Insulin for prophylaxis of insulin-dependent diabetes

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These latest results, and the arterial hypoxaemia, sleep disturbances, and reduction in lung volumes seen with nasal occlusion, all favour the existence of nasal receptors, but there is no direct evidence to support this contention. Nevertheless, there is undoubtedly enough evidence to encourage more research into the respiratory functions of this

neglected appendage. Sant’Ambrogio G, Mathew OP, Fisher JT, Sant’Ambrogio FB. Laryngeal receptors responding to transmural pressure, airflow and local muscle activity. Respir Physiol 1983; 54: 317-30. 2. Mathew OP, Sant’Ambrogio G, Fisher JT, Sant’Ambrogio FB. Respiratory afferent activity in the superior laryngeal nerves. Respir Physiol 1984; 58: 41-50. 3. Kuna ST, Woodson GE, Sant’Ambrogio G. Effects of laryngeal anesthesia on pulmonary function testing in normal subjects. Am Rev Respir Dis 1988; 137: 656-61. 4. DeWeese EL, Sullivan TY. Effects of upper airway anaesthesia on pharyngeal patency during sleep. J Appl Physiol 1988; 64: 1346-53. 5. Mathew OP. Upper airway negative-pressure effects on respiratory activity of upper airway muscles. J Appl Physiol 1984; 56: 500-05. 6. Allen WF. Effect of various inhaled vapors on respiration and blood pressure in anesthetized, unanesthetized, sleeping and anosmic subjects. Am J Physiol 1929; 88: 620-32. 7. Angell-James JE, Daly M de B. Reflex respiratory and cardiovascular effects of stimulation of receptors in the nose of the dog. J Physiol 1969; 1.

62: 1287-93. 8. Douglas NJ, White DP, Weil JV, Zwillich CW. Effect of breathing on ventilation and ventilatory drive. Respir Physiol 1983; 51: 209-18. 9. Ramadan MF, Campbell IT, Linge K. The effect of nose breathing and mouth breathing on pulmonary ventilation. Clin Otol 1984; 9: 136. 10. Cassisi NJ, Biller HF, Ogura JH. Changes in arterial oxygen tension and pulmonary mechanics with the use of posterior packing in epistaxis: a preliminary report. Laryngoscope 1971; 81: 1261-66. 11. Zwillich CW, Pickett CK, Hanson FN, Weil JV. Disturbed sleep and prolonged apnea during nasal obstruction in normal man. Am Rev Respir Dis 1981; 124: 159-60. 12. Taasan V, Wynne JW, Cassisi N, Block AJ. The effect of nasal packing on sleep disordered breathing and nocturnal oxygen desaturation. Laryngoscope 1981; 91: 1163-72. 13. White DP, Cadieux RJ, Lombard RM, Bixler EO, Kales A, Zwillich CW. The effects of nasal anesthesia on breathing during sleep. Am Rev Respir Dis 1985; 132: 972-75. 14. Swift AC, Campbell IT, McKown TM. Oronasal obstruction, lung volumes, and arterial oxygenation. Lancet 1988; i: 73-75. 15. Campbell IT, Willatt DJ. Ventilatory characteristics of nose and mouth breathing in man. J Physiol 1989; 412: 33P. 16. Campbell IT, Nelson V. The effect of respiratory resistance on end-tidal position in man. J Physiol 1990; 429: 62P. 17. Harding R, Buttress JA, Caddy DJ, Wood GA. Respiratory and upper airway responses to nasal obstruction in awake lambs and ewes. Respir Physiol 1987; 68: 177-88. 18. Harding R, Wood GA. The role of carotid bodies in the establishment of oral breathing during nasal obstruction in lambs and ewes. Respir Physiol 1990; 80: 71-82. 19. Rodenstein DO, Perlmutter N, Stanescu DC. Infants are not obligatory nasal breathers. Am Rev Respir Dis 1985; 131: 343-47. 20. Easton PA, Jadue C, Arnup ME, Meatherall RC, Anthonisen NR. Effects of upper or lower airway anesthesia on hypercapnic ventilation in humans. J Appl Physiol 1985; 59: 1090-97. 21. McBride B, Whitelaw WA. A physiological stimulus to upper airway receptors in humans. J Appl Physiol 1981; 51: 1189-97. 22. Niinima V, Cole P, Mintz S, Shephard RJ. Oronasal distributon of respiratory airflow. Respir Physiol 1981; 43: 69-75. 23. Rodenstein DO, Stanescu DC. The soft palate and oronasal breathing in man. J Appl Physiol 1984; 57: 651-57.

prophylaxis of insulindependent diabetes

Insulin for

Diabetes management has more than its fair share of holy grails, but one of the most highly cherished must be the prevention of the insulin-dependent form of the disease. Despite its acute clinical onset,

insulin-dependent diabetes mellitus (IDDM) is the culmination of chronic, progressive autoimmune destruction of the pancreatic 0-cells. Insulitisinfiltration of the islets by lymphocytes and other front-line cells of the immune task-force-may smoulder for several years. Blood glucose concentrations rise and diabetic symptoms appear only when the p-cell mass is eroded to a few percent of normal and insulin deficiency becomes critical.l,2 The long prediabetic phase is characterised by various circulating autoantibodies, notably islet-cell surface antibodies (ICSA)3 and others directed against 0-cell antigens including insulin, proinsulin, and an enzyme, glutamic acid decarboxylase, which may provoke the "friendly fire" of autoimmunity-4--8 Autoantibody titres may predict the subsequent risk of progression to diabetes, which is about 50% if the ICSA titre exceeds 40 Juvenile Diabetes Foundation LlnltS.3’9 However, IDDM does not develop in some autoantibody-positive individuals, even when insulin secretion is already mildly

impaired. 10,11 The ability to identify individuals in the prediabetic phase, which lasts several years, is an open invitation to preventive treatment. Immunosuppression, the most obvious option, is already undergoing trials, the main drawback being the side-effects of drugs. 12 An alternative is insulin, which can prevent the autoimmune IDDM that develops spontaneously in BB

and NOD mice. In these rodents the prediabetic period is compressed into a few months, and is characterised by insulitis and circulating autoantibodies, including islet-cell surface antibodies and anti-glutamic-acid-decarboxylase.1,13 When given to prediabetic BB rats or NOD mice, insulin reduces the subsequent frequency of diabetes by as much as 80%.’" Insulin halts the inward invasion of lymphocytes from the islet peripheryl5 and may reduce the drive on surviving p-cells to secrete insulin: enforced metabolic idleness may decrease the expression of provocative autoantigens such as glutamic acid decarboxylase.16 As long ago as 1940, Charles Best17 suggested that insulin might prevent diabetes by "resting" the 0-cell, but trials in man have not yet been attempted. One obstacle is concern about the long-term safety of insulin administration in non-diabetic subjects. Apart from the obvious hazard of hypoglycaemia, repeated injections of insulin can induce insulitis in various animal species, presumably because the host’s 0-cells are caught in the cross-fire of antibodies raised against the exogenous insulin. 18,19 Despite the alarming histological appearances of "islets drowning in a sea of lymphocytes" ,18 clinical diabetes was seldom reported in these studies.",’9 However, follow-up tended to be short and it is still possible that prophylactic insulin treatment might precipitate the very disease that it is intended to prevent. In the study by Bock et al in this issue (p 1504), the researchers sought to determine whether giving rats

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insulin repeatedly to non-diabetic subjects increased their risk of getting IDDM. They studied 481 psychiatric patients who had been given insulin-shock therapy (hypoglycaemic convulsions) 30-60 years previously, when the technique was widely used. Typically, 60 units were given on eighty occasions. Whether diabetes developed subsequently was determined from psychiatric hospital records and, in 27 individuals who are still hospital inpatients, by fasting blood glucose measurements. Only 1 case of IDDM was recorded, which is no more than we would expect by chance. Bock et al conclude that trials of prophylactic insulin can be undertaken

safely.

platform sturdy enough to launch a new therapeutic offensive on IDDM? In Bock’s study cases could have been missed through poor screening (which was by testing for glycosuria on average every 3 years) and because some patients were followed for only a few months when the disease may take a decade Is this

declare itself. The total duration of insulin-shock treatment is not stated but some patients had received only 6 injections; prophylactic therapy might necessitate daily injections for years. Finally, although today’s highly purified human insulin preparations are much less immunogenic and probably safer than those used for insulin-shock treatment, one cannot exclude the possibility that exogenous insulin might aggravate established insulitis in prediabetic to

subjects. Even if proven safe, would insulin prophylaxis be attractive to the consumer? Treatment would be given to normoglycaemic, symptom-free individuals; since the peak age of onset of IDDM is 12-13 years, most would be children. Bock et al note the puzzling observation that orally administered insulin can also prevent IDDM in the NOD mouse,2° but oral insulin has so far shown very little promise in man. For the foreseeable future, therefore, prophylaxis would probably mean daily insulin injections, regular monitoring of blood glucose concentrations, and the ever-present threat of hypoglycaemia. These are the problems that spoil life for many diabetic patients, despite the reward of relief of symptoms. Moreover, since the lucky minority of autoantibody-positive subjects who will not become diabetic cannot yet be identified, treatment would be speculative in some cases, and this could be difficult to justify with a drug as intrusive as insulin. Trials of preventive treatment in IDDM should undoubtedly be extended, but prophylactic insulin is not the strategy of choice. In the words of a 16-year-old girl, diabetic since the age of 3, who was consulted about this issue: "I’d rather leave it to nature." 1. Eisenbarth

G. Insulin-dependent diabetes mellitus: a chronic autoimmune disease. N Engl J Med 1986; 314: 1360-68. 2. Gorsuch AN, Spencer KM, Lister J, et al. Evidence for a long pre-diabetic period m type I (insulin-dependent) diabetes mellitus. Lancet 1981; ii: 1363-65. 3. Bonifacio E, Bingley PJ, Shattock M, et al. Quantification of islet-cell

antibodies and prediction of insulin-dependent diabetes. Lancet 1990; 335: 147-49. 4. Böhmer K, Keilacker

H, Kuglin B, et al. Proinsulin autoantibodies are closely associated with type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies. Diabetologia 1991; 34: 830-34. 5. Atkinson MA, Maclaren NK, Scharp DW, Lacy PE, Riley WJ. 64 000 Mr autoantibodies as predictors of insulin-dependent diabetes. Lancet more

1990; 335: 1357-60. 6. Baekkeskov S, Jan-Aanstoot H, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABAsynthesizing enzyme glutamic add decarboxylase. Nature 1990; 37: 151-56. 7. Barmeier H, McCullough DK, Neifing JL, et al. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 1991; 34: 727-33. 8. Atkinson MA, Kaufman DL, Campbell L, et al. Response of peripheralblood mononuclear cells to glutamate decarboxylase in insulindependent diabetes. Lancet 1992; 339: 458-59. 9. 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. 10. Heaton DA, Millward BA, Gray P, et al. Evidence of beta cell dysfunction which does not lead on to diabetes: a study of identical twins of insulin-dependent diabetics. Br Med J 1987; 294: 145-46. 11. Leslie RDG, Pyke DA. Escaping insulin-dependent diabetes. Br Med J 1991; 302: 1103-04. 12. Dupré J, Mahon JL, Stiller CR. Prevention of insulin-dependent diabetes mellitus. In: Pickup JC, Williams G, eds. Textbook of diabetes. Oxford: Blackwell Scientific Publications, 1991: 971-76. 13. Baekkeskov S, Dyrberg T, Lernmark Å. Autoantibodies to a 64kilodalton islet cell protein precede the onset of spontaneous diabetes in the BB rat. Science 1984; 224: 1348-50. 14. Vlahos WD, Seemayer TA, Yale J-F. Diabetes prevention in BB rats by inhibition of endogenous insulin secretion. Metabolism 1991; 40: 825-29. 15. Atkinson MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990; 39: 933-37. 16. Björk E, Kämpe O, Andersson A, Karlsson FA. Expression of the 64K/glutamic acid decarboxylase rat islet autoantigen is influenced by the rate of insulin secretion. Diabetologia. 92; 32: 490-93. 17. Haist RE, Campbell J, Best CH. The prevention of diabetes. N Engl J Med 1940; 223: 607-15. 18. Le Compte PM, Steinke J, Soeldner JS, Renold AE. Changes in the islets of Langerhans in cows injected with heterologous and homologous insulin. Diabetes 1966; 15: 586-96. 19. Klöppel G. "Insulin" induced insulitis. Acta Endocrinol 1976; 83 (suppl): 107-21. 20. Zhong ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in non obese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 1991; 88: 10252-56.

Vibration

therapy for pain

Application of intense stimuli to the skin is a well known home remedy for pain relief. Countless generations of bruised knees have been taken to mother so that she could "rub it better". Ancient Greeks used vigorous massage to deal with sporting injuries, and by the early renaissance de Mandeville was able to include percussion as a recognised treatment for pain. Percussion analgesia for amputation stump pain was certainly recognised in the aftermath of the American Civil War, but this approach was not reported until the mid-1940s. At that time cutaneous vibration was noted to produce an initial increase in pain that was followed by numbness and analgesia when stimulation was continued for 25 min or more. Analgesia induced in this way often persisted for hours, or even days.1-3 During the past decade there has been a modest resurgence of interest in vibration; several studies have confirmed the effect and have refined the practice.4-8 Nonetheless, a large