Insulin deficient diabetes

Diabetologia, Jan 1979

Summary Comparisons are made between the incidence, prognosis and treatment of juvenile-onset diabetes and other endocrinopathies in the young. 548 patients with insulin deficient diabetes diagnosed before 20 years of age have been reviewed. Excess mortality, especially at 35–40 years of age was found. Profiles of blood glucose and serum insulin have been studied and compared to those of normal subjects. The variation of insulin absorption and effect of insulin antibodies on the free insulin levels achieved after exogenous insulin injection have been demonstrated. The common occurence of nocturnal subclinical hypoglycaemia following intermediate or long-acting insulin was often found to be the cause of poor diabetic control. Five out of 33 patients with ‘difficult’ diabetes had an unexplained resistance to high levels of free-insulin. The value of self-monitoring and HbAl measurements in the improvement of diabetic control and possibly life expectation is reviewed. The incidence of thyroid disease was found to be increased in 1779 insulin deficient diabetics of all ages and persistence of islet-cell antibodies suggests that the diabetes may be due to autoimmunity in some of these patients.

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Insulin deficient diabetes

Contrasts with Other Endocrine Deficiencies 0 1 J. D. N. N a b a r r o 0 B. E. Mustaffa 0 D. V. Morris 0 M. J. Walport 0 A. B. Kurtz 0 0 The Cobbold Laboratories, The Middlesex Hospital Medical School , London, England 1 Based on the 29th Banting Memorial Lecture delivered to the British Diabetic Association , 15th September, 1978 0 0 1 2 - 1 8 6 X / 7 9 / 0 0 1 6 / 0 0 0 5 / $ 0 1 . 6 0 - Diabetologia Summary. C o m p a r i s o n s are m a d e b e t w e e n the incidence, prognosis and t r e a t m e n t of juvenile-onset diabetes and other endocrinopathies in the young. 548 patients with insulin deficient diabetes diagnosed b e f o r e 20 years of age h a v e b e e n reviewed. Excess mortality, especially at 3 5 - 4 0 years of age was found. Profiles of b l o o d glucose and s e r u m insulin h a v e b e e n studied and c o m p a r e d to those of n o r m a l subjects. T h e variation of insulin absorption and effect of insulin antibodies on the free insulin levels achieved after exogenous insulin injection have b e e n demonstrated. T h e c o m m o n occurence of nocturnal subclinical hypoglycaemia following intermediate or long-acting insulin was often found to be the cause of p o o r diabetic control. Five out of 33 patients with 'difficult' diabetes h a d an unexplained resistance to high levels of free-insulin. T h e value of self-monitoring and HbA1 m e a s u r e m e n t s in the i m p r o v e m e n t of diabetic control and possibly life expectation is reviewed. T h e incidence of thyroid disease was found to b e increased in 1779 insulin deficient diabetics of all ages and persistence of islet-cell antibodies suggests that the diabetes m a y b e due to a u t o i m m u n i t y in s o m e of these patients. K e y words: Insulin deficient diabetes, islet-cell antibodies, free insulin concentration, a u t o i m m u n e diabetes mellitus, Self-monitoring of b l o o d glucose, HbA1. Patients with h o r m o n e deficiencies r e s p o n d well to the r e p l a c e m e n t t h e r a p y that is n o w available. It is only in insulin deficiency that l o n g - t e r m complications s e e m to occur. T o s o m e extent this m a y r e p r e sent lack of ascertainment because there is little information available on the l o n g - t e r m follow-up of such conditions as juvenile hypothyroidism. T h e figures given in T a b l e 1 are for patients seen in the wards and general endocrine and diabetic o u t - p a t i e n t clinics of the Middlesex Hospital, L o n d o n b e t w e e n 1954 and 1978. Also included are patients seen elsewhere by o n e of the authors ( J D N N ) . T h e total n u m b e r of diabetics seen during this period was 5536, of these 3757 w e r e r e g a r d e d as being n o n insulin dependent: it is the policy of this clinic only to use insulin w h e n absolutely essential. T h e s e figures (Table 1) highlight the rarity of other types of horm o n e deficiency in young people. Thyroid Parathyroid Adrenal Cortex Gonadal failure Anterior Pituitary Diabetes insipidus Insulin deficiency - Primary Iatrogenic - Primary Iatrogenic - Primary Iatrogenie - Primary - All hormones Gonadotrophins Gonadotrophins + growth hormone Growth hormone Iatrogenic Total For most of these hormone deficiency conditions, simple oral replacement therapy is used. Vitamin D preparations are used instead of parathyroid hormone for hypoparathyroidism and the synthetic steroid fludrocortisone as a salt retaining steriod in Addison's disease because aldosterone is ineffective when given by mouth. A long-acting analogue of antidiuretic hormone is given by nasal insufflation for diabetes insipidus. Replacement therapy by injection is seldom required, a monthly injection of long-acting testosterone is the most effective treatment of male hypogonadism, injections of gonadotrophin may be used for induction of ovulation in some women and growth hormone deficient dwarfs have to have their treatment by injection for a few years. For patients with insulin deficient diabetes the hormone has been available for over 50 years, but treatment is not satisfactory. In no way is this intended to belittle the fantastic change that the discovery of insulin has made to the young diabetic. However, he or she still needs to inject the insulin and cannot expect to achieve a normal life span. There are a number of factors which make insulin deficiency a 'special' case. One is the metabolic consequences of insulin deficiency, a second is the fluctuation of insulin level during the day and from day to day depending on carbohydrate intake, a third the fact that insulin is normally released into the portal venous system and has perhaps physiologically its predominant action on the liver whereas it has to be injected peripherally so that all the tissues are exposed to its action and the liver is not subjected to a higher concentration. Possibly, a fourth factor should also be considered that many insulin preparation have been impure and insulin treated patients have had varying levels of antibodies to insulin in their blood which have influenced free insulin concentrations. Insulin Deficient Diabetes, Autoimmunity and Association with Other Endocrine Disorders The first evidence that autoimmunity might be a cause of endocrine disease was obtained by Roitt, Doniach and others in 1956 [ 1 ]. Since that time, many workers have tried to find a similar mechanism in insulin deficient diabetes. The increased incidence of thyroid and gastric parietal cell antibodies in patients with diabetes has been well documented [ 2 ]. Cellular autoimmunity in diabetes was recognised in the early 1970's [ 3, 4 ] and humoral antibodies shortly afterwards [ 5, 6 ]. It seems unlikely, however, that the islet cell antibodies present in patients with insulin deficient diabetes are the cause of the condition. In the early stages of the disease they are present in a very high proportion of patients [ 7, 8 ], but they disappear rapidly and by the time the patient has had the condition for 10 years, the incidence has dropped to 10%. There are, however, a small proportion of patients in whom the islet cell antibodies persist apparently indefinitely. Many of these patients have other organ specific auto-antibodies and sometimes evidence of other endocrine deficiency states particularly hypothyroidism and Addison's disease [8]. It is reasonable to postulate that in this small group of insulin deficient diabetics the condition really is the result of the organ specific antibodies although it must be pointed out that the antibodies seem to react with all islet cells and not just the t-cell. In the series of 1779 insulin deficient diabetics referred to in Table 1, the incidence of thyroid and other auto-immune disorders has been reviewed (Table 2). Using data from the Whickham study [ 9 ], it can be shown that the incidence of hyper- and hypothyroidism is significantly greater in insulin deficient diabetics than in the general population (Table 3). Many of these patients were seen before it was possible to detect islet cell antibodies, but islet cell antibodies have been sought in a proportion of them by Dr. G. F. Bottazzo and Professor D. Doniach and the incidence greatly exceeds the 10% figure for J. D. N. Nabarro et al.: InsulinDeficientDiabetes Table 4. Persistent Islet Cell Antibodies (ICA) in patients with insulin deficient diabetes and autoimmune disease Autoimmunedisease diabetics of m o r e than 10 years' duration (Table 4). These workers have recentIy r e p o r t e d similar findings in a different group of diabetic patients [ 10 ]. D i a b e t e s D i a g n o s e d b e f o r e 2 0 Y e a r s o f A g e R e f e r e n c e has already b e e n m a d e to the u n f o r t u n a t e fact that young people who develop insulin deficient diabetes have a reduced life expectation. T h e 548 patients in this age group have b e e n reviewed. T h e age of onset of the condition is shown in Figure 1, it will be n o t e d that the p e a k age is a little later than that r e p o r t e d by B l o o m and others [ 11 ]. This may be the result of m o r e consistent reporting by pediatricians. T h e duration of follow-up since the onset of the condition is shown in Figure 2. Those known to be dead are also indicated. These figures are open to criticism because some patients m a y only have b e e n r e f e r r e d because of complications, whereas others m a y have continued to survive without any complications. T h e gravity of the situation is, however, emphasised by the excess mortality shown in Figure 3 - in the 3 5 - 4 0 year age group, the death rate is 13.9 times that expected. M a c G r e g o r [ 12 ], gave an equally depressing report of seven deaths in 45 children who developed diabetes b e f o r e they were 12 and who had b e e n followed for between 12 and 27 years. T h e overall picture is very similar to that recently r e p o r t e d f r o m D e n m a r k in a 40 year followup of young diabetics [ 13 ]. T h e cause of death in these patients is shown in Table 5. T h e high incidence of death from hypoglycaemia is notable: in the three patients in w h o m this followed h y p o p h y s e c t o m y for retinitis, pituitary surgery had had excellent results as far as preservation of vision was concerned, but, in retrospect, they should probably not have b e e n selected for this f o r m of t r e a t m e n t as they were single men. T h e y were treated b e f o r e light coagulation b e c a m e available. T h e figures given in Table 6 suggest that those with onset between 5 and 9 years of age may live a little Number of Patients 100 80 60 12.5 20J 40 Ratio 7.5 Actual Expected Deaths 5.0 iI 2 6 10 14 Age of Onset-Years I 18 lO i 20 longer than the other groups but show a higher incidence of blindness. It is, however, important to get this into proper perspective because without insulin all would have died within two or three years of diagnosis. ReferJ.D.N. Nabarro et al.: Insulin Deficient Diabetes ence to Figure 2 will show that many are alive and well twenty or thirty years after the diagnosis of diabetes and the start of insulin injection therapy. Insulin Therapy in Insulin Deficient Diabetics To try to improve the long-term prognosis for the insulin deficient diabetic, it is relevant to examine the circulating insulin pattern in the normal subject and to compare it with that achieved with insulin injections in insulin deficient diabetics. At the same time it is accepted that the insulin profile in peripheral venous blood gives little indication of the insulin content of portal vein blood to which the liver of a nondiabetic is exposed. Glucose and insulin profiles in eight normal men are shown in Figure 4. This is drawn from data obtained by Dr. R. R. Holman and Dr. R. C. Turner of the Radcliffe Infirmary, Oxford [ 14 ]. The peak shown one hour after each meal is the mean of the highest level found after the meal in samples taken at 10 minute intervals. The highest level occurred any time between 20 and 60 minutes after the start of the meal. In contrast the serum insulin level after a subcutaneous injection rises much more slowly and, provided no insulin antibodies are present, reaches a peak about 150 minutes after the injection (Fig. 5). During the day it might be possible to achieve a pattern resembling the insulin concentrations in the peripheral blood by giving soluble insulin three times a day. To avoid hypoglycaemia, however, it would be necessary to use slowly absorbed carbohydrate, possibly with additional dietary fibre [ 15 ] and to give additional carbohydrate between meals. The problem of ensuring an adequate serum insulin concentration during the night hours necessitates the use of longer acting insulin. For reasons of expediency many physicians use a mixture of rapidly acting and an intermediate acting insulin in the morning and evening. This reduces the number of injections to two a day and hopefully provides reasonable blood glucose levels. The most commonly used intermediate acting insulin is isophane insulin. Figure 6 shows the free-insulin level in a diabetic patient who had two injections of soluble insulin during the day and soluble and isophane insulin in the evening. The free insulin was measured by the polyethylene glycol precipitation method of Nakagawa et al. [ 16 ]. The levels during the night were too high, there was subclinical hypoglycaemia detected by serial measurements of blood sugar. It might be argued that this could easily be corrected with a smaller dose of isophane insulin, but with this preparation, it is difficult to find a dose that will avoid nocturnal hypoglycaemia but control blood glucose up to the time of the next injection. As an alternative to isophane insulin in the evening, we are now studying the effect of an insulin zinc suspension ( L e n t e - M o n o t a r d ) and this m a y p r o d u c e a sarisfactory night time pattern. W e h a v e not found it easy to control patients on two injections of quick-acting and lente insulin and we are now studying a regime with quick-acting and isophane insulins in the m o r n ing and quick-acting and lente insulin in the evening (Fig. 7). T h e effect of insulin antibodies on the diurnal insulin p a t t e r n of insulin treated diabetics is considerable. Figure 5 shows the free insulin levels after an injection of quick-acting insulin in two diabetics, one without insulin antibodies and one with antibodies. It is clear that with a high level of antibodies it will be very difficult to achieve a physiological p e a k of free insulin concentration. T h e level of antibodies d e v e l o p e d varies greatly f r o m patient to patient, and we have, at present, no m e a n s of detecting which patient will develop antibodies. It seems advisable to start all newly diagnosed insulin deficient diabetics on a highly purified insulin, which, although it does not p r e v e n t a n t i b o d y f o r m a t i o n completely, seems to k e e p it at a m u c h lower level. This limits the type of insulin p r e p a r a t i o n that can be used to A c t r a p i d M C or L e o Neutral insulins for quick action; L e o R e t a r d as an isophane insulin and M o n o t a r d M C which m a y have a longer action. Semitard M C is available as an intermediate acting insulin, but carries greater risk of nocturnal hypoglycaemia. In the last year, we h a v e b e e n studying b l o o d Soluble . lOu Soluble Soluble Isophane , lOu 10u 14u Meals Free Insulin mull 30 6O sugar and free insulin profiles partly in our own unit and partly in conjunction with Dr. R. B. Tattersall and Dr. E. A. M. G a l e in Nottingham. T h r e e points have e m e r g e d f r o m these studies. T h e first and_probably the m o s t i m p o r t a n t is the occurrence of asymptomatic h y p o g l y c a e m i a during the night. This is gen Free Insulin mu/I \ Mean 10 Brood Sugar mmol/I 7.5 5.0 2.5 9Q o~ 9 #" 9 e e erally accepted as being a c o m m o n occurrence with Semilente insulin given b e f o r e supper. W e have b e e n surprised to discover how often it occurs with isophane insulin given b e f o r e the evening meal. W e have also e n c o u n t e r e d it with M o n o t a r d insulin in a dose as small as 12 units. P r o b a b l y the most important o u t c o m e of our studies has b e e n the realisation of the n e e d to check blood sugars in the early hours of the morning if diabetic control is proving difficult. T h e second point that has e m e r g e d has b e e n the vari~".'-~'.'.~1 ili 5 I0 20 25 15 %HbA1 ation of the rate of absorption of insulin. T h e r e obviously must be some variation and in long standing diabetics with fibrosis in most of the possible injection sites this m a y b e c o m e a serious problem. Figure 8 shows the free insulin levels i n a patient following an injection of 12 units of isophane insulin. O n one occassion absorption was rapid and on the o t h e r much slower. T h e third point is that some diabetics are apparently resistant to surprisingly high levels of free insulin. This is illustrated in Figure 9 where the m e a n free insulin and blood sugar levels between midnight and 0800 h are shown in 53 studies on 33 patients. With m e a n free insulin below 35 m U / l there is the expected relationship with the association of a low free insulin and a high blood sugar or a high free insulin and hypoglycaemia. H o w e v e r , there are 7 studies on 5 patients who had high free insulins with hyperglycaemia or, in one case, normoglycaemia. These patients were not obese, diabetic control was difficult to achieve and we do not know the reason for their insulin resistance. Monitoring Diabetic Control It is well recognised that single blood sugar measurements in a clinic are a very p o o r indication of overall diabetic control. Serial measurements t a k e n in hospital are artificial and rarely satisfactory. T h e r e is no doubt that h o m e self-monitoring with one of the currently available 'stick' reading machines offers the possibility of greatly improved diabetic control and increases the patient's understanding of his or her disease [ 17, 18 ]. In our experience very frequent m e a s u r e m e n t s are n o t really n e c e s s a r y a n d we ask the patient to c h e c k b l o o d glucose f o u r times a day n o t e v e r y d a y - but periodically. This m a y be o f p a r ticular value in establishing the levels of b l o o d glucose in the early h o u r s of the m o r n i n g . T h e o t h e r i m p o r t a n t d e v e l o p m e n t in the m o n i t o r ing of diabetic c o n t r o l is the use of a simple m e t h o d for m e a s u r i n g the glycosylated h a e m o g l o b i n s [ 19 ]. U s i n g the m e t h o d described b y W e l c h and B o u c h e r [ 20 ], we have m e a s u r e d the levels of H b A 1 a + b + c in 72 c o n t r o l n o n - d i a b e t i c subjects a n d 348 patients f r o m o u r diabetic clinic. T h e results are s h o w n in Figure 10. T h e y give little g r o u n d f o r c o m p l a c e n c y , a n d we have n o t f o u n d the high c o r r e l a t i o n b e t w e e n clinical assessment of c o n t r o l and b l o o d sugar levels v. H b A 1 described b y G o n e n a n d R u b e n s t e i n [ 19 ]. W e have, h o w e v e r , n o t e d the gradual fall in level w h e n a n e w diabetic is t r e a t e d a n d a rising level o r u n e x p e c t e d l y high level in a t r e a t e d p a t i e n t is a w a r n ing that s o m e t h i n g is going wrong. T h e Future C u r r e n t l y available insulin p r e p a r a t i o n s could be better used to treat patients with diabetes. W e should be using the purest insulins p r o b a b l y of p o r c i n e origin. T h e best results w o u l d p r o b a b l y b e o b t a i n e d with a rapidly acting insulin b e f o r e breakfast a n d b e f o r e lunch, with b e f o r e the e v e n i n g m e a l a rapidly acting highly purified insulin with a small dose o f a l o n g e r acting insulin. If t h r e e injections a day w e r e n o t a c c e p t a b l e to the p a t i e n t the m o r n i n g injection m i g h t b e q u i c k - a c t i n g with an i n t e r m e d i a t e acting insulin. T h e dose w o u l d be a d j u s t e d by the patient o n the results of his o w n b l o o d sugar m e a s u r e m e n t s a n d the l o n g - t e r m assessment of c o n t r o l m a d e b y the D i a betic Clinic using H b A 1 m e a s u r e m e n t s . I n the f u t u r e a truly m i n i a t u r e i m p l a n t a b l e or p o r t a b l e artificial p a n c r e a s seems a long w a y ahead. P a n c r e a t i c or islet cell t r a n s p l a n t a t i o n also seems to b e a v e r y r e m o t e possibility. E v e n if rejection p r o b lems could be o v e r c o m e , the difficulties in o b t a i n i n g d o n o r material s e e m insuperable. M e t e r e d insulin infusion m a y p r o v i d e b e t t e r control w i t h o u t any f e e d - b a c k b a s e d o n b l o o d sugar levels. I n t r a v e n o u s infusion seems t o o h a z a r d o u s f o r c o n t i n u o u s use, but d e v e l o p m e n t s are in h a n d with s u b c u t a n e o u s infusion [ 21 ]. T h e possibility of i n t r a p e r i t o n e a l infusion is w o r t h f u r t h e r study b e c a u s e at least part of the insulin is likely to e n t e r the p o r t a l v e n o u s d r a i n a g e syst e m [ 22 ]. Clearly w e h a v e a great deal still to d o to realise the full potential of B a n t i n g and B e s t ' s g r e a t discovery. Acknowledgements. In addition to those mentioned in the text, we wish to thank Miss J. A. Matthews for her skilled help in performing most of the free insulin measurements, and Miss L. Worsley for carrying out the HbA 1measurements. The blood sugar estimations were carried out in the Courtauld Institute of Biochemistry (Dr. A. L. Miller). The figures were drawn by Mr. Paul Darton, N. D.D., M.A.A. We are indebted to The Nordisk Insulin Laboratories for financial support. BEM was a British Council Research Fellow from Universiti Kebangsa~in, Kuala Lumpur, Malaysia. R e f e r e n c e s 1. Roitt , I.M. , Doniach , D., Campbell , P.N. , Hudson , R.V. : Autoantibodies in Hashimoto's disease (lymphadenoid goitre) . Lancet 19S6 If , 820 - 821 2. Irvine , W. J. , Clarke , B. F. , Scarth , L. , Cullen , D. R. , Duncan , L. J. P. : Thyroid and gastric autoimmunity in patients with diabetes mellitus . Lancet 1970 II, 163 - 168 3. Nerup , J. , Andersen , O. O. , Bendixen , G. , Egeberg , J. , Gunnarsson , R. , Kromann , H. , Poulsen , J.E. : Cell-mediated immunity in diabetes mellitus . Proc. R. Soc. Med . 67 , 506 - 513 ( 1974 ) 4. Irvine , W.J., MacCuish , A.C., Campbell , C.J. , Duncan , L. J. P. : Organ-specific cell-mediated auto-immunity in diabetes mellitus . Acta Endocrinol. [Suppl.] (Kbh.) 205 , 65 - 76 ( 1976 ) 5. Bottazzo , G. F. , Florin-Christensen , A. , Doniach , D. : Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies . Lancet 1974 II, 1279 - 1282 6. MacCuish , A.C. , Barnes , E.W. , Irvine , W.J. , Duncan , L. 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J. D. N. Nabarro, B. E. Mustaffa, D. V. Morris, M. J. Walport, A. B. Kurtz. Insulin deficient diabetes, Diabetologia, 1979, 5-12, DOI: 10.1007/BF00423143