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The Beta Cell in Diabetes—MoreSinned Against than Sinning?

A GENETIC basis for diabetes mellitus (althoughthe subject of considerable controversy’) has beenwidely accepted for many years. Lately the possibi-lity of infection as a cause of at least some formsof the syndrome has been revived by direct2 and in-direct studies3 of the role of viruses in diabetes of

laboratory animals and man. There is of course noreason why these two lines of thought should notbe combined in terms of a genetically determinedresponse to certain infective agents. Indeed the

relationship between some histocompatibility(HLA) antigens and insulin-dependent diabetes hasbeen interpreted in this way. 4 On the other hand,insulin-independent diabetes is becoming more

clearly separated from the insulin-dependent formbecause of a lack of HLA association low levels ofanti-islet-cell autoantibodies, and stronger geneticinfluence as evidenced by studies of concordancerates in identical twins8 (although readers of thesecolumns will be aware of the dispute on the lastpoint9). If we could identify the tissue and meta-bolic site of the primary defect, we should be wellon the way towards determining whether the mech-anism for the production of some forms of humandiabetes is genetic, acquired, or combined. Sus-

picion falls heavily on the islet of Langerhans celland insulin secretion largely because p-cell mass isreduced and responses to dynamic tests of insulinsecretion are defective. Could dynamic tests tell uswhether the &bgr;-cell abnormality is inborn or

acquired?Insulin secretion, comprising the production,

storage, and release of insulin, can be studied onlyindirectly in man. Investigations of release usuallyinvolve the assay of insulin in peripheral plasmaand the assumption that the peripheral insulin con-centrations achieved after various stimuli are littleinfluenced by changes in the rates of insulin uptakeand destruction. The situation in the "basal" state

1. Zonana, J., Rimoin, D. L. New Engl. J. Med. 1976, 295, 603.2. Craighead, J. E., McLane, M. F. Science, 1968, 162, 913.3. Gamble, D. R., Taylor, K. W., Cummmg, H., Br. med. J. 1973, iv, 260.4. Nerup, J., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Poulson, J.

E., Ryder, L. P., Nielsen, L. S., Thomsen, M., Svejgaard, A. Lancet 1974,ii, 864.

5. Cudworth, A. G., Woodrow, J. C. Br. med. J. 1975, iii, 133.6 Cudworth, A. G., Woodrow, J. C. ibid. 1976, ii, 846.7 Lendrum, R., Walker, G., Cudworth, A. G., Woodrow, J. C., Gamble, D. R.

ibid. 1976, i, 1565.8. Nelson, P. G., Pyke, D. A., Cudworth, A. G., Woodrow, J. C, Batchelor,

J R. Lancet, 1975, ii, 193.9. Pyke, D. A., Theophanides, C. G., Tattersall, R. B. ibid. 1976, ii, 1201.

(i.e., after an overnight fast) is more doubtful. In-deed, it has been argued that the mechanism of in-sulin release during a glucose stimulation test

differs from that in the basal state-in other

words, basal insulin secretion does not simply re-flect the glucose stimulation achieved by the basalglucose concentration. 10 Although a reduction inbasal glucose by a prolonged fast, exogenous insu-lin, or alcohol is accompanied by a fall in plasma-insulin concentration, this, fall might be mediatedindirectly by catecholamines.11 TURNER andHOLMAN 12 have suggested that the hyperglycsemiaof maturity-onset diabetes results from impairedp-cell function which in turn leads to increasedhepatic glucose output. The resultant rise inbasal glucose concentration stimulates the cellsuntil they secrete enough insulin to maintain a nor-mal basal plasma-insulin concentration. Accordingto this hypothesis, maintenance of basal insulinconcentration is a more important homoeostaticfunction in diabetes than is glucose regulation,because a "normal" basal insulin is required for itsanabolic effects. Published reports cast doubt onthis concept of a narrowly maintained normal basalinsulin concentration, even in non-obese non-diabe-tic subjects. The assay used by TURNER andHOLMAN is said to give a seven-fold range of basalconcentrations in such subjects; 13 and the pub-lished values of basal insulin concentrations in non-obese maturity-onset diabetics give an equallyconfused picture, normal14 and high" mean valuesbeing reported. Since insulin resistance will affectthe amount of insulin required for a "normal" in-sulin effect, and since hyperglycsemia may affectfactors causing insulin resistance (e.g., glucagon),interpretation of a particular basal insulin level ina hyperglycaemic diabetic is difficult.A further difficulty in unravelling the implica-

tions of basal and stimulated insulin concentrationsin hyperglycxmic diabetics is lack of informationabout how chronic exposure to hyperglycsemiaaffects tissues for which glucose has a direct regula-tory role. Almost certainly, chronic exposure of tis-sues to high insulin concentrations leads to a lossof sensitivity to insulin, possibly mediated by a lossof insulin receptors.16 The long-observed physiolo-gical phenomenon of a reciprocal relationshipbetween exposure to an agonist and tissue sensiti-vity to that agonist may well extend to glucosewhen it functions as an agonist of the cell. In the

10. Porte, D., Bagdade, J. D A. Rev. Med. 1970, 21, 219.11. Bagdade, J. D., Bierman, E. L., Porte, D. Diabetes, 1972, 21, 65.12. Turner, R. C., Holman, R. R. Lancet, 1976, i, 1272.13. Albano, J. D. M., Ekins, R. P., Maritz, G., Turner, R. C. Acta endocr.,

Copenh. 1972, 70, 487.14. Lerner, R. L., Porte, D., J. clin. Invest. 1972, 51, 1624.15. Varsano-Aharon, N., Echemendia, E., Yalow, R. S., Berson, S. A. Metabo-

lism, 1970, 19, 409.16. Roth, J., Kahn, C. R., Lesniak, M. A., Gorden, P., De Meyts, P., Megyesi,

K., Neville, D. M., Jr., Gavin, J. R., III, Soll, A. H., Freychet, P., Goldfine, I. D., Bar, R. S., Archer, J. A. Rec. Prog. Hormone Res. 1975, 31,95.

178

chronically hyperglycxmic diabetic, deficiencies ininsulin secretion, both before and after acute glu-cose administration, may be attributable simply toadaptive changes resulting from hyperglycaemia.Thus, whilst specific loss of response to a glucosestimulus in diabetes would be evidence for a meta-bolic block and against generalised acquireddamage to the p cell, it might also result fromchronic hyperglycaemia. On this point existing evi-dence is contradictory.17-;10 Interpretation of sti-mulation experiments is further complicated by thefact that often the non-glucose stimuli employed(e.g., glucagon and secretin) potentiate theeffect of glucose itself, possibly by increasing thej3-cell cyclic A.M.P. concentration, and have onlysmall effects in the absence of a glucose stimulus.Therefore, it is not justifiable to compare the effectof this type of stimulus in a hyperglycsemic diabetic,in whom the compound may maximally potentiatethe glucose effect, with that in a normoglycaemicnon-diabetic, in whom glucose stimulation is slight.The presence of similar insulin responses in thesetwo situations does not necessarily indicate that thediabetic response is unimpaired. The advent of var-ious electronic devices designed to administer smallamounts of insulin in rapid response to changes inblood-glucose-the "artificial pancreas"’—maynow allow chronic maintenance of diabetics in true

normoglycaemia and the resolution of this problem.In addition to changes which may be secondary

to adaptation to hyperglycaemia, the diabetic &bgr; cellmay be suffering from exhaustion due to oversti-mulation. After an acute glucose stimulus the nor-mal &bgr; cell releases insulin in two phases.22 Depletionof insulin stores due to chronic overstimulation

might distort this pattern of release without indi-cating a specific defect of one aspect of the releaseprocess. Improvement in the amount of insulinreleased acutely is seen when the chronic glucosestimulus is reduced by diet,23 exogenous insu-lin, 24 2-1 or temporary inhibition of insulin secretion.26 The last technique also produced evidencefor chronic basal hyperstimulation of insulin secre-tion, since basal insulins were lowered in diabeticsby an inhibitory drug (diazoxide) but were unaffec-ted in normal subjects. This method of "resting"the p cell allowed a greatly enhanced subsequentresponse to an acute stimulus. If the abnormalkinetics of insulin release in diabetes were due to

depleted stores of the hormone, this manoeuvre

17. Floyd, J. C., Fa)ans, S. S., Conn, J. W., Thiffault, C., Knopf, R. F.Guntsche, E. J. clin. Endocr. Metab. 1968, 28, 266.

18. Rojas, L., Soeldner, J. S., Gleason, R. E., Kahn, C. B., Marble, A. ibid.1969, 29, 1569.

19. Cerasi, E., Luft, R., Hormone metab. Res. 1970, 2, 246.20. Crockford, P. M., Williams, R., Hazzard, W. R., Williams, R. H. Diabetes,

1969, 18, 216.21. Br Med. J. 1974, iv, 178.22. Curry, D. L., Bennett, L. L., Grodsky, G. M. Endocrinology, 1968, 83, 572.23. Rudnick, P. A., Taylor, K. W. Br. med. J. 1965, i, 1225.24. Johansen, K., Orskov, H. ibid. 1969, i, 676.25. Turner, R. C., McCarthy, S. T., Holman, R. R., Harris, E. ibid, 1976, i,

1252. 26. Greenwood, R. H., Mahler, R. F., Hales, C. N. Lancet, 1976, i, 444.

might be expected to reverse the change. However,the early rapid release remained defective despitethe overall greatly increased output. An estimateof the amount of insulin stored in the cell and therate at which it could be exhausted would also bevaluable in diabetes. Unfortunately, very littlework has been done on laboratory animals to deter-mine to what extent acute evacuation of pancreaticinsulin may be feasible. Attempts have been madein man to determine the effect of massive -cell sti-mulation and its ability to exhaust the output of in-sulin.27 Oral glucose followed by intravenous glu-cagon and tolbutamide, although apparentlyproducing a near-maximum stimulation of insulinsecretion, did not reveal defects of secretory capa-city which could not be detected by the administra-tion of oral glucose. Furthermore, repeated stimu-lation at hourly intervals gave no evidence of readyexhaustibility of insulin release in insulin-deficientdiabetics.28 Perhaps further refinement of this typeof test, with more frequent insulin determinationsand measurement of proinsulin as an index ofrelease of immature granules,29 will increase its dis-criminatory value.Many of the problems of investigation of the

nature of the defect of glucose-stimulated insulinrelease would be overcome by a sequential study ofthis process before and during the onset of diabetes.In insulin-dependent diabetes such an investigationis barely feasible because of the very low incidenceof the condition. However, work on the associationof the HLA types with this condition and on thepresence of autoantibodies before onset30 mayallow a preliminary screening procedure whichwould greatly increase the eventual yield of dia-betics. The apparently strong influence of geneticfactors in insulin-independent diabetes suggeststhat family-studies would be valuable in this group.Up to now, investigations of genetically selectedpotential diabetics have not clearly separated fami-lies with insulin-dependent diabetes from thosewith the insulin-independent form. We do know,however, that a poor insulin response to glucosecan be detected in normoglycaemic potential dia-betics,18 and in the general population similar ab-normalities can be found,31 sometimes leading onto diabetes.32 33 Intensive investigation of insulinsecretion in a carefully selected group of such nor-moglycaemic people would go a long way towardsdetermining the primary guilt or innocence of thebeleagured p cell.

’

27. Ryan, W. G., Schwartz, T. B., Nibbe, A. F. Diabetes, 1971, 20, 404.28. Vinik, A. I., Kalk, W. J., Botha, J. L., Jackson, W. P. U., Blake, K. C. H.

ibid. 1976, 25, 11.29. Gorden, P., Hendricks, C. M., Roth, J. Diabetologia, 1974, 10, 469.30. Lancet, 1976, ii, 1124.31. Hales, C. N., Greenwood, F. C., Mitchell, F. L., Strauss, W. T. Diabetologia,

1968, 4, 73.32. Fajans, S. S., Floyd, J. C., Conn, J. W., Pek, S. in Early Diabetes: Advances

in Metabolic Disorders, suppl. 1 (edited by R. Camarini-Davalos andH. S. Cole); p. 377. New York, 1970.

33. Strauss, W. T., Hales, C. N. Diabetologia, 1974, 10, 237.