- Email: [email protected]
Autism and megalencephaly
1225
NUMBERS AND PERCENTAGES OF GENOTYPES (ALLELES 1 AND 2) IN DRD3-TYPED INDIVIDUALS
Follow-up in familial adenomatous polyposis SiR,—In
1989
we
reported the results of a prospective
upper
gastrointestinal screening programme in familial adenomatous polyposis (FAP), in which we showed that 92% of FAP patients had duodenal adenomas.1 These adenomas were concentrated around the ampulla. We have now had the opportunity to rescreen 52 of these patients, 21 of whom had stage I or II duodenal polyposis (minor disease). There were 29 men and 23 women whose average age at their first endoscopy was 43 years (range 20-67). They were rescreened at a mean 3 years and 4 months later (range of follow-up 2 years 2 months to 4 years 9 months). Videotapes from their first and second endoscopies were compared by two assessors (R. K. S. P., A. D. S.) who were blinded to the chronological order of each paired set of tapes. The two assessors were only asked to record whether the first viewed tape was the same, better, or worse than the second. Duodenal polyposis worsened in 21 patients (40%), of whom 3 patients developed either suspected (death without necropsy in 1 and metastatic rectal cancer in the other), or confirmed duodenal cancer. All these 3 had advanced (stage IV)1 duodenal polyposis at first endoscopy. Duodenal polyposis remained stable in 26 patients (50%) and improved in 5 (10%). Of the 21 patients with less advanced duodenal polyposis, 7 progressed. These findings show that even lesser duodenal polyposis in FAP patients is progressive. It is less clear what should be done about it. Duodenal surgical clearance of advanced disease does not seem worthwhile on its own, since all patients so treated at St Mark’s Hospital and at the Hopital St Antoine in Paris have redeveloped severe disease within 13-3 months of surgery.2 Equally, nonsteroidal anti-inflammatory drugs (NSAID) may be less effective in advanced duodenal disease, and there can be side-effects.3 Advanced disease may well be best treated by a combined approach of physical polyp removal (either endoscopic with photodynamic therapy or surgical) and an appropriate NSAID (perhaps at low dose). For lesser disease it is now important to establish whether early chemotherapeutic intervention will work.
Polyposis Registry, St Mark’s Hospital, London EC1V2PS, UK
K. P. NUGENT A. D. SPIGELMAN C. B. WILLIAMS I. C. TALBOT R. K. S. PHILLIPS
1. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RKS. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 1989; ii: 783-85. 2. Penna C, Phillips RKS, Tiret E, Spigelman AD. Surgical polypectomy of duodenal adenomas in familial adenomatous polyposis: experience of two European centres. 3.
Br J Surg (in press). Nugent KP, Farmer KCR, Spigelman AD, Williams CB, Phillips RKS. Randomised double blind placebo controlled clinical trial of the effect of Sulindac on duodenal and rectal polyposis and cell proliferation in familial adenomatous polyposis. Br J Surg (in press).
*Cases and control from present study at University School
GTS and 0 88 for CMT, and with a probability of the normal homozygote appearing affected of 0-001. Strongly negative lod scores were produced, which remained at less than - at all recombinant fractions of 10% or less. These results provide good evidence against the cosegregation of the DRD3 locus with GTS and CMT in this pedigree. We therefore tested Comings hypothesis that the genotype at this locus might exert a modifying effect on the expression of another (unknown) locus. The table shows the numbers and percentages of the genotypes (alleles 1 and 2) in affected individuals who could be typed at DRD3, the CEPH (Centre d’etude du Polymorphisms Humain) controls used by Comings et al, the English and French control groups used by Crocq et aland the unaffected members of our own pedigree. No increase in homozygosity among the affected members of our pedigree was seen. We conclude that DRD3 does not act as a major gene in this pedigree, nor is there any evidence for it exerting an oligogenic effect. Autosomal dominant transmission has been described in GTS5,6 and there is no reason to think that linkage analysis will be unsuccessful in pedigrees in which this operates. However, a proportion of cases may exist in whom there is a large oligogenic component. These cases are more likely to occur sporadically or in small pedigrees, and it may be wise to keep them separate from those occurring in large pedigrees when a strategy is being pursued.
linkage
Molecular Academic
Psychiatry Laboratory, Department of Psychiatry, University College London Medical School, Middlesex Hospital, London W1P 7PN, UK
PETER BRETT MARY ROBERTSON HUGH GURLING
Academic Department of Psychiatry, St Mary’s Hospital Medical School, London W2
DAVID CURTIS
1. Curtis D, Robertson MM, a
SiR,-After Dr Comings and colleagues’ report (April 3, p 906) of an association between Tourette’s syndrome and homozygosity of the MscI RFLP at the dopamine D3 receptor gene (DRD3), we have investigated this polymorphism in a large pedigree containing 29 members with Gilles de la Tourette syndrome (GTS) and a further 20 with genetically related chronic multiple tics (CMT). In this pedigree transmission of these syndromes is consistent with an autosomal dominant gene with incomplete penetrance.I With the extended sib-pair method of linkage analysis2 there was no evidence of cosegregation between either GTS or CMT with DRD3. This analysis provided no evidence for a role for the D3 receptor on the hypothesis of a putative non-Mendelian oligogenic mode of transmission. Classic linkage analysis was done with MLINK/LINKAGEon the assumption of a disease gene frequency of 00005 with the heterozygote penetrance set to 0-5 for
Gurling HMD Autosomal dominant gene transmission in large kindred with Gilles De La Tourette Syndrome. Br J Psychiatry 1992; 160:
845-49. 2.
3.
Failure to find linkage and increased homozygosity for the dopamine D3 receptor gene in Tourette’s syndrome
College London Medical
Sandkuyl LA. Analysis of affected sib pairs using information from extended families. In: Elston RC, Spence MA, Hodge SE, MacCluer JW, eds. Multipoint mapping and linkage based upon affected pedigree members. Genetic analysis workshop 6. New York, NY: Alan Liss, 1989. Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet 1985; 37: 482-98.
Crocq M-A, Mant R, Asherson P, et al. Association between schizophrenia and homozygosity in Tourette syndrome. Am J Med Genet 1992; 29: 858-60. 5. Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette’s syndrome and associated behaviors: evidence of autosomal dominant transmission. N Engl J Med 1986; 315: 993-97. 6. Devor EJ. Complex segregation analysis of Gilles de la Tourette syndrome: further evidence for a major locus mode of transmission. Am J Hum Genet 19894; 36: 4.
704-09.
Autism and
megalencephaly
SIR,-Autism is a severe neurodevelopmental disorder, which is
frequently accompanied by mental retardation and epilepsy. Although medical conditions and obstetric hazards have been postulated as frequent causes of the behavioural syndrome, the evidence suggests that autism is usually a specific and strongly genetic disease.1 The neurobiological basis of the disorder is not known. Subtle histological abnormalities of uncertain significance have been found at necropsy,2-4 and no neurochemical studies have
1226
reported on this material. We report that a substantial proportion of cases are associated with megalencephaly. The brains of 3 of 4 mentally handicapped autistic individuals were heavier than means for the normal population:
been
Age (yr) 4 22 24 27 *Mean
Brain weight
(kg)
Normal range*
1-53 1-60 1-81 1-45
1-25-1-35 (4-5) 1-39-1-49 (22-30) ..
..
weights ±25 standard devlatlons;5 age range
in
parentheses.
Brain weights were reported in only one of the recent postmortem studies;2 1 of the 2 idiopathic cases (age 33) had an enlarged brain
INSULIN SENSITIVITY INDEX
(1.52kg). Establishing the pathological basis of the megalencephaly will need quantitative study; however, qualitative examination reveals no obvious decrease in neuronal density, suggesting that there may be an excessive number of neurons. Two sets of clinical observations suggest that the postmortem findings are unlikely to have arisen by chance. In a nationwide epidemiological autistic twin sample, 9 (42%) of 19 autistic subjects under the age of 16 (the upper limit of normative data) had a head circumference above the 97th centile-a finding not attributable to twinning or a secular increase in head circumference. Among a sample of autistic singletons selected from a clinic series for a family genetic study, 37% of those under 16 had a similarly increased head
circumference. Most individuals with megalencephaly are not autistic. It remains to be established whether this is a consequence of pathological heterogeneity or whether megalencephaly is a contributory factor to autism, a consequence of a key pathological process, or a marker of the timing of abnormal development. Whatever the aetiological mechanism, our findings indicate that some cases of autism are associated with abnormal brain development.
De Crespigny Park, London SE5 8AF, UK
ANTHONY BAILEY PHILLIP LUTHERT PATRICK BOLTON ANNE LE COUTEUR MICHAEL RUTTER
Institute of Child Health, London WC1
BRIAN HARDING
Institute of Psychiatry,
1. Bailey A. The biology of autism. Psychol Med 1993; 23: 7-11. 2. Williams R, Hauser S, Purpura D, Delong G, Swisher C. Autism and mental
retardation. Arch Neurol 1980; 37: 749-53. 3. Ritvo E, Freeman B, Scheibel A, et al. Lower purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC autopsy research report. Am J Psychiatry 1986; 143: 862-66. 4. Bauman M. Microscopic neuroanatomic abnormalities in autism. Pediatrics 1991; 87 (suppl): 791-96. 5. Dekaban A, Sadowsky D. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 1978; 4: 345-56.
Insulin sensitivity and blood pressure in non-obese normotensive patients with
hyperandrogenism SIR,-Dr Allemann and colleagues (Feb 6, p 327) report impaired insulin sensitivity in non-obese normotensive male children of essential hypertensive parents. Impaired insulin sensitivity preceeded the development of overt hypertension and gain or redistribution of body fat. They therefore recommend, as we also do, reconsideration of the notion that insulin sensitivity is low as a result of altered fat distribution. Insulin resistance frequently accompanies ovarian hyperandorgenism.1 However, the relation between insulin resistance and arterial blood pressure in
hyperandrogenism remains to be determined. Zimmermann et al2 reported that insulin resistance and hyperinsulinaemia in polycystic ovary syndrome (PCO) was not associated with increased blood pressure. Conway et al3 showed that incremental insulin, by a glucose tolerance test and multiple regression analysis, was significantly associated with systolic and diastolic blood pressure in PCO groups. Obesity is possibly one reason for the difference in the
studies. 38 non-obese normotensive
two
women
(aged
17-28
years), who
]&
I t5
U
22
4
26
BMI
Systolic blood
pressure, insulin sensitivity index, and BMI in non-obese normotensive women with androgen excess.
presented with androgen excess were therefore investigated. The women were recruited during 5 years from the gynaecologicalendocrine and infertility clinics at Kitasato University Hospital. All had oligomenorrhoea, hirsutism (score of 7 or more on the Ferriman and Gallway scale4), luteinising-hormone to follicle stimulating hormone ratios of 2 or more, high urinary testosterone (over 10 mg daily), and raised plasma total and/or free testosterone concentrations. Cushing’s syndrome, androgen-secreting tumour, non-classic 21-hydroxylase deficiency, thyroid dysfunction, and hyperprolactinaemia were excluded. Ovarian morphology was not used as a diagnostic criterion, because ovaries with normal appearance can be associated with ovarian hyperandrogenism. All consistently showed blood pressure below 140/90 mm Hg and a body mass index (BMI) below 25 kg/m2. After a 12 h overnight fast, the patients drank a glucose solution (75 g in 200 mL water). Venous blood samples were obtained during the period of fasting and 30, 60, 90, and 120 min after glucose load. Each sample was assayed for glucose and immunoreactive insulin. The insulin sensitivity index was determined on the basis of the ratio of the area under the glucose curve to the area under the insulin curve in the oral glucose tolerance test. The area under the curve was calculated by the trapezium rule. The index was correlated with insulin sensitivity measured by euglycaemic clamp (r = 0-84, p < 0-0003, n = 12). No correlation between systolic blood pressure and BMI was recorded (figure). However, we found a negative correlation between systolic blood pressure and insulin sensitivity index. Although insulin resistance may serve as a simple marker for hypertension, the present data in non-obese young subjects indicate that selective insulin resistance and hypertension are probably directly related. Department of Internal Medicine, School of Medicine, Kitasato Univeristy, Sagamihara 228, Japan
YOSHIFUMI ABE
insulin-induced hyperandrogenism in insulin-resistant Endocrinol Rev 1991; 12: 3-13. 2. Zimmermann S, Phillips RA, Dunaif A, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab 1992, 75: 508-13. 3. Conway S, Agrawal R, Beterridge J, et al. Risk factor for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992; 37: 1. Poretssky L. On the paradox of states.
119-25. 4. Ferriam P,
Gallway JD. Clinical assessment of body hair Endocrinol Metab 1961; 21: 1440-47.
growth in
women.
J Clin
NUMBERS AND PERCENTAGES OF GENOTYPES (ALLELES 1 AND 2) IN DRD3-TYPED INDIVIDUALS
Follow-up in familial adenomatous polyposis SiR,—In
1989
we
reported the results of a prospective
upper
gastrointestinal screening programme in familial adenomatous polyposis (FAP), in which we showed that 92% of FAP patients had duodenal adenomas.1 These adenomas were concentrated around the ampulla. We have now had the opportunity to rescreen 52 of these patients, 21 of whom had stage I or II duodenal polyposis (minor disease). There were 29 men and 23 women whose average age at their first endoscopy was 43 years (range 20-67). They were rescreened at a mean 3 years and 4 months later (range of follow-up 2 years 2 months to 4 years 9 months). Videotapes from their first and second endoscopies were compared by two assessors (R. K. S. P., A. D. S.) who were blinded to the chronological order of each paired set of tapes. The two assessors were only asked to record whether the first viewed tape was the same, better, or worse than the second. Duodenal polyposis worsened in 21 patients (40%), of whom 3 patients developed either suspected (death without necropsy in 1 and metastatic rectal cancer in the other), or confirmed duodenal cancer. All these 3 had advanced (stage IV)1 duodenal polyposis at first endoscopy. Duodenal polyposis remained stable in 26 patients (50%) and improved in 5 (10%). Of the 21 patients with less advanced duodenal polyposis, 7 progressed. These findings show that even lesser duodenal polyposis in FAP patients is progressive. It is less clear what should be done about it. Duodenal surgical clearance of advanced disease does not seem worthwhile on its own, since all patients so treated at St Mark’s Hospital and at the Hopital St Antoine in Paris have redeveloped severe disease within 13-3 months of surgery.2 Equally, nonsteroidal anti-inflammatory drugs (NSAID) may be less effective in advanced duodenal disease, and there can be side-effects.3 Advanced disease may well be best treated by a combined approach of physical polyp removal (either endoscopic with photodynamic therapy or surgical) and an appropriate NSAID (perhaps at low dose). For lesser disease it is now important to establish whether early chemotherapeutic intervention will work.
Polyposis Registry, St Mark’s Hospital, London EC1V2PS, UK
K. P. NUGENT A. D. SPIGELMAN C. B. WILLIAMS I. C. TALBOT R. K. S. PHILLIPS
1. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RKS. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 1989; ii: 783-85. 2. Penna C, Phillips RKS, Tiret E, Spigelman AD. Surgical polypectomy of duodenal adenomas in familial adenomatous polyposis: experience of two European centres. 3.
Br J Surg (in press). Nugent KP, Farmer KCR, Spigelman AD, Williams CB, Phillips RKS. Randomised double blind placebo controlled clinical trial of the effect of Sulindac on duodenal and rectal polyposis and cell proliferation in familial adenomatous polyposis. Br J Surg (in press).
*Cases and control from present study at University School
GTS and 0 88 for CMT, and with a probability of the normal homozygote appearing affected of 0-001. Strongly negative lod scores were produced, which remained at less than - at all recombinant fractions of 10% or less. These results provide good evidence against the cosegregation of the DRD3 locus with GTS and CMT in this pedigree. We therefore tested Comings hypothesis that the genotype at this locus might exert a modifying effect on the expression of another (unknown) locus. The table shows the numbers and percentages of the genotypes (alleles 1 and 2) in affected individuals who could be typed at DRD3, the CEPH (Centre d’etude du Polymorphisms Humain) controls used by Comings et al, the English and French control groups used by Crocq et aland the unaffected members of our own pedigree. No increase in homozygosity among the affected members of our pedigree was seen. We conclude that DRD3 does not act as a major gene in this pedigree, nor is there any evidence for it exerting an oligogenic effect. Autosomal dominant transmission has been described in GTS5,6 and there is no reason to think that linkage analysis will be unsuccessful in pedigrees in which this operates. However, a proportion of cases may exist in whom there is a large oligogenic component. These cases are more likely to occur sporadically or in small pedigrees, and it may be wise to keep them separate from those occurring in large pedigrees when a strategy is being pursued.
linkage
Molecular Academic
Psychiatry Laboratory, Department of Psychiatry, University College London Medical School, Middlesex Hospital, London W1P 7PN, UK
PETER BRETT MARY ROBERTSON HUGH GURLING
Academic Department of Psychiatry, St Mary’s Hospital Medical School, London W2
DAVID CURTIS
1. Curtis D, Robertson MM, a
SiR,-After Dr Comings and colleagues’ report (April 3, p 906) of an association between Tourette’s syndrome and homozygosity of the MscI RFLP at the dopamine D3 receptor gene (DRD3), we have investigated this polymorphism in a large pedigree containing 29 members with Gilles de la Tourette syndrome (GTS) and a further 20 with genetically related chronic multiple tics (CMT). In this pedigree transmission of these syndromes is consistent with an autosomal dominant gene with incomplete penetrance.I With the extended sib-pair method of linkage analysis2 there was no evidence of cosegregation between either GTS or CMT with DRD3. This analysis provided no evidence for a role for the D3 receptor on the hypothesis of a putative non-Mendelian oligogenic mode of transmission. Classic linkage analysis was done with MLINK/LINKAGEon the assumption of a disease gene frequency of 00005 with the heterozygote penetrance set to 0-5 for
Gurling HMD Autosomal dominant gene transmission in large kindred with Gilles De La Tourette Syndrome. Br J Psychiatry 1992; 160:
845-49. 2.
3.
Failure to find linkage and increased homozygosity for the dopamine D3 receptor gene in Tourette’s syndrome
College London Medical
Sandkuyl LA. Analysis of affected sib pairs using information from extended families. In: Elston RC, Spence MA, Hodge SE, MacCluer JW, eds. Multipoint mapping and linkage based upon affected pedigree members. Genetic analysis workshop 6. New York, NY: Alan Liss, 1989. Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet 1985; 37: 482-98.
Crocq M-A, Mant R, Asherson P, et al. Association between schizophrenia and homozygosity in Tourette syndrome. Am J Med Genet 1992; 29: 858-60. 5. Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette’s syndrome and associated behaviors: evidence of autosomal dominant transmission. N Engl J Med 1986; 315: 993-97. 6. Devor EJ. Complex segregation analysis of Gilles de la Tourette syndrome: further evidence for a major locus mode of transmission. Am J Hum Genet 19894; 36: 4.
704-09.
Autism and
megalencephaly
SIR,-Autism is a severe neurodevelopmental disorder, which is
frequently accompanied by mental retardation and epilepsy. Although medical conditions and obstetric hazards have been postulated as frequent causes of the behavioural syndrome, the evidence suggests that autism is usually a specific and strongly genetic disease.1 The neurobiological basis of the disorder is not known. Subtle histological abnormalities of uncertain significance have been found at necropsy,2-4 and no neurochemical studies have
1226
reported on this material. We report that a substantial proportion of cases are associated with megalencephaly. The brains of 3 of 4 mentally handicapped autistic individuals were heavier than means for the normal population:
been
Age (yr) 4 22 24 27 *Mean
Brain weight
(kg)
Normal range*
1-53 1-60 1-81 1-45
1-25-1-35 (4-5) 1-39-1-49 (22-30) ..
..
weights ±25 standard devlatlons;5 age range
in
parentheses.
Brain weights were reported in only one of the recent postmortem studies;2 1 of the 2 idiopathic cases (age 33) had an enlarged brain
INSULIN SENSITIVITY INDEX
(1.52kg). Establishing the pathological basis of the megalencephaly will need quantitative study; however, qualitative examination reveals no obvious decrease in neuronal density, suggesting that there may be an excessive number of neurons. Two sets of clinical observations suggest that the postmortem findings are unlikely to have arisen by chance. In a nationwide epidemiological autistic twin sample, 9 (42%) of 19 autistic subjects under the age of 16 (the upper limit of normative data) had a head circumference above the 97th centile-a finding not attributable to twinning or a secular increase in head circumference. Among a sample of autistic singletons selected from a clinic series for a family genetic study, 37% of those under 16 had a similarly increased head
circumference. Most individuals with megalencephaly are not autistic. It remains to be established whether this is a consequence of pathological heterogeneity or whether megalencephaly is a contributory factor to autism, a consequence of a key pathological process, or a marker of the timing of abnormal development. Whatever the aetiological mechanism, our findings indicate that some cases of autism are associated with abnormal brain development.
De Crespigny Park, London SE5 8AF, UK
ANTHONY BAILEY PHILLIP LUTHERT PATRICK BOLTON ANNE LE COUTEUR MICHAEL RUTTER
Institute of Child Health, London WC1
BRIAN HARDING
Institute of Psychiatry,
1. Bailey A. The biology of autism. Psychol Med 1993; 23: 7-11. 2. Williams R, Hauser S, Purpura D, Delong G, Swisher C. Autism and mental
retardation. Arch Neurol 1980; 37: 749-53. 3. Ritvo E, Freeman B, Scheibel A, et al. Lower purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC autopsy research report. Am J Psychiatry 1986; 143: 862-66. 4. Bauman M. Microscopic neuroanatomic abnormalities in autism. Pediatrics 1991; 87 (suppl): 791-96. 5. Dekaban A, Sadowsky D. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 1978; 4: 345-56.
Insulin sensitivity and blood pressure in non-obese normotensive patients with
hyperandrogenism SIR,-Dr Allemann and colleagues (Feb 6, p 327) report impaired insulin sensitivity in non-obese normotensive male children of essential hypertensive parents. Impaired insulin sensitivity preceeded the development of overt hypertension and gain or redistribution of body fat. They therefore recommend, as we also do, reconsideration of the notion that insulin sensitivity is low as a result of altered fat distribution. Insulin resistance frequently accompanies ovarian hyperandorgenism.1 However, the relation between insulin resistance and arterial blood pressure in
hyperandrogenism remains to be determined. Zimmermann et al2 reported that insulin resistance and hyperinsulinaemia in polycystic ovary syndrome (PCO) was not associated with increased blood pressure. Conway et al3 showed that incremental insulin, by a glucose tolerance test and multiple regression analysis, was significantly associated with systolic and diastolic blood pressure in PCO groups. Obesity is possibly one reason for the difference in the
studies. 38 non-obese normotensive
two
women
(aged
17-28
years), who
]&
I t5
U
22
4
26
BMI
Systolic blood
pressure, insulin sensitivity index, and BMI in non-obese normotensive women with androgen excess.
presented with androgen excess were therefore investigated. The women were recruited during 5 years from the gynaecologicalendocrine and infertility clinics at Kitasato University Hospital. All had oligomenorrhoea, hirsutism (score of 7 or more on the Ferriman and Gallway scale4), luteinising-hormone to follicle stimulating hormone ratios of 2 or more, high urinary testosterone (over 10 mg daily), and raised plasma total and/or free testosterone concentrations. Cushing’s syndrome, androgen-secreting tumour, non-classic 21-hydroxylase deficiency, thyroid dysfunction, and hyperprolactinaemia were excluded. Ovarian morphology was not used as a diagnostic criterion, because ovaries with normal appearance can be associated with ovarian hyperandrogenism. All consistently showed blood pressure below 140/90 mm Hg and a body mass index (BMI) below 25 kg/m2. After a 12 h overnight fast, the patients drank a glucose solution (75 g in 200 mL water). Venous blood samples were obtained during the period of fasting and 30, 60, 90, and 120 min after glucose load. Each sample was assayed for glucose and immunoreactive insulin. The insulin sensitivity index was determined on the basis of the ratio of the area under the glucose curve to the area under the insulin curve in the oral glucose tolerance test. The area under the curve was calculated by the trapezium rule. The index was correlated with insulin sensitivity measured by euglycaemic clamp (r = 0-84, p < 0-0003, n = 12). No correlation between systolic blood pressure and BMI was recorded (figure). However, we found a negative correlation between systolic blood pressure and insulin sensitivity index. Although insulin resistance may serve as a simple marker for hypertension, the present data in non-obese young subjects indicate that selective insulin resistance and hypertension are probably directly related. Department of Internal Medicine, School of Medicine, Kitasato Univeristy, Sagamihara 228, Japan
YOSHIFUMI ABE
insulin-induced hyperandrogenism in insulin-resistant Endocrinol Rev 1991; 12: 3-13. 2. Zimmermann S, Phillips RA, Dunaif A, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab 1992, 75: 508-13. 3. Conway S, Agrawal R, Beterridge J, et al. Risk factor for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992; 37: 1. Poretssky L. On the paradox of states.
119-25. 4. Ferriam P,
Gallway JD. Clinical assessment of body hair Endocrinol Metab 1961; 21: 1440-47.
growth in
women.
J Clin