377
received impure bovine/porcine insulin can establish the safety of human insulin. Studies of prophylactic human insulin must include a detailed mechanism for monitoring adverse effects of therapy. Anything less will rightly fuel Professor Brook’s (May 9, p 1156) sceptical view of diabetes research. Department of Medicine, University of Birmingham and East Birmingham Hospital
S. C. BAIN
Department of Surgery, University of Oxford, John Radcliffe Hospital, Nuffield
J. A. TODD
Oxford OX3 9DU, UK
MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990; 39: 933-37. 2 Chase P, Dupre J, Mahon J, et al. Nicotinamide and prevention of diabetes. Lancet 1. Atkinson
1992; 339: 1051-52. 3. Drell DW, Notions AL. Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 132-43. 4. Editorial. Diabetic honeymoon: prolonged at a price? Lancet 1989 i: 1235-36. 5. Shah SC, Malone JI, Simpson NE. A randomised trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 6. Tarn A, Thomas J, Dean B, et al. Predicting insulin-dependent diabetes. Lancet 1988; i: 845-60. 7. Riley WJ, Maclaren NK, Krischer J, et al. A prospective study of the development of diabetes in relatives of patients with insulin dependent diabetes. N Engl J Med 1990; 323: 1167-72. 8. Finney GOH. Juvenile onset diabetes and schizophrenia? Lancet 1989; ii: 1214-15.
SIR,-Your June
20 editorial about the
use
of insulin for
prophylaxis of insulin-dependent diabetes ends with an interesting consultative comment from a 16-year-old girl with IDDM that she would "... rather leave it to nature". This brings to mind the story of a poor, rock covered, unproductive farm, known mainly for its stunted weeds. It was acquired by an industrious farmer who cleared the rocks, added top-soil and fertiliser, and finally produced outstanding crops. At this time the local minister happened by and commented, "John, what a miracle you and God have wrought from this unfriendly land!" The farmer leaned on his hoe and slowly responded, "Preacher, you’re right, but God wasn’t doing so well until I helped Him". The issue is not the discomfort and inconvenience of multiple injections, nor even the risk of hypoglycaemia, none of which are inconsiderable. Rather, it is whether this approach can reduce insulitis, prevent beta-cell destruction, and ultimately, not only IDDM, but its long-term vascular complications. Only by controlled clinical trials can we judge whether "prophylactic insulin is not the strategy of choice". Anecdotes are "cute" and make a point but do not test hypotheses, which still require sound science. Mount Sinai School of Medicine, New York, NY 10029, USA
ROBERT MATZ
Insulin resistance and
cigarette smoking
SIR,-Mr Godsland and colleagues (June 27, p 1619) present data that do not accord with our results (May 19, p 1128) showing that cigarette smokers are hyperinsulinaemic and resistant to insulin-mediated glucose uptake. They conclude that "the effects, if any, of smoking on insulin sensitivity evidently remain to be resolved". We do not quarrel with their conclusion, but we would comment on
their data.
Only 11 individuals smoked more than fourteen cigarettes a day, by contrast with our study population of 20 individuals who smoked at least twenty cigarettes daily. Furthermore, the plasma insulin response in this small subset was quantified in response to intravenous glucose, not to oral glucose as in our study. In addition, and probably of greatest importance, Godsland et al used a mathematical model to quantify insulin sensitivity, whereas we used a direct measure of insulin-mediated glucose uptake, which has been shown
to
correlate very
closely with values obtained with the
hyperinsulinaemic, glucose-clamp technique.1 The method Godsland et al cite was introduced by Bergman and colleagues2 and is based on modelling the changes in plasma glucose and insulin concentrations after
an
intravenous bolus of
glucose.
We have
shown that this model has
a
very poor correlation with the
hyperinsulinaemic, glucose-clamp technique,3,4 and this has been acknowledged by Bergman in a subsequent version of the minimum model. As a result, Bergman has suggested that measurement of insulin sensitivity in non-diabetic individuals should be done by adding an intravenous bolus of tolbutamide after the initial intravenous bolus of glucose. Since Godsland et al did not use this modification, their failure
to demonstrate any difference between smokers and non-smokers in respect of insulin sensitivity could well have been because they used an insensitive method to quantify insulin sensitivity. Finally, we would clarify the issues surrounding an incorrect citation we made in our original article (see correction, June 13, p 1492). In our report, reference 21 (Janzon et al, Diabetologia 1983; 25: 86) was cited as showing hyperinsulinaemia in cigarette smokers. In fact, this paper showed that smokers had a defect in glucose removal in response to an intravenous glucose challenge, without an increase in plasma insulin concentration. The only evidence of which we are aware that smokers have higher plasma insulin concentrations is the report by Eliasson et al.6 In an earlier version of our text we commented on both the apparent glucose intolerance and higher insulin levels in smokers, and included both references, but later mention of the abnormal glucose tolerance tests was removed for simplicity. Unfortunately, at the same time we deleted the reference to plasma insulin concentrations-ie, we removed the wrong reference. It is noteworthy that Godsland and colleagues also cite the paper by Janzon and colleagues in support of their finding that insulin concentrations are not increased in smokers, without commenting on the glucose intolerance described by these researchers. The relation between chronic smoking and insulin metabolism should be defined, but we hope that attention is also paid to the appropriateness of the methods that are used in these efforts. Division of Endocrinology, Gerontology and Metabolisn Stanford University Medical Center, G C ERALD Stanford, CA 94305, USA
Department of Medicine, Core Laboratory, General Clinical Research
M. REAVEN
Y-D. IDA CHEN
1. Greenfield MS, Dobeme L, Kraemer RB, Robey TA, Reaven GM. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 1981; 30: 387-92. 2. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68: 1456-67. 3. Foley JE, Chen Y-DI, Lardinois CK, Hollenbeck CB, Liu GC, Reaven GM. Estimates of in vivo insulin action in humans: comparison of the insulin clamp and the minimal model techniques. Horm Metabol Res 1985; 17: 406-09. 4. Dormer CC, Fraze E, Chen Y-DI, Hollenbeck CB, Foley JE, Reaven GM. Presentation of a new method for specific measurement of in vivo insulinstimulated glucose disposal in humans: comparison of this approach with the insulin clamp and minimal model techniques. J Clin Endocrinol Metab 1985; 60: 723-26. 5. Bergman RN, Prager R, Volund A, Olesfsky JM. Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 1987; 79: 790-800. 6. Eliasson M, Lundblad D, Hågg E. Cardiovascular risk factors in young snuff-users and cigarette smokers. J Intern Med 1991: 230: 17-22.
Genetics of hypertension SIR,-Your May 9 editorial (p 1142) seems to confirm some aspects of what I discovered about Ghanaian essential hypertension. Surveying over 30 years some three generations of a Ghanaian extended family, and making a detailed study of the offspring of polygamous and polyandric fathers and mothers, I was able to prove that Ghanaian essential hypertension has all the features of a Mendelian homozygous recessive condition. I further demonstrated that such hypertensives were "propranolol responsive", thus linking this to the renin-angiotensin system, and possibly enabling one to "design clinical-pharmacological and biochemical tests for the identification of the heterozygote".1 In his editorial about my report, Konotey-Ahulu said, "should such a biochemical test, or indeed gene mapping procedure, readily identify heterozygotes, then anyone who has received even one hypertension gene (NH-N being Normal gene, H Hypertensive gene) will be found to be ’positive’, asymptomatic though he may be".2
received impure bovine/porcine insulin can establish the safety of human insulin. Studies of prophylactic human insulin must include a detailed mechanism for monitoring adverse effects of therapy. Anything less will rightly fuel Professor Brook’s (May 9, p 1156) sceptical view of diabetes research. Department of Medicine, University of Birmingham and East Birmingham Hospital
S. C. BAIN
Department of Surgery, University of Oxford, John Radcliffe Hospital, Nuffield
J. A. TODD
Oxford OX3 9DU, UK
MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990; 39: 933-37. 2 Chase P, Dupre J, Mahon J, et al. Nicotinamide and prevention of diabetes. Lancet 1. Atkinson
1992; 339: 1051-52. 3. Drell DW, Notions AL. Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 132-43. 4. Editorial. Diabetic honeymoon: prolonged at a price? Lancet 1989 i: 1235-36. 5. Shah SC, Malone JI, Simpson NE. A randomised trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320: 550-54. 6. Tarn A, Thomas J, Dean B, et al. Predicting insulin-dependent diabetes. Lancet 1988; i: 845-60. 7. Riley WJ, Maclaren NK, Krischer J, et al. A prospective study of the development of diabetes in relatives of patients with insulin dependent diabetes. N Engl J Med 1990; 323: 1167-72. 8. Finney GOH. Juvenile onset diabetes and schizophrenia? Lancet 1989; ii: 1214-15.
SIR,-Your June
20 editorial about the
use
of insulin for
prophylaxis of insulin-dependent diabetes ends with an interesting consultative comment from a 16-year-old girl with IDDM that she would "... rather leave it to nature". This brings to mind the story of a poor, rock covered, unproductive farm, known mainly for its stunted weeds. It was acquired by an industrious farmer who cleared the rocks, added top-soil and fertiliser, and finally produced outstanding crops. At this time the local minister happened by and commented, "John, what a miracle you and God have wrought from this unfriendly land!" The farmer leaned on his hoe and slowly responded, "Preacher, you’re right, but God wasn’t doing so well until I helped Him". The issue is not the discomfort and inconvenience of multiple injections, nor even the risk of hypoglycaemia, none of which are inconsiderable. Rather, it is whether this approach can reduce insulitis, prevent beta-cell destruction, and ultimately, not only IDDM, but its long-term vascular complications. Only by controlled clinical trials can we judge whether "prophylactic insulin is not the strategy of choice". Anecdotes are "cute" and make a point but do not test hypotheses, which still require sound science. Mount Sinai School of Medicine, New York, NY 10029, USA
ROBERT MATZ
Insulin resistance and
cigarette smoking
SIR,-Mr Godsland and colleagues (June 27, p 1619) present data that do not accord with our results (May 19, p 1128) showing that cigarette smokers are hyperinsulinaemic and resistant to insulin-mediated glucose uptake. They conclude that "the effects, if any, of smoking on insulin sensitivity evidently remain to be resolved". We do not quarrel with their conclusion, but we would comment on
their data.
Only 11 individuals smoked more than fourteen cigarettes a day, by contrast with our study population of 20 individuals who smoked at least twenty cigarettes daily. Furthermore, the plasma insulin response in this small subset was quantified in response to intravenous glucose, not to oral glucose as in our study. In addition, and probably of greatest importance, Godsland et al used a mathematical model to quantify insulin sensitivity, whereas we used a direct measure of insulin-mediated glucose uptake, which has been shown
to
correlate very
closely with values obtained with the
hyperinsulinaemic, glucose-clamp technique.1 The method Godsland et al cite was introduced by Bergman and colleagues2 and is based on modelling the changes in plasma glucose and insulin concentrations after
an
intravenous bolus of
glucose.
We have
shown that this model has
a
very poor correlation with the
hyperinsulinaemic, glucose-clamp technique,3,4 and this has been acknowledged by Bergman in a subsequent version of the minimum model. As a result, Bergman has suggested that measurement of insulin sensitivity in non-diabetic individuals should be done by adding an intravenous bolus of tolbutamide after the initial intravenous bolus of glucose. Since Godsland et al did not use this modification, their failure
to demonstrate any difference between smokers and non-smokers in respect of insulin sensitivity could well have been because they used an insensitive method to quantify insulin sensitivity. Finally, we would clarify the issues surrounding an incorrect citation we made in our original article (see correction, June 13, p 1492). In our report, reference 21 (Janzon et al, Diabetologia 1983; 25: 86) was cited as showing hyperinsulinaemia in cigarette smokers. In fact, this paper showed that smokers had a defect in glucose removal in response to an intravenous glucose challenge, without an increase in plasma insulin concentration. The only evidence of which we are aware that smokers have higher plasma insulin concentrations is the report by Eliasson et al.6 In an earlier version of our text we commented on both the apparent glucose intolerance and higher insulin levels in smokers, and included both references, but later mention of the abnormal glucose tolerance tests was removed for simplicity. Unfortunately, at the same time we deleted the reference to plasma insulin concentrations-ie, we removed the wrong reference. It is noteworthy that Godsland and colleagues also cite the paper by Janzon and colleagues in support of their finding that insulin concentrations are not increased in smokers, without commenting on the glucose intolerance described by these researchers. The relation between chronic smoking and insulin metabolism should be defined, but we hope that attention is also paid to the appropriateness of the methods that are used in these efforts. Division of Endocrinology, Gerontology and Metabolisn Stanford University Medical Center, G C ERALD Stanford, CA 94305, USA
Department of Medicine, Core Laboratory, General Clinical Research
M. REAVEN
Y-D. IDA CHEN
1. Greenfield MS, Dobeme L, Kraemer RB, Robey TA, Reaven GM. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 1981; 30: 387-92. 2. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68: 1456-67. 3. Foley JE, Chen Y-DI, Lardinois CK, Hollenbeck CB, Liu GC, Reaven GM. Estimates of in vivo insulin action in humans: comparison of the insulin clamp and the minimal model techniques. Horm Metabol Res 1985; 17: 406-09. 4. Dormer CC, Fraze E, Chen Y-DI, Hollenbeck CB, Foley JE, Reaven GM. Presentation of a new method for specific measurement of in vivo insulinstimulated glucose disposal in humans: comparison of this approach with the insulin clamp and minimal model techniques. J Clin Endocrinol Metab 1985; 60: 723-26. 5. Bergman RN, Prager R, Volund A, Olesfsky JM. Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 1987; 79: 790-800. 6. Eliasson M, Lundblad D, Hågg E. Cardiovascular risk factors in young snuff-users and cigarette smokers. J Intern Med 1991: 230: 17-22.
Genetics of hypertension SIR,-Your May 9 editorial (p 1142) seems to confirm some aspects of what I discovered about Ghanaian essential hypertension. Surveying over 30 years some three generations of a Ghanaian extended family, and making a detailed study of the offspring of polygamous and polyandric fathers and mothers, I was able to prove that Ghanaian essential hypertension has all the features of a Mendelian homozygous recessive condition. I further demonstrated that such hypertensives were "propranolol responsive", thus linking this to the renin-angiotensin system, and possibly enabling one to "design clinical-pharmacological and biochemical tests for the identification of the heterozygote".1 In his editorial about my report, Konotey-Ahulu said, "should such a biochemical test, or indeed gene mapping procedure, readily identify heterozygotes, then anyone who has received even one hypertension gene (NH-N being Normal gene, H Hypertensive gene) will be found to be ’positive’, asymptomatic though he may be".2
