- Email: [email protected]
Designing a doctor
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(quantitatively the largest source of glucose uptake) is reported to be unaltered in NIDDM.22 Gene polymorphism studies of GLUT 4 have not furnished any evidence of inherited defects in NIDDM.19 Glucose transporters may also have a role in the
pathogenesis of insulin-dependent diabetes mellitus (IDDM), for which there is compelling evidence for an autoimmune aetiology. Several antibodies to islet cell proteins are present in the circulation of newly diagnosed IDDM patients; the much-studied 64 kD islet antigen may be glutamic acid decarboxylase.23 However, Johnson et aF4 lately reported that purified IgG from such IDDM patients reduced glucose (actually 3-0-methyl glucose) uptake into isolated rat islets, an effect that was abolished by preincubation with islet cells and hepatocytes (containing GLUT 2) but not erythrocytes (not expressing GLUT 2). This finding suggests that one target of the autoimmune process in IDDM may be the GLUT 2 glucose transporter on the surface of pancreatic B cells, antibodies to which may impair glucose sensing and, therefore, reduce insulin secretion. Whether these mechanisms operate in vivo with human islets and the extent to which glucose transporter defects contribute to the pathogenesis of IDDM must be evaluated by further experiments. Although a reduced insulin response to glucose administration has been reported in many individuals at high risk of getting IDDM (first-degree relatives of patients), this subclinical B-cell dysfunction does not usually deteriorate, at least over 5 years offollow-up.25 P. Molecular aspects of sugar ion cotransport. Annu Rev Biochem 1986; 55: 225-48. 2. Mueckler M. Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes 1990; 39: 6-11. 3. Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucose transporters. Diabetes Care 1990; 13: 198-208. 4. Unger RH. Diabetic hyperglycemia: link to impaired glucose transport in pancreatic &bgr; cells. Science 1991; 251: 1200-05. 5. Pilch PF. Glucose transporters: what’s in a name? Endocrinology 1990; 1.
Wright JK, Seckler R, Overath
126: 3-5. 6. Craik JD, Elliott KRF. Kinetics of 3-0-methyl-D-glucose transport in isolated rat hepatocytes. Biochem J 1979; 182: 503-08. 7. Cushman SW, Wardzala LJ. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell: apparent translocation of intracellular transport systems to the plasma membrane. J Biol Chem 1980; 255: 4758-62. 8. Suzuki I, Kono T. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci USA 1980; 77: 2542-45. 9. Douen AG, Ramlal SR, Bilan PJ, et al. Exercise induces recruitment of the "insulin-responsive glucose transporter". Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J Biol Chem 1990; 265: 13427-30. 10. DeFronzo RA. The triumvirate: &bgr;-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988; 37: 667-87. 11. Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic &bgr;-cells and hepatocytes. Diabetes 1990; 39: 647-52. 12. Orci L, Thoren B, Ravazzola M, Lodish HF. Localization of the pancreatic beta cell glucose transporter to specific plasma membrane domains. Science 1989; 245: 295-97. 13. Newgard CB, Quaade C, Hughes SD, Milburn JL. Glucokinase and glucose transporter expression in liver and islets: implications for control of glucose homeostasis. Biochem Soc Trans 1990; 18: 851-53. 14. Thorens B, Sarkar HK, Kaback HR, Lodish HF. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney and pancreatic islets. Cell 1988; 55: 281-90.
15.
Johnson JH, Ogawa A, Chen L, et al. Underexpression of &bgr; cell high Km glucose transporters in non-insulin-dependent diabetes. Science 1990;
250: 546-49. 16. Orci L, Ravazzola M, Baetens D, et al. Evidence that down-regulation of &bgr;-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycaemia. Proc Natl Acad Sci USA 1990; 87: 9953-57. 17. Thorens B, Weir GC, Leahy JL, Lodish HF, Bonner-Weir S. Reduced expression of the liver/beta-cell glucose transporter isoform in glucoseinsensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci USA 1990; 87: 6492-96. 18. Alcolardo JC, Li S, Baroni MG, Stocks J, Galton DJ. Association of a liver/islet cell glucose transporter gene variant and patients with a strong family history of non-insulin-dependent diabetes mellitus. Presented at British Diabetic Association Meeting, Brighton, April, 1991. 19. Matsutani A, Koranyi L, Cox N, Permutt MA. Polymorphisms of GLUT 2 and GLUT 4 genes. Diabetes 1990; 39: 1534-42. 20. Sinha MK, Raineri-Maldonado C, Buchan C, et al. Adipose tissue glucose transporters in NIDDM. Decreased levels of muscle/fat isoform. Diabetes 1991; 40: 472-77. 21. Sivitz WI, Desautel SL, Dayano T, Bell GI, Pesin JE. Regulation of glucose transporter messenger RNA in insulin-deficient states. Nature 1990; 340: 72-73. 22. Pedersen O, Bak JF, Andersen PH, et al. Evidence against altered expression of GLUT 1 or GLUT 4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 1990; 39: 865-70. 23. Baekkeskov S, Aanstoot H-J, Christgau S, et al. Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56. 24. Johnson JH, Crider BP, McCorkle K, Alford M, Unger RH. Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. N Engl J Med 1990; 322: 653-59. 25. McCulloch DK, Klaff LJ, Kahn SE, et al. Non-progression of subclinical &bgr;-cell dysfunction amongst first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study. Diabetes 1990; 39: 549-56.
Designing
a
doctor
Fathers! is this the course of study that you could wish your sons to pursue?1
There is a well-worn tale of the man who was lost and asked the way to his destination. Came the reply: "I wouldn’t start from here". This was the gloomy reaction of some, three years ago, when they read a declaration that had emerged from the World Conference on Medical Education. The Edinburgh Declaration called upon the medical profession to redesign medical education so that it would truly meet "the defmed needs of the society in which it is situated".2 Even those who build a new curriculum from scratch must reckon on a wary response from a conservative profession; and in an established school, with its well fortified territories and its beloved traditions, the obstacles are yet more formidable. But still, the past twenty years have seen big changes in schools both old and new, not the least of them being the problem based curriculum pioneered at McMaster in Canada. The Lancet asked Dr Richard Godfrey, of Southampton University Hospitals, to put together half-a-dozen articles from places of innovation-a series of snapshots illustrating the main areas of advance and contention. In a closing item he will offer some thoughts of his own. For an opener, on the next page, Dr Chris McManus gazes into his crystal ball. 1. Editorial. Medical education. Lancet 1841; i: 161-62. 2. Anon. The Edinburgh Declaration. Lancet 1988; ii: 464.
(quantitatively the largest source of glucose uptake) is reported to be unaltered in NIDDM.22 Gene polymorphism studies of GLUT 4 have not furnished any evidence of inherited defects in NIDDM.19 Glucose transporters may also have a role in the
pathogenesis of insulin-dependent diabetes mellitus (IDDM), for which there is compelling evidence for an autoimmune aetiology. Several antibodies to islet cell proteins are present in the circulation of newly diagnosed IDDM patients; the much-studied 64 kD islet antigen may be glutamic acid decarboxylase.23 However, Johnson et aF4 lately reported that purified IgG from such IDDM patients reduced glucose (actually 3-0-methyl glucose) uptake into isolated rat islets, an effect that was abolished by preincubation with islet cells and hepatocytes (containing GLUT 2) but not erythrocytes (not expressing GLUT 2). This finding suggests that one target of the autoimmune process in IDDM may be the GLUT 2 glucose transporter on the surface of pancreatic B cells, antibodies to which may impair glucose sensing and, therefore, reduce insulin secretion. Whether these mechanisms operate in vivo with human islets and the extent to which glucose transporter defects contribute to the pathogenesis of IDDM must be evaluated by further experiments. Although a reduced insulin response to glucose administration has been reported in many individuals at high risk of getting IDDM (first-degree relatives of patients), this subclinical B-cell dysfunction does not usually deteriorate, at least over 5 years offollow-up.25 P. Molecular aspects of sugar ion cotransport. Annu Rev Biochem 1986; 55: 225-48. 2. Mueckler M. Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes 1990; 39: 6-11. 3. Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucose transporters. Diabetes Care 1990; 13: 198-208. 4. Unger RH. Diabetic hyperglycemia: link to impaired glucose transport in pancreatic &bgr; cells. Science 1991; 251: 1200-05. 5. Pilch PF. Glucose transporters: what’s in a name? Endocrinology 1990; 1.
Wright JK, Seckler R, Overath
126: 3-5. 6. Craik JD, Elliott KRF. Kinetics of 3-0-methyl-D-glucose transport in isolated rat hepatocytes. Biochem J 1979; 182: 503-08. 7. Cushman SW, Wardzala LJ. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell: apparent translocation of intracellular transport systems to the plasma membrane. J Biol Chem 1980; 255: 4758-62. 8. Suzuki I, Kono T. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci USA 1980; 77: 2542-45. 9. Douen AG, Ramlal SR, Bilan PJ, et al. Exercise induces recruitment of the "insulin-responsive glucose transporter". Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J Biol Chem 1990; 265: 13427-30. 10. DeFronzo RA. The triumvirate: &bgr;-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988; 37: 667-87. 11. Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic &bgr;-cells and hepatocytes. Diabetes 1990; 39: 647-52. 12. Orci L, Thoren B, Ravazzola M, Lodish HF. Localization of the pancreatic beta cell glucose transporter to specific plasma membrane domains. Science 1989; 245: 295-97. 13. Newgard CB, Quaade C, Hughes SD, Milburn JL. Glucokinase and glucose transporter expression in liver and islets: implications for control of glucose homeostasis. Biochem Soc Trans 1990; 18: 851-53. 14. Thorens B, Sarkar HK, Kaback HR, Lodish HF. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney and pancreatic islets. Cell 1988; 55: 281-90.
15.
Johnson JH, Ogawa A, Chen L, et al. Underexpression of &bgr; cell high Km glucose transporters in non-insulin-dependent diabetes. Science 1990;
250: 546-49. 16. Orci L, Ravazzola M, Baetens D, et al. Evidence that down-regulation of &bgr;-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycaemia. Proc Natl Acad Sci USA 1990; 87: 9953-57. 17. Thorens B, Weir GC, Leahy JL, Lodish HF, Bonner-Weir S. Reduced expression of the liver/beta-cell glucose transporter isoform in glucoseinsensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci USA 1990; 87: 6492-96. 18. Alcolardo JC, Li S, Baroni MG, Stocks J, Galton DJ. Association of a liver/islet cell glucose transporter gene variant and patients with a strong family history of non-insulin-dependent diabetes mellitus. Presented at British Diabetic Association Meeting, Brighton, April, 1991. 19. Matsutani A, Koranyi L, Cox N, Permutt MA. Polymorphisms of GLUT 2 and GLUT 4 genes. Diabetes 1990; 39: 1534-42. 20. Sinha MK, Raineri-Maldonado C, Buchan C, et al. Adipose tissue glucose transporters in NIDDM. Decreased levels of muscle/fat isoform. Diabetes 1991; 40: 472-77. 21. Sivitz WI, Desautel SL, Dayano T, Bell GI, Pesin JE. Regulation of glucose transporter messenger RNA in insulin-deficient states. Nature 1990; 340: 72-73. 22. Pedersen O, Bak JF, Andersen PH, et al. Evidence against altered expression of GLUT 1 or GLUT 4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 1990; 39: 865-70. 23. Baekkeskov S, Aanstoot H-J, Christgau S, et al. Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56. 24. Johnson JH, Crider BP, McCorkle K, Alford M, Unger RH. Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. N Engl J Med 1990; 322: 653-59. 25. McCulloch DK, Klaff LJ, Kahn SE, et al. Non-progression of subclinical &bgr;-cell dysfunction amongst first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study. Diabetes 1990; 39: 549-56.
Designing
a
doctor
Fathers! is this the course of study that you could wish your sons to pursue?1
There is a well-worn tale of the man who was lost and asked the way to his destination. Came the reply: "I wouldn’t start from here". This was the gloomy reaction of some, three years ago, when they read a declaration that had emerged from the World Conference on Medical Education. The Edinburgh Declaration called upon the medical profession to redesign medical education so that it would truly meet "the defmed needs of the society in which it is situated".2 Even those who build a new curriculum from scratch must reckon on a wary response from a conservative profession; and in an established school, with its well fortified territories and its beloved traditions, the obstacles are yet more formidable. But still, the past twenty years have seen big changes in schools both old and new, not the least of them being the problem based curriculum pioneered at McMaster in Canada. The Lancet asked Dr Richard Godfrey, of Southampton University Hospitals, to put together half-a-dozen articles from places of innovation-a series of snapshots illustrating the main areas of advance and contention. In a closing item he will offer some thoughts of his own. For an opener, on the next page, Dr Chris McManus gazes into his crystal ball. 1. Editorial. Medical education. Lancet 1841; i: 161-62. 2. Anon. The Edinburgh Declaration. Lancet 1988; ii: 464.