- Email: [email protected]
Insulin resistance, iron, and the liver
COMMENTARY
clinicians and patients, to accept randomisation to a provisional stent strategy. Earlier initiation of the study might have avoided this difficulty but would have had to be balanced against a formal assessment of a new procedure too early in its clinical development. The double-open design meant that both patients and doctors were aware of the treatment allocation. The lack of masking may assume particular importance when key outcome measures involve perceptions or value judgments by individuals, for example, the need for target-vessel revascularisation. The treatment of in-stent restenosis can be difficult and is a less appealing prospect than primary stent implantation for balloon-angioplasty restenosis. Most of the participants in the trial had single-vessel coronary disease, and it is possible that recurrent symptoms in a proportion of the primary stent group could have been managed with intensification of medical therapy, thus limiting the number of additional revascularisation procedures. Certainly it seems odd that the patientreported quality of life and functional status were similar in the two groups despite the significantly lower frequency of the composite endpoint in the primary stent group. Some studies elect to perform routine coronary angiography at follow-up, but this approach is not suitable for pragmatic strategy trials. Centralised computer analysis of angiographic records provides precise information about vessel geometry that can be important in understanding the mechanisms of restenosis, but it is difficult to relate these data to clinical outcomes. Furthermore, routine diagnostic angiography may drive additional revascularisation procedures that are not clinically indicated.1 It may be useful if study documentation demanded a more complete and structured reporting of clinical assessment throughout follow-up. Reported symptoms, details of medical therapy, and objective measures of functional capacity could be recorded, ideally by observers unaware of the treatment allocation. The two treatment strategies might involve different periods of specific risk for outcome measures. Follow-up periods should be extended to allow these outcome measures to accrue. These measures would not eliminate the difficulties of potential bias in a complex clinical area but would afford an opportunity to examine trial results for more predictable effects. R H Stables Cardiothoracic Centre and Royal Liverpool University Hospital, Liverpool L7 8XP, UK 1
Ruygrok PN, Melkert R, Morel MA, et al. Does angiography six months after coronary intervention influence management and outcome? Benestent II Investigators. J Am Coll Cardiol 1999; 34: 1507–11.
Insulin resistance, iron, and the liver In a report in 1997,1 a French group led by Yves Deugnier described a new clinical-pathological syndrome of primary hepatic iron overload (HIO), in which the transferrin saturation was normal, the frequency of the HLA A3 genotype (which is linked to genetic haemochromatosis) was normal, and serum and liver iron concentrations were raised disproportionately to the increase in serum ferritin concentration. Among the 65 patients with this syndrome, 72% had a body-mass index (BMI) greater than 25 kg/m2, 65% were dyslipidaemic, and 43% had abnormal glucose tolerance—ie, there was a high frequency of some of the features of the insulin-resistance syndrome (IRS).2 In a
THE LANCET • Vol 355 • June 24, 2000
subsequent study of 161 patients,3 the same group of investigators broadened the scope of unexplained HIO by including patients with increased transferrin saturation or non-alcoholic steato-hepatitis (NASH—ie, steatosis accompanied by lobular inflammation, sinusoidal fibrosis, and hepatocyte degeneration/necrosis). No patients were homozygous for Cys282Tyr but a higher than expected proportion of individuals were compound heterozygotes for the two main point mutations (Cys282Tyr and His63Asp) of HFE (the gene associated with genetic haemochromatosis), a finding that is expected in a cohort selected on the basis of iron overload. Also, with this extended definition, the patients with the syndrome of unexplained HIO, mostly middle-aged men, had a high rate of IRS (94%), by the investigators’ definition. Syndromes are clusters of non-chance associations, and the components of a syndrome can generally be related to a common element. In IRS, central fat accumulation (truncal or abdominal/visceral), impaired glucose metabolism (or overt diabetes mellitus), raised blood pressure (or clinical hypertension), and dyslipidaemia (typically, higher serum triglyceride concentrations along with lower serum HDLcholesterol concentrations, and small, dense LDL particles) cluster with insulin resistance, as indicated by a low totalbody insulin-mediated glucose disposal on euglycaemic clamp studies. Since clamp studies are time-consuming and labour-intensive, fasting hyperinsulinaemia is the most commonly used surrogate for insulin resistance.4 Obesity— as defined by the BMI—is not an essential component of the IRS,2,4 but if it were a criterion it would increase the prevalence of the syndrome because of the frequent occurrence of insulin resistance in obese individuals.5 In the studies of primary HIO,1,3 or hepatic steatosis,6–9 the IRS has been defined in differing ways, or with too broad criteria.1,3 For example, the French group in their study of patients with HIO,3 used obesity as a criterion but did not report actual BMI values or any measure of fat distribution (waist circumference or ratio of waist-to-hip circumference), or plasma insulin concentrations. Nevertheless, the occurrence of HIO, hepatic steatosis, or both among patients with the IRS is probably higher than among the insulin-sensitive proportion of the population. In particular, middle-aged men without symptoms who are investigated for raised serum iron concentrations are likely to have an IRS-like phenotype. Conversely, it is probable that screening individuals with features of the IRS would identify many cases of non-genetic iron overload. Several issues need to be clarified, however, before a new syndrome—insulin-resistance-associated HIO or IRHIO, as proposed by the French group—is accepted as a distinct entity. First, the IRS should be identified by consistent criteria, among which hyperinsulinaemia, or better, insulin resistance on euglycaemic clamp, is essential.10 Second, the diagnosis of HIO is not easy and needs a simple and reliable method of confirmation.11 Third, IRHIO seems to distinctly prefer men, but the IRS is common among postmenopausal women: are insulin-resistant women protected from iron overload? Fourth, since the IRS includes links of variable strength, it is important to determine which component of the IRS best correlates with HIO. Visceral obesity seems to be the best candidate, since increasing evidence links visceral-fat accumulation with widespread lipid deposition in liver parenchyma.6,7 Finally, if the IRS and HIO are part of the same syndrome, they should be modified in parallel by manoeuvres that affect either feature. For example, in an overweight individual weight loss generally leads to a 2181
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Associations between IRS and liver disorders
Hepatic iron overload
IRS Insulin resistance Hyperinsulinaemia Glucose intolerance Abdominal obesity Dyslipidaemia Hypertension
Liver steatosis and NASH
both hepatic steatosis3 and iron overload3 have been causally related to hepatic fibrosis and/or NASH; IRS, on the other hand, is thought to be a disorder with an increased risk of atherosclerotic cardiovascular disease.10 Therefore, irrespective of which particular clinical features first attract medical attention, patients should be carefully worked up for the companion set of changes, with special attention to assessing liver damage and cardiovascular disease. Patients with the full syndrome should be advised about alcohol consumption and the use of drugs with hepatotoxic potential. Liver function should be monitored and cardiovascular risk assessed and managed as appropriate. Ele Ferrannini
Areas are proportional to assumed prevalence of each disorder and overlap reflects strengths of associations
Metabolism Unit, C N R Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa 56026, Italy 1
regression of most components of the IRS: does it reduce the iron overload? Conversely, does the IRS improve when phlebotomy is used to relieve iron overload? The mechanisms underlying the association of iron overload, liver damage, or both with the IRS have not been identified. Defects in both insulin action and secretion are common among patients with familial haemochromatosis in the pre-cirrhotic stage.12 Also, genetic haemochromatosis is more frequent among diabetic patients than in the nondiabetic population, in one study the odds ratio among 1361 patients was 6·3.13 Thus, genetic linkage may exist between haemochromatosis and diabetes, and the occurrence of non-genetic HIO in the IRS may be the expression of residual genetic effects. For example, C282Y heterozygosity and C282Y/H63D compound heterozygosity, which are less penetrant with respect to iron overload,3 may be in linkage disequilibrium with unidentified loci of diabetes predisposition. At the physiological level, HIO with hepatic steatosis may interfere with insulin extraction in the liver, and thereby contribute to peripheral hyperinsulinaemia6,14 with the attendant downregulation of insulin receptors and hence, insulin action.15 In this proposed sequence, central obesity, often associated with NASH,7 would be the dominant feature of the IRS, and transfusional siderosis16 would be a model of HIO-induced insulin resistance. Alternatively, insulin resistance may lead to liver steatosis from unrestrained lipolysis and increased delivery of nonesterified fatty acids to the liver.2 Transferrin receptors, insulin-regulatable glucose transporters, and insulin-like growth factor II receptors have been shown to co-localise in microsomal membranes in cultured adipocytes, and insulin causes the simultaneous translocation of all three proteins to the cell membrane.17–19 Thus, one of insulin’s primary actions, namely to stimulate glucose transport, may be inherently coupled with the redistribution of transferrin receptors to the cell surface, where they mediate uptake of extracellular iron. If the effect of insulin on transferrin receptors was also present in hepatocytes or reticuloendothelial cells, it would be tempting to speculate that the hyperinsulinaemia of the IRS may be directly responsible for the accumulation of iron in the liver. Another explanation involves inflammation: since the IRS is an atherogenic state,10 widespread activation of inflammatory cytokines in the subendothelial space increases transcription of ferritin mRNA in macrophages; these cells may subsequently transfer ferritin to hepatocytes.20 Although still quite tentative, the concept of IRHIO (figure) nevertheless seems to be clinically useful. In fact, 2182
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Moirand R, Mortaji AM, Loréal O, Paillard F, Brissot P, Deugnier Y. A new syndrome of liver iron overload with normal transferrin saturation. Lancet 1997; 349: 95–97. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995; 75: 473–86. Mendler MH,Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117: 1155–63. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991; 34: 416–22. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. J Clin Invest 1997; 100: 1166–73. Goto T, Onuma T,Takebe K, Kral JG.The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord 1995; 19: 841–45. Banerji MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes Relat Metab Disord 1995; 19: 846–50. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513–17. Knobler H, Schattner A, Zhornicki T, et al. Fatty liver—an additional and treatable feature of the insulin resistance syndrome. QJM 1999; 92: 73–79. Ferrannini E, Stern MP. Primary insulin resistance: a risk syndrome. In: Leslie RDG, Robbins DC, eds. Diabetes: clinical science in practice. Cambridge: Cambridge University Press, 1995: 200–20. Guyader D, Gandon Y, Robert JY, et al. Magnetic resonance imaging and assessment of liver iron content in genetic hemochromatosis. J Hepatol 1992; 15: 304–08. Rowe JW,Wands JR, Mezey E, et al. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore) 1977; 56: 197–211. Conte D, Manachino D, Colli A, et al. Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus. Ann Intern Med 1998; 128: 370–73. Niederau C, Berger M, Stremmel W, et al. Hyperinsulinaemia in noncirrhotic haemachromatosis: impaired hepatic insulin degradation? Diabetologia 1984; 26: 441–44. Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia 1994; 37: 1025–35. Dandona P, Hussain MA,Varghese Z, Politis D, Flynn DM, Hoffbrand AV. Insulin resistance and iron overload. Ann Clin Biochem 1983; 20: 77–79. Davis RJ, Corvera S, Czech MP. Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane. J Biol Chem 1986; 261: 8708–11. Tanner LI, Lienhard GE. Insulin elicits a redistribution oftransferrin receptors in 3T3-L1 adipocytes through an increase in the rate constant for receptor externalization. J Biol Chem 1987; 262: 8975–80. Tanner LI, Lienhard GE. Localization of transferrin receptors and insulin-like growth factor II receptors in vesicles from 3T3-L1 adipocytes that contain intracellular glucose transporters. J Cell Biol 1989; 108: 1537–45. Sibille JC, Kondo H, Aisen P. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein. Hepatology 1988; 8: 296–301.
THE LANCET • Vol 355 • June 24, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
clinicians and patients, to accept randomisation to a provisional stent strategy. Earlier initiation of the study might have avoided this difficulty but would have had to be balanced against a formal assessment of a new procedure too early in its clinical development. The double-open design meant that both patients and doctors were aware of the treatment allocation. The lack of masking may assume particular importance when key outcome measures involve perceptions or value judgments by individuals, for example, the need for target-vessel revascularisation. The treatment of in-stent restenosis can be difficult and is a less appealing prospect than primary stent implantation for balloon-angioplasty restenosis. Most of the participants in the trial had single-vessel coronary disease, and it is possible that recurrent symptoms in a proportion of the primary stent group could have been managed with intensification of medical therapy, thus limiting the number of additional revascularisation procedures. Certainly it seems odd that the patientreported quality of life and functional status were similar in the two groups despite the significantly lower frequency of the composite endpoint in the primary stent group. Some studies elect to perform routine coronary angiography at follow-up, but this approach is not suitable for pragmatic strategy trials. Centralised computer analysis of angiographic records provides precise information about vessel geometry that can be important in understanding the mechanisms of restenosis, but it is difficult to relate these data to clinical outcomes. Furthermore, routine diagnostic angiography may drive additional revascularisation procedures that are not clinically indicated.1 It may be useful if study documentation demanded a more complete and structured reporting of clinical assessment throughout follow-up. Reported symptoms, details of medical therapy, and objective measures of functional capacity could be recorded, ideally by observers unaware of the treatment allocation. The two treatment strategies might involve different periods of specific risk for outcome measures. Follow-up periods should be extended to allow these outcome measures to accrue. These measures would not eliminate the difficulties of potential bias in a complex clinical area but would afford an opportunity to examine trial results for more predictable effects. R H Stables Cardiothoracic Centre and Royal Liverpool University Hospital, Liverpool L7 8XP, UK 1
Ruygrok PN, Melkert R, Morel MA, et al. Does angiography six months after coronary intervention influence management and outcome? Benestent II Investigators. J Am Coll Cardiol 1999; 34: 1507–11.
Insulin resistance, iron, and the liver In a report in 1997,1 a French group led by Yves Deugnier described a new clinical-pathological syndrome of primary hepatic iron overload (HIO), in which the transferrin saturation was normal, the frequency of the HLA A3 genotype (which is linked to genetic haemochromatosis) was normal, and serum and liver iron concentrations were raised disproportionately to the increase in serum ferritin concentration. Among the 65 patients with this syndrome, 72% had a body-mass index (BMI) greater than 25 kg/m2, 65% were dyslipidaemic, and 43% had abnormal glucose tolerance—ie, there was a high frequency of some of the features of the insulin-resistance syndrome (IRS).2 In a
THE LANCET • Vol 355 • June 24, 2000
subsequent study of 161 patients,3 the same group of investigators broadened the scope of unexplained HIO by including patients with increased transferrin saturation or non-alcoholic steato-hepatitis (NASH—ie, steatosis accompanied by lobular inflammation, sinusoidal fibrosis, and hepatocyte degeneration/necrosis). No patients were homozygous for Cys282Tyr but a higher than expected proportion of individuals were compound heterozygotes for the two main point mutations (Cys282Tyr and His63Asp) of HFE (the gene associated with genetic haemochromatosis), a finding that is expected in a cohort selected on the basis of iron overload. Also, with this extended definition, the patients with the syndrome of unexplained HIO, mostly middle-aged men, had a high rate of IRS (94%), by the investigators’ definition. Syndromes are clusters of non-chance associations, and the components of a syndrome can generally be related to a common element. In IRS, central fat accumulation (truncal or abdominal/visceral), impaired glucose metabolism (or overt diabetes mellitus), raised blood pressure (or clinical hypertension), and dyslipidaemia (typically, higher serum triglyceride concentrations along with lower serum HDLcholesterol concentrations, and small, dense LDL particles) cluster with insulin resistance, as indicated by a low totalbody insulin-mediated glucose disposal on euglycaemic clamp studies. Since clamp studies are time-consuming and labour-intensive, fasting hyperinsulinaemia is the most commonly used surrogate for insulin resistance.4 Obesity— as defined by the BMI—is not an essential component of the IRS,2,4 but if it were a criterion it would increase the prevalence of the syndrome because of the frequent occurrence of insulin resistance in obese individuals.5 In the studies of primary HIO,1,3 or hepatic steatosis,6–9 the IRS has been defined in differing ways, or with too broad criteria.1,3 For example, the French group in their study of patients with HIO,3 used obesity as a criterion but did not report actual BMI values or any measure of fat distribution (waist circumference or ratio of waist-to-hip circumference), or plasma insulin concentrations. Nevertheless, the occurrence of HIO, hepatic steatosis, or both among patients with the IRS is probably higher than among the insulin-sensitive proportion of the population. In particular, middle-aged men without symptoms who are investigated for raised serum iron concentrations are likely to have an IRS-like phenotype. Conversely, it is probable that screening individuals with features of the IRS would identify many cases of non-genetic iron overload. Several issues need to be clarified, however, before a new syndrome—insulin-resistance-associated HIO or IRHIO, as proposed by the French group—is accepted as a distinct entity. First, the IRS should be identified by consistent criteria, among which hyperinsulinaemia, or better, insulin resistance on euglycaemic clamp, is essential.10 Second, the diagnosis of HIO is not easy and needs a simple and reliable method of confirmation.11 Third, IRHIO seems to distinctly prefer men, but the IRS is common among postmenopausal women: are insulin-resistant women protected from iron overload? Fourth, since the IRS includes links of variable strength, it is important to determine which component of the IRS best correlates with HIO. Visceral obesity seems to be the best candidate, since increasing evidence links visceral-fat accumulation with widespread lipid deposition in liver parenchyma.6,7 Finally, if the IRS and HIO are part of the same syndrome, they should be modified in parallel by manoeuvres that affect either feature. For example, in an overweight individual weight loss generally leads to a 2181
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Associations between IRS and liver disorders
Hepatic iron overload
IRS Insulin resistance Hyperinsulinaemia Glucose intolerance Abdominal obesity Dyslipidaemia Hypertension
Liver steatosis and NASH
both hepatic steatosis3 and iron overload3 have been causally related to hepatic fibrosis and/or NASH; IRS, on the other hand, is thought to be a disorder with an increased risk of atherosclerotic cardiovascular disease.10 Therefore, irrespective of which particular clinical features first attract medical attention, patients should be carefully worked up for the companion set of changes, with special attention to assessing liver damage and cardiovascular disease. Patients with the full syndrome should be advised about alcohol consumption and the use of drugs with hepatotoxic potential. Liver function should be monitored and cardiovascular risk assessed and managed as appropriate. Ele Ferrannini
Areas are proportional to assumed prevalence of each disorder and overlap reflects strengths of associations
Metabolism Unit, C N R Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa 56026, Italy 1
regression of most components of the IRS: does it reduce the iron overload? Conversely, does the IRS improve when phlebotomy is used to relieve iron overload? The mechanisms underlying the association of iron overload, liver damage, or both with the IRS have not been identified. Defects in both insulin action and secretion are common among patients with familial haemochromatosis in the pre-cirrhotic stage.12 Also, genetic haemochromatosis is more frequent among diabetic patients than in the nondiabetic population, in one study the odds ratio among 1361 patients was 6·3.13 Thus, genetic linkage may exist between haemochromatosis and diabetes, and the occurrence of non-genetic HIO in the IRS may be the expression of residual genetic effects. For example, C282Y heterozygosity and C282Y/H63D compound heterozygosity, which are less penetrant with respect to iron overload,3 may be in linkage disequilibrium with unidentified loci of diabetes predisposition. At the physiological level, HIO with hepatic steatosis may interfere with insulin extraction in the liver, and thereby contribute to peripheral hyperinsulinaemia6,14 with the attendant downregulation of insulin receptors and hence, insulin action.15 In this proposed sequence, central obesity, often associated with NASH,7 would be the dominant feature of the IRS, and transfusional siderosis16 would be a model of HIO-induced insulin resistance. Alternatively, insulin resistance may lead to liver steatosis from unrestrained lipolysis and increased delivery of nonesterified fatty acids to the liver.2 Transferrin receptors, insulin-regulatable glucose transporters, and insulin-like growth factor II receptors have been shown to co-localise in microsomal membranes in cultured adipocytes, and insulin causes the simultaneous translocation of all three proteins to the cell membrane.17–19 Thus, one of insulin’s primary actions, namely to stimulate glucose transport, may be inherently coupled with the redistribution of transferrin receptors to the cell surface, where they mediate uptake of extracellular iron. If the effect of insulin on transferrin receptors was also present in hepatocytes or reticuloendothelial cells, it would be tempting to speculate that the hyperinsulinaemia of the IRS may be directly responsible for the accumulation of iron in the liver. Another explanation involves inflammation: since the IRS is an atherogenic state,10 widespread activation of inflammatory cytokines in the subendothelial space increases transcription of ferritin mRNA in macrophages; these cells may subsequently transfer ferritin to hepatocytes.20 Although still quite tentative, the concept of IRHIO (figure) nevertheless seems to be clinically useful. In fact, 2182
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Moirand R, Mortaji AM, Loréal O, Paillard F, Brissot P, Deugnier Y. A new syndrome of liver iron overload with normal transferrin saturation. Lancet 1997; 349: 95–97. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995; 75: 473–86. Mendler MH,Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117: 1155–63. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991; 34: 416–22. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. J Clin Invest 1997; 100: 1166–73. Goto T, Onuma T,Takebe K, Kral JG.The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord 1995; 19: 841–45. Banerji MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes Relat Metab Disord 1995; 19: 846–50. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513–17. Knobler H, Schattner A, Zhornicki T, et al. Fatty liver—an additional and treatable feature of the insulin resistance syndrome. QJM 1999; 92: 73–79. Ferrannini E, Stern MP. Primary insulin resistance: a risk syndrome. In: Leslie RDG, Robbins DC, eds. Diabetes: clinical science in practice. Cambridge: Cambridge University Press, 1995: 200–20. Guyader D, Gandon Y, Robert JY, et al. Magnetic resonance imaging and assessment of liver iron content in genetic hemochromatosis. J Hepatol 1992; 15: 304–08. Rowe JW,Wands JR, Mezey E, et al. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore) 1977; 56: 197–211. Conte D, Manachino D, Colli A, et al. Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus. Ann Intern Med 1998; 128: 370–73. Niederau C, Berger M, Stremmel W, et al. Hyperinsulinaemia in noncirrhotic haemachromatosis: impaired hepatic insulin degradation? Diabetologia 1984; 26: 441–44. Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia 1994; 37: 1025–35. Dandona P, Hussain MA,Varghese Z, Politis D, Flynn DM, Hoffbrand AV. Insulin resistance and iron overload. Ann Clin Biochem 1983; 20: 77–79. Davis RJ, Corvera S, Czech MP. Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane. J Biol Chem 1986; 261: 8708–11. Tanner LI, Lienhard GE. Insulin elicits a redistribution oftransferrin receptors in 3T3-L1 adipocytes through an increase in the rate constant for receptor externalization. J Biol Chem 1987; 262: 8975–80. Tanner LI, Lienhard GE. Localization of transferrin receptors and insulin-like growth factor II receptors in vesicles from 3T3-L1 adipocytes that contain intracellular glucose transporters. J Cell Biol 1989; 108: 1537–45. Sibille JC, Kondo H, Aisen P. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein. Hepatology 1988; 8: 296–301.
THE LANCET • Vol 355 • June 24, 2000
For personal use only. Not to be reproduced without permission of The Lancet.