a distinct syndrome of metabolic disturbance predisposing to coronary heart disease (syndrome X). Facchini et al imply that cigarette smoking might induce this syndrome. We have investigated the associations between cigarette smoking, insulin sensitivity, and lipid and lipoprotein levels in 131 healthy, non-obese women who were taking no drugs likely to affect lipid or carbohydrate metabolism. After an overnight fast and abstinence from smoking (> 12 h), fasting serum lipids and lipoproteins were measured and an intravenous glucose tolerance test (IVGTT: 0-5 g/kg glucose load) was done. Glucose tolerance was shown as the glucose elimination constant k, and insulin and C-peptide responses were expressed as the incremental area under the concentration profiles. Mathematical modelling analysis was used to derive measures of insulin sensitivity (SD and glucose-dependent glucose disposal (Sg).2 Data were standardised, according to a linear regression model, for age, percentage of ideal body weight, exercise habit, alcohol intake, family histories of heart disease and diabetes, parity, and menopausal status. The table shows mean values for standardised metabolic variables in women who had never smoked and in those who smoked 5-14 cigarettes daily (about 10 pack-years,
according to Facchini’s definition), or more than 14 daily (about 15 pack-years). HDL cholesterol concentrations were reduced in smokers, mainly because of a decrease in the HDL2 sub fraction.
1620
METABOLIC VARIABLES (STANDARDISED DATA) IN FEMALE SMOKERS AND NON-SMOKERS (SD*)
*Asymmetric SDs result from non-smokers (never smoked)
back-transformation of data. tDerived from
Minimal model indices of insulin sensitivity S,, and
log-transformed
glucose-dependent glucose disposal
There was a non-significant trend to higher triglyceride values with increasing smoking. However, there was no evidence of any effect of smoking on IVGTT glucose, insulin and C-peptide concentrations, insulin sensitivity, or glucose-dependent glucose
disposal. The discrepancy between our findings and those of Facchini et al cannot be explained by a difference in the acute effects of smoking, since in neither study had smoking been allowed before the test (Chen Y-DA, personal communication). The method for measuring insulin sensitivity in our study differed from the insulin suppression test Facchini et al use, but our modelling analysis is a well-validated procedure and we have found it effective in other studies.3,4 In any case, the lack of difference in IVGTT glucose, insulin, and C-peptide concentration responses that we found between smokers and non-smokers argues against underlying
differences in factors determining glucose and insulin concentrations. Not all studies of insulin responses in smokers provide evidence for increased insulin concentrations.s The effects, if any, of smoking on insulin sensitivity evidently remain to be resolved.
Wynn Institute for Metabolic Research, 21 Wellington Road, London NW8 9SQ, UK
I. F. GODSLAND V. WYNN C. WALTON J. C. STEVENSON
1. Reaven G. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes
1988; 37: 1595-607. Ider Y, Bowden C, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667-77. 3. Godsland I, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin resistance, secretion and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 1992; 74: 64-70. 4. Walton C, Godsland I, Proudler A, Felton C, Wynn V. Evaluation of four
=
data. tDenved from square root-transformed data.
§p
blood glucose concentrations registered during the 24 h blood glucose profiles before the start of rhGH treatment (range 1-6-2-0 mmol/1), none of the four diabetics reported any autonomic or neuroglycopenic symptoms ofhypoglycaemia.4 On day 7 of rhGH treatment patients 1 and 2 noticed sweating at blood glucose concentrations of 2-2 and 2-5 mmol/1. Within the next 2-3 weeks all four reported sweating, hunger, general muscle weakness, and moderate occipital headache at blood glucose values of 2-2-35
mmol/1. It would be very difficult to speculate about the mechanism of action of rhGH on the reappearance of hypoglycaemia awareness in insulin-dependent diabetes mellitus. However Williams and Patrick’s endorsement encourages us in our future research. Department of Endocrinology, "Zvezdara" University Medical Centre, 11000 Belgrade, Yugoslavia
MIROSLAV I. WURZBURGER GORDANA M. PRELEVIĆ
Department of Endocrinolgy, St Thomas’ Hospital, London SE1 7EH, UK
PETER H. SÖNKSEN
59-year-old man with idiopathic osteoporosis. The baseline value of IGF-I was 159 µg/1 (IRMA-mat, Byk-Sangtec Diagnostica, Dietzenbach, Germany; normal 130-450 µg/1) and increased to a maximum of 920 gg/1 on the second day of treatment. No adverse effects
were
observed.
During the week of IGF-I treatment, markers for bone formation increased (figure). Bone-specific alkaline phosphatase (bALP), measured by wheat-germ lectin extraction (Boehringer Mannheim Diagnostica), increased by 40%. Osteocalcin, measured by radioimmunoassay (CEA, Oris, France), increased by 50%, and carboxyterminal pepetide of procollagen type I (PICP, Farmos Diagnostica, Turku) by 100%. Markers for bone resorption also increased. Urinary hydroxyproline to creatinine ratio (OHPr/Cr) and calcium to creatinine (Ca/Cr) increased by 110%, and carboxyterminal telopeptide of collagen type I (ICTP, Farmos) increased by 120%. The biomarkers were also measured over the subsequent 4 weeks, and the formative indices (osteocalcin, PICP, and bALP) remained elevated at 20-70% above baseline values, whereas the resorptive markers (ICTP and OHPr/Cr) were only slightly raised, and Ca/Cr was even 50% lower than before
MI, Prelevic GM, Wheeler M, Sonksen PH. The effect of human growth hormone on serum IGF-I concentration m type I diabetes. Diabetologia 1991; 34 (suppl 2): A13. 2. Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabetic Med 1990; 7: 711-17. 3. Hepburn DA, Patrick AW, Brash HM, Thomas I, Frier BM. Hypoglycaemia unawareness in type I diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation. Diabetic Med 1991; 8: 934-45. 4. Patrick AW, Bodmer CW, Tieszen KL, White MC, Williams G Human insulin and awareness of acute hypoglycaemia symptoms in insulin-dependent diabetes. Lancet 1991; 338: 528-32.
Supraphysiological concentrations of IGF-I after subcutaneous administration of recombinant hormone activated bone formation as well as resorption in this patient with idiopathic osteoporosis. This is suggestive of endocrine effects of circulating IGF-I on bone. The changes in biomarkers in our patient, with remaining anabolic activity and a decrease in urinary excretion of calcium during follow-up indicate that intermittent treatment with IGF-I might benefit patients with osteoporosis and low IGF-I.
Insulin-like growth factor I stimulates bone turnover in osteoporosis
Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden
1. Wurzburger
recombinant
SIR,-We have reported low plasma concentrations of insulinlike growth factor I (IFG-1) in young men with osteoporosis.1 This finding, with numerous studies in vitro in which IGF-I has been found to have anabolic effects on osteoblasts,2-4 suggests a causal role for IGF-I in the pathophysiology of osteoporosis in these patients and that IGF-I might be therapeutic. We have now assessed the effects of subcutaneous injections of 160 µg/kg per day of recombinant human IGF-I (Kabi Pharmacia) over 7 days on blood and urinary biochemical markers for bone metabolism in a
treatment.
Ljunghall S, Johansson AG, Burman P, Kampe O, Lindh E, Karlsson FA. Low plasma levels of insulin-like growth factor I (IGF-I) in male patients with idiopathic osteoporosis. J Int Med (in press). 2. Canalis E. Effect of insulinlike growth factor I on DNA and protein systhesis in cultured rat calvaria. J Clin Invest 1980; 66: 709-19. 3. Hock JM, Centrella M, Canalis E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication Endocrinology 1988; 122: 254-60. 4. Schmid C, Guler H-P, Rowe D, Froesch ER. Insulin-like growth factor I regulates type I procollagen messenger ribonucleic add steady state levels in bone of rats. Endocrinology 1989; 125: 1575-80. 1.
Insulin resistance and
Biochemical markers in patient with osteoporosis during 7 days of IGF-I treatment and 4 weeks thereafter. Left= bone formation, in and in urine.
serum
and right= bone resorption, in
serum
ANNA G. JOHANSSON ERIK LINDH SVERKER LJUNGHALL
cigarette smoking
SIR,-Dr Facchini and colleagues (May 9, p 1128) report the characteristic lower high-density lipoprotein (HDL) cholesterol concentrations and higher fasting serum triglyceride values in smokers than in non-smokers, but, additionally, report the novel fmding that smokers have reduced insulin sensitivity. Reaven1 has suggested that reduced HDL cholesterol, raised triglyceride and insulin concentrations, and insulin resistance are elements in a distinct syndrome of metabolic disturbance predisposing to coronary heart disease (syndrome X). Facchini et al imply that cigarette smoking might induce this syndrome. We have investigated the associations between cigarette smoking, insulin sensitivity, and lipid and lipoprotein levels in 131 healthy, non-obese women who were taking no drugs likely to affect lipid or carbohydrate metabolism. After an overnight fast and abstinence from smoking (> 12 h), fasting serum lipids and lipoproteins were measured and an intravenous glucose tolerance test (IVGTT: 0-5 g/kg glucose load) was done. Glucose tolerance was shown as the glucose elimination constant k, and insulin and C-peptide responses were expressed as the incremental area under the concentration profiles. Mathematical modelling analysis was used to derive measures of insulin sensitivity (SD and glucose-dependent glucose disposal (Sg).2 Data were standardised, according to a linear regression model, for age, percentage of ideal body weight, exercise habit, alcohol intake, family histories of heart disease and diabetes, parity, and menopausal status. The table shows mean values for standardised metabolic variables in women who had never smoked and in those who smoked 5-14 cigarettes daily (about 10 pack-years,
according to Facchini’s definition), or more than 14 daily (about 15 pack-years). HDL cholesterol concentrations were reduced in smokers, mainly because of a decrease in the HDL2 sub fraction.
1620
METABOLIC VARIABLES (STANDARDISED DATA) IN FEMALE SMOKERS AND NON-SMOKERS (SD*)
*Asymmetric SDs result from non-smokers (never smoked)
back-transformation of data. tDerived from
Minimal model indices of insulin sensitivity S,, and
log-transformed
glucose-dependent glucose disposal
There was a non-significant trend to higher triglyceride values with increasing smoking. However, there was no evidence of any effect of smoking on IVGTT glucose, insulin and C-peptide concentrations, insulin sensitivity, or glucose-dependent glucose
disposal. The discrepancy between our findings and those of Facchini et al cannot be explained by a difference in the acute effects of smoking, since in neither study had smoking been allowed before the test (Chen Y-DA, personal communication). The method for measuring insulin sensitivity in our study differed from the insulin suppression test Facchini et al use, but our modelling analysis is a well-validated procedure and we have found it effective in other studies.3,4 In any case, the lack of difference in IVGTT glucose, insulin, and C-peptide concentration responses that we found between smokers and non-smokers argues against underlying
differences in factors determining glucose and insulin concentrations. Not all studies of insulin responses in smokers provide evidence for increased insulin concentrations.s The effects, if any, of smoking on insulin sensitivity evidently remain to be resolved.
Wynn Institute for Metabolic Research, 21 Wellington Road, London NW8 9SQ, UK
I. F. GODSLAND V. WYNN C. WALTON J. C. STEVENSON
1. Reaven G. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes
1988; 37: 1595-607. Ider Y, Bowden C, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667-77. 3. Godsland I, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin resistance, secretion and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 1992; 74: 64-70. 4. Walton C, Godsland I, Proudler A, Felton C, Wynn V. Evaluation of four
=
data. tDenved from square root-transformed data.
§p
