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Is diabetes always diabetes?
Diabezes Research and Clinical Practice, 18 (1992) 13 l- 136 0
1992 Elsevier Science Publishers
131
B.V. All rights reserved 0168-8227/92/$05.00
DIABET 00687
Brief Report Is A. Akinmokun,
diabetes always diabetes? P. Harris, P.D. Home and K.G.M.M.
Alberti
Department of Medicine, Univer.sitv of Newcastle upon Tyne, The Medical School, Frandington Place, Newcastle upon Qne. NE2 4HH,
UK
(Received 3 March 1992) (Accepted 2 July 1992)
Summary Diabetes is always taken to be a life-long diagnosis. In order to re-examine this question, 75 g glucose tolerance tests (OGTT) were performed twice on 37 previously confirmed diabetic patients (mean duration of diabetes of 4.6 years; range 1-15 years) with normal glycosylated haemoglobin levels on regular review. Weight loss since institution of a healthy diet was 7.6 f 4.8 kg ( f SE). Normal glucose tolerance was found in 27 y0 of patients and impaired glucose tolerance in 2 1 y0 with no significant change on rechallenge. HbA, was 6.3 + 1.5% (k SD) (normal ~7.5%) in patients with normal glucose tolerance compared to 7.0 k 0.9% (& SD) in those with impaired glucose tolerance, P-cO.05. The response of the OGTT in these patients varied with dietary intake and weight. Such individuals could be regarded as having perfectly controlled diabetes or alternatively to have been cured. The definition of diabetes should be reviewed to allow people to escape the diagnosis where permanent change in dietary habits is established. Key words: Non-insulin-dependent criteria
diabetes
mellitus;
Introduction The diagnosis of diabetes is assumed to long in the absence of any precipitating such as stress or drug therapy [l-3], as sized in the 1985 WHO technical report The oral glucose tolerance test (OGTT)
be lifecause empha[4]. is rec-
Correspondence to: K.G.M.M. Alberti, Department of Medicine, University of Newcastle upon Tyne. The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Glucose
tolerance;
Obesity;
Diet; Diagnostic
ommended for the diagnosis of diabetes where random blood glucose concentration with or without symptoms is not thought to be diagnostic [5,6]. Clinically the basis of management is that blood glucose levels can be controlled in many patients by restriction of rapidly absorbed carbohydrate [ 71. Current criteria for diabetes allow individuals to be diagnosed according to the level of blood glucose at the time of diagnosis without cognizance of the dietary background and the degree of adiposity of the individual con-
132 cerned [ 891. Patients with blood glucose levels in the diagnostic range are thus labelled diabetic, a label which often affects the individual’s employment [lo], insurance status and/or their social standing in society as well as the psychological state of the patient. With increasing awareness of the condition and more widespread screening, people with lesser degrees of metabolic disturbance are being diagnosed. The hypothesis underlying this study is that there is now a cohort of people who fit the WHO criteria at diagnosis, but no longer do so when following a diet no different from that recommended for the general population. If this is so, it has important consequences not only for the individual, but also for clinical management and resource allocation. Indeed, do they still have diabetes mellitus?
Materials and Methods Subjects Thirty-seven diet-controlled patients previously diagnosed as having diabetes mellitus were studied. All patients were being followed on a regular basis in the outpatient clinic of the Freeman Hospital, Newcastle upon Tyne, UK. The following information was obtained: age, sex, weight at diagnosis, weight at time of test, duration of diabetes, and family history of diabetes. Patients were included in the study if they had documentary evidence of diabetes (WHO criteria: whole blood venous glucose fasting > 6.7 mmol/l, random or 2 h post prandial > 10.0 mmol/l on more than one occasion) in the absence of acute illness, with at least two consecutive estimations of HbA, level >7.5% (reference range 5.0-7.5?/,). Patients were excluded from the study if they had received insulin or oral hypoglycaemic agents at any time since diagnosis. Clinical characteristics of subjects are shown in Table 1. Methods Standard oral glucose tolerance tests were performed on two consecutive days in each patient
1
TABLE Clinical
characteristics
of subjects Mean
Range
(+_ SEM) 62 + 2
Age (years)
sex Duration
of diabetes
BMI at diagnosis BMI
(years)
(kg/m’)
at diagnosis
Weight
(kg)
at test (kg)
HbA,
at diagnosis
HbA,
at test (“,)
Fasting
4&3 30 + 5
at test (kg/m’)
Weight
40-79
27M/ IOF
28+4*
23-41
83.5 + 2.5
60-123
17.6 + 1.5*** 9.2 + 0.5
(“,)
blood
glucose
(mmol/l)
serum
insulin
(mu/l)
1-5 24-45
56-99 7.5-16.0
6.5+0.1**
5.4-7.5
6.1 +0.9
4.0-7.6
10.3 & 1.3
2.0-33.6
at test Fasting
* P<0.0003,**P
*** Pi 0.000 1 compared
with value
at time of diagnosis.
following an overnight fast of IO-14 h. Testing took place at 09.00 h, with the patient seated. Patients remained on their usual sugar-free diet prior to testing. Smoking and drinking were forbidden throughout the test. Blood glucose was measured fasting, 1 and 2 h following a 75 g anhydrous glucose load using degassed Lucozade (Beecham, UK, 388 ml). HbA,, serum insulin, C-peptide and lipid levels were also measured in the overnight fasting state. Glucose tolerance tests were classified according to WHO criteria (WHO 1985). Whole blood glucose was measured using the Yellow Springs glucose analyser YSI 23A (Yellow Springs Instruments, OH, USA). Insulin was measured by double-antibody radioimmunoassay (sensitivity 2 m U/l; intra-assay coefficient of variation of 7 ?&) using human insulin as standard [ 111. C-peptide was measured by radioimmunoassay with ethanol precipitation (sensitivity 0.02 nmol/l, with intra-assay coefficient of variation of 3 9~) [ 121. HbA, was measured using electroendosmosis [ 131. Samples for total cholesterol, HDL-cholesterol and triglycerides were centrifuged, aliquotted and frozen at -70 “C until analysis. Lipid analyses were performed by standard
133
enzymatic techniques on an automated analyser.
at first, 74% (n = 14) remained so, while 25% (n = 5) were IGT, but none had normal OGTTs on retesting. All eight subjects who were IGT on the first test remained so on rechallenge. Patients with diabetic tolerance curves were significantly older than those with normal glucose tolerance, (64 k 11 vs. 56 k 9 years; P-K0.05) (Table 2). Not surprisingly, mean fasting blood glucose and HbA, were significantly lower in patients who had normal glucose tolerance compared to those with persistent diabetes (PC0.05) (Table 2). Weight loss since diagnosis of diabetes mellitus was greater 13.5 + 10.9 kg (range 1.4-3 1.9) in patients who had reverted to normal glucose tolerance compared to those who showed IGT or diabetes; 5.7 k 4.1 kg (range 0.3-10.7) and 5.4 + 3.8 kg (range 0.9-9.0), respectively (both P-c 0.001). There were no significant differences in the cholesterol and triglyceride levels, fasting insulin and C-peptide levels or known duration of diabetes in the three groups. Of those who remained diabetic, 35% had gained weight since diagnosis compared to only one patient in the group with normal glucose tolerance. More patients had a positive family history of diabetes mellitus in both the IGT and the
chemistry
Statistical analysis Descriptive and Student’s paired t-test statistics were calculated with the Statworks software programme (Apple Computers, Cupertino, CA, USA); PcO.05was taken as significant. Results are shown as mean + SD except where otherwise stated.
Results In the first OGTT, 5 1% of subjects (n = 19) continued to show diabetic glucose tolerance; 22% (n = 8) showed impaired glucose tolerance (IGT) and 27% (n = 10) had normal tolerance. Of those who showed diabetic tolerance, seven (37%) had fasting blood glucose concentrations < 6.7 mmol/ 1 (Table 2). On repeat OGTT testing on the following day, 382, (n = 14) showed diabetic curves, 38% (n = 14) IGT and 24% (n = 9) had normal tolerance. Of the subjects who were normal at first testing, one subject became IGT, but none were diabetic on retesting. Of those who were diabetic TABLE 2 Characteristics
of patients according to degree of glucose intolerance
Number Age (years) BMI at diagnosis (kg/m2) BMI at test (kg/m2) Duration of diabetes (years) Fasting blood glucose (mmol/l) HbA, at diagnosis (‘,b) HbA, at test (y&) Mean weight loss (kg) Fasting serum insulin (mu/l) Serum cholesterol (mmol/l) Serum triglycerides (mmol/l) Weight gainers (R) Family history of DM (7; positive)
Normal
IGT
Diabetic
10 **56 + 9 30.0 ; 2.4 27.8 T 1.1 423 **4.9 + 0.6 **8.1 T 0.6 **5.8 ; 0.2 *13.5 I 10.9 10.2 * 5.7 6.4 T 0.9 1.6 f 0.6 10 20
8 61& 12 28.8 f 6.6 27.0 & 5.8 3+2 6.1 +0.7 8.6 + 1.2 6.4 & 0.5 5.7k4.1 10.4 & 7.0 5.6 + 0.7 1.7 f 0.6 12.5 50
19 64k 11 29.3 * 4.3 28.1 + 3.8 5+3 6.6 2 0.7 10.1 & 0.7 7.0 + 0.2 5.4 & 3.8 10.3 k 8.0 5.6 f 1.3 1.8 f 0.6 35 36
* P<:O.OOl (normal vs. IGT; normal vs. diabetic), ** PcO.05
(normal vs. diabetic). Results expressed as mean + SD.
134
diabetic group (50 and 36%, respectively) compared to the 2O’;b found in patients with normal glucose tolerance. Discussion The diagnosis of diabetes is generally based on the demonstration of abnormal fasting or random blood glucose levels [4,5]. In cases where these tests are not diagnostic, the oral glucose tolerance test (OGTT) is then performed to reach a diagnosis [5,6]. The OGTT has a poor reproducibility, having a coefficient of variation of up to 404; depending on the population studied [ 6,141. However, it remains an invaluable tool in the diagnosis of IGT and in subjects with lesser degrees of hyperglycaemia. Although severity of diabetes may fluctuate from time to time in an individual with mild cases becoming severe and vice versa, most clinicians agree that diabetes is incurable. As pointed out in previous studies [ 15,161, the closest to recovery once the diagnosis is made is return to normal glucose tolerance in the obese subjects following weight loss. This was, however, referred to as remission as diabetes would probably return with increase in weight. Various degrees of abnormality of glucose intolerance are frequently found in association with obesity. More than 40’& of the type 2 diabetic patients attending our diabetic clinic are overweight. The metabolic relationship between obesity and diabetes mellitus has been well documented [ 17-211. It is generally agreed that increased adiposity especially of the android type is a risk factor for the development and perpetuation of type 2 diabetes [22]. What is not clear however is the critical amount of adiposity necessary for the development of diabetes mellitus, and the genetic component required. It is not surprising, therefore, that the diagnosis of diabetes mellitus is made independent of the degree of adiposity and, indeed, of the dietary background of the individual concerned. It has been suggested that following institution of a suitable diet, maximum responses in terms of
blood glucose control are usually observed within days or weeks [ 23-251, this giving the impression that improved glycaemic control may be related to calorie restriction or dietary composition rather than weight loss. Weight loss and weight maintenance have both been shown by several studies as important factors in achieving and maintaining normal glucose tolerance [21,23,24,26-301. Nonetheless, the possibility of regression of diabetes mellitus is usually not addressed in practice; hence patients who are diagnosed as having diabetes will carry this label for the rest of their lives. The suggestion that a high-sugar diet may play a role in the development of diabetes has been based on the assumption that sucrose presents a powerful challenge to B-cells and generates higher blood glucose levels than complex carbohydrates. It is also suggested that diabetes is commoner among some populations with a high sugar intake [31,32], although these assumptions have been heavily criticised [33,34]. A recent extensive review. for example, found no evidence that sugar intake in England was related to glucose intolerance [ 351. Consumption of sugars may, however, be important in causation and perpetuation of obesity due to the easily consumed excess calories. This is likely to be the link between sugar consumption and diabetes. In our study, 359; of those who remain diabetic following a period of supposed dietary restriction had gained weight as opposed to only IO”, of those with normal glucose tolerance. Although it has been argued that non-responders to dietary regimens may have problems with insulin secretion, this is not the case in this study. There was no significant difference in the fasting insulin levels in the three categories of patients. One could argue rather that reversibility of diabetes in these patients was related to improved insulin sensitivity following caloric restriction and weight loss. In the present study, we have shown that a quarter of the patients studied showed normal glucose tolerance for a mean of 4 years following institution of a conventional sugar-free diet with caloric content designed to attain body weight.
135 This obviously poses epidemiological as well as clinical problems. Do these people still have diabetes? Would these subjects with now normal glucose tolerance develop diabetes if changed to a free sugar-rich diet with increase in weight? There are no straightforward answers to these questions at the present time. However, our results suggest that obese middle-aged persons diagnosed and managed as true diabetes mellitus can regain and retain normal glucose tolerance by reduction of weight towards normal. This again confirms the favourable prognosis in terms of reversibility to normal glucose tolerance which may be expected in diabetes associated with obesity. This should give hope and encouragement. It could also suggest, perhaps, that the diagnosis of diabetes mellitus should not be totally abandoned in such individuals as this may lead to self-neglect and ultimately the potential for late complications. This study also identifies factors such as age, fasting blood glucose level, HbA,, weight gain and positive family history of diabetes mellitus as important predictive factors for regression or otherwise of diabetes mellitus in the clinic population Normal fasting blood glucose, a modest elevation of HbA, and a higher initial BMI makes regression of previous diabetes a possibility. It is also noteworthy that patients who reverted back to normal glucose tolerance were relatively younger, suggesting that perpetuation of diabetes mellitus in the obese patient may be related to duration of obesity, although age is an important risk factor. This requires further clarification. In conclusion, it may be suggested that the diagnosis of diabetes mellitus should not be based solely on the results of initial investigations at presentation. Subjects who develop consistently normal glucose and HbA, levels with lifestyle changes alone should be reassessed periodically to determine their glucose tolerance status. If found to be consistently normal, this could have wide implications, especially from the point of view of employment, insurance and social status of the individual concerned. We also suggest a review of the definition of the disease to allow people to escape the diagnosis where, for exam-
ple, a permanent lished.
change in dietary habit is estab-
Acknowledgements We aret the Ltd.
are grateful to Sisters M. Brown and MargMiller, Ms. L. Ashworth and her staff and to British Diabetic Association and Hoechst for financial support.
References 1 Datey, K.K. and Nanda, N.C. (1967) Hyperglycemia after acute myocardial infarction, its relation to diabetes mellitus. N. Engl. J. Med. 276, 262-265. 2 Chazan, J.A. and Boshell, B.R. (1965) Etiological factors in thiazide-induced or aggravated diabetes mellitus. Diabetes 14, 132-136. 3 Gomez, E.C. and Frost, P. (1976) Induction of glycosuria and hyperglycemia by topical corticosteroid therapy. Arch. Dermatol. 112, 1559-1562. 4 WHO Study Group. Diabetes mellitus (1985) WHO Technical Report Series No. 727. WHO, Geneva. 5 National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28, 1039-1057. 6 Nelson, R.L. (1988) Oral glucose tolerance test. Indications and limitations. Mayo Clin. Proc. 63, 263-269. I Hadden, D.R., Montgomery, D.A.D., Skelly, R.J., Trimble, E.R., Weaver, J.A., Wilson, E.A. et al. (1975) Maturity onset diabetes mellitus: response to intensive dietary management. Br. Med. J. 3, 276-278. 8 Jarrett, R.J. and Keen, H. (1976) Hyperglycaemia and diabetes mellitus. Lancet ii, 1009-1012. 9 WHO Expert Committee on Diabetes Mellitus (1980) WHO Technical Report Series No. 646. WHO, Geneva. 10 Robinson, N., Yateman, N.A., Protopapa, L.E. and Bush, L. (1990) Employment problems and diabetes. Diabetic Med. I. 16-22. 11 Soeldner, J.S. and Slone. D. (1965) Critical variables in the radioimmunoassay of serum insulin using the double antibody technic. Diabetes 14, 771-779. 12 Heding, L.G. (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11, 541-548. 13 Menard, L., Dempsey, M.E., Blankstein, L.A., Aleyassine, H., Wacks, M. and Soeldner, J.S. (1980) Quantitative determination of glycosylated hemoglobin A, by agar gel electrophoresis. Clin. Chem. 26. 1598- 1602. 14 Home, P. (1988) The OGTT: gold that does not shine. Diabetic Med. 5, 313-314.
136 15 Naunyn, B. (1906) Der diabetes mellitus. In: A. Holder (Ed), Nothnagels Handbuch. Vol. 7.2. 16 Newburgh, L.H. and Conn, J.W. (1939) A new interpretation of hyperglycemia in obese middle-aged persons. JAMA 112, 7-11. 17 Himsworth, H.P. (1935) The dietetic factor determining the glucose tolerance and sensitivity to insulin of healthy men. Clin. Sci. 2, 67-94. 18 Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes 37. 1595-1607. 19 Olefsky, J.M.. Kolterman, O.G. and Scarlett, J.A. (1982) Insulin action and resistance in obesity and noninsuhndependent type II diabetes mellitus. Am. J. Physiol. 343. El5-E30. 20 Hadden, D.R., Blair, A.L.T., Wilson. E.A., Boyle, D.M.. Atkinson, A.B., Kennedy, A.L. et al. (1986) Natural history of diabetes presenting age 40-69 years: a prospective study of the influence of intensive dietary therapy. Q. J. Med. 59, 579-598. 21 Genuth, S.M. (1977) Insulin secretion in obesity and diabetes: an illustrative case. Ann. Intern. Med. 87, 714716. 22 McKeigue, P.M., Shah, B. and Marmot, M.G. (1991) Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 337. 382-386. 23 Henry, R.R., ScheatTer. L. and Olefsky. J.M. (1985) Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 61, 917-925. 24 Wing. R.R., Koeske, R., Epstein, L.H.. Nowalk, M.P., Gooding, W. and Becker, D. (1987) Long-term effects of modest weight loss in type II diabetic patients. Arch. Intern. Med. 147, 1749-1753. 25 Nagulesparan. M.. Savage, P.J., Bennion, L.J., Unger. R.H. and Bennett, P.H. (1981) Diminished effect of caloric restriction on control of hyperglycemia with increasing known duration of type II diabetes mellitus. J. Clin. Endocrinol. Metab. 53. 560-568.
26 Stanik. S. and Marcus, R. (1980) Insulin secretion improves following dietary control of plasma glucose in severely hyperglycemic obese patients. Metabolism 29,346350. 27 Doar, J.W.H., Thompson, M.E.. Wilde, C.E. and Sewell, P.F.J. (1975) Influence oftreatment with diet alone on oral glucose-tolerance test and plasma sugar and insulin levels in patients with maturity-onset diabetes mellitus. Lancet i. 1263-1266. 28 Watts, N.B., Spanheimer. R.G., Di Girolamo. M., Gebhart, S.S.P., Musey. V.C.. Siddiq, Y.K., and Phillips, L. S. (1990) Prediction of glucose response to weight loss in patients with non-insulin-dependent diabetes mellitus. Arch. Intern. Med. 150, 803-806. 39 Hughes, T.A., Gwynne, J.T., Switzer, B.R., Herbst, C. and White, G. (1984) Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type II diabetes mellitus. Am. J. Med. 77, 7-17. 30 Savage, P.J.. Bennion, L.J., Flock, E.V., Nagulesparan, M., Mott, D.. Roth, J. et al. (1979) Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. J. Clin. Endocrinol. Metab. 48, 999-1007. 31 Yudkin, J. and Roddy, J. (1964) Levels of dietary sucrose in patients with occlusive atherosclerotic disease. Lancet ii, 6-8. 32 Cohen, A.M., Bavly, S. and Poznanski, R. (1961) Change of diet of Yemenite Jews in relation to diabetes and ischaemic heart-disease. Lancet ii, 1399-1401. 33 West, K.M. (1978) Factors associated with occurrence of diabetes. In: Epidemiology of Diabetes and Its Vascular Lesions. Elsevier. New York, pp. 191-284. 34 Sorokin. M. (1975) Hospital morbidity in the Fiji Islands with special reference to the saccharine disease. S. Afr. Med. J. 49, 1481-1485. 35 Mann, J.E. (1987) Simple sugars and diabetes. Diabetic Med. 4. 135-139.
1992 Elsevier Science Publishers
131
B.V. All rights reserved 0168-8227/92/$05.00
DIABET 00687
Brief Report Is A. Akinmokun,
diabetes always diabetes? P. Harris, P.D. Home and K.G.M.M.
Alberti
Department of Medicine, Univer.sitv of Newcastle upon Tyne, The Medical School, Frandington Place, Newcastle upon Qne. NE2 4HH,
UK
(Received 3 March 1992) (Accepted 2 July 1992)
Summary Diabetes is always taken to be a life-long diagnosis. In order to re-examine this question, 75 g glucose tolerance tests (OGTT) were performed twice on 37 previously confirmed diabetic patients (mean duration of diabetes of 4.6 years; range 1-15 years) with normal glycosylated haemoglobin levels on regular review. Weight loss since institution of a healthy diet was 7.6 f 4.8 kg ( f SE). Normal glucose tolerance was found in 27 y0 of patients and impaired glucose tolerance in 2 1 y0 with no significant change on rechallenge. HbA, was 6.3 + 1.5% (k SD) (normal ~7.5%) in patients with normal glucose tolerance compared to 7.0 k 0.9% (& SD) in those with impaired glucose tolerance, P-cO.05. The response of the OGTT in these patients varied with dietary intake and weight. Such individuals could be regarded as having perfectly controlled diabetes or alternatively to have been cured. The definition of diabetes should be reviewed to allow people to escape the diagnosis where permanent change in dietary habits is established. Key words: Non-insulin-dependent criteria
diabetes
mellitus;
Introduction The diagnosis of diabetes is assumed to long in the absence of any precipitating such as stress or drug therapy [l-3], as sized in the 1985 WHO technical report The oral glucose tolerance test (OGTT)
be lifecause empha[4]. is rec-
Correspondence to: K.G.M.M. Alberti, Department of Medicine, University of Newcastle upon Tyne. The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Glucose
tolerance;
Obesity;
Diet; Diagnostic
ommended for the diagnosis of diabetes where random blood glucose concentration with or without symptoms is not thought to be diagnostic [5,6]. Clinically the basis of management is that blood glucose levels can be controlled in many patients by restriction of rapidly absorbed carbohydrate [ 71. Current criteria for diabetes allow individuals to be diagnosed according to the level of blood glucose at the time of diagnosis without cognizance of the dietary background and the degree of adiposity of the individual con-
132 cerned [ 891. Patients with blood glucose levels in the diagnostic range are thus labelled diabetic, a label which often affects the individual’s employment [lo], insurance status and/or their social standing in society as well as the psychological state of the patient. With increasing awareness of the condition and more widespread screening, people with lesser degrees of metabolic disturbance are being diagnosed. The hypothesis underlying this study is that there is now a cohort of people who fit the WHO criteria at diagnosis, but no longer do so when following a diet no different from that recommended for the general population. If this is so, it has important consequences not only for the individual, but also for clinical management and resource allocation. Indeed, do they still have diabetes mellitus?
Materials and Methods Subjects Thirty-seven diet-controlled patients previously diagnosed as having diabetes mellitus were studied. All patients were being followed on a regular basis in the outpatient clinic of the Freeman Hospital, Newcastle upon Tyne, UK. The following information was obtained: age, sex, weight at diagnosis, weight at time of test, duration of diabetes, and family history of diabetes. Patients were included in the study if they had documentary evidence of diabetes (WHO criteria: whole blood venous glucose fasting > 6.7 mmol/l, random or 2 h post prandial > 10.0 mmol/l on more than one occasion) in the absence of acute illness, with at least two consecutive estimations of HbA, level >7.5% (reference range 5.0-7.5?/,). Patients were excluded from the study if they had received insulin or oral hypoglycaemic agents at any time since diagnosis. Clinical characteristics of subjects are shown in Table 1. Methods Standard oral glucose tolerance tests were performed on two consecutive days in each patient
1
TABLE Clinical
characteristics
of subjects Mean
Range
(+_ SEM) 62 + 2
Age (years)
sex Duration
of diabetes
BMI at diagnosis BMI
(years)
(kg/m’)
at diagnosis
Weight
(kg)
at test (kg)
HbA,
at diagnosis
HbA,
at test (“,)
Fasting
4&3 30 + 5
at test (kg/m’)
Weight
40-79
27M/ IOF
28+4*
23-41
83.5 + 2.5
60-123
17.6 + 1.5*** 9.2 + 0.5
(“,)
blood
glucose
(mmol/l)
serum
insulin
(mu/l)
1-5 24-45
56-99 7.5-16.0
6.5+0.1**
5.4-7.5
6.1 +0.9
4.0-7.6
10.3 & 1.3
2.0-33.6
at test Fasting
* P<0.0003,**P
*** Pi 0.000 1 compared
with value
at time of diagnosis.
following an overnight fast of IO-14 h. Testing took place at 09.00 h, with the patient seated. Patients remained on their usual sugar-free diet prior to testing. Smoking and drinking were forbidden throughout the test. Blood glucose was measured fasting, 1 and 2 h following a 75 g anhydrous glucose load using degassed Lucozade (Beecham, UK, 388 ml). HbA,, serum insulin, C-peptide and lipid levels were also measured in the overnight fasting state. Glucose tolerance tests were classified according to WHO criteria (WHO 1985). Whole blood glucose was measured using the Yellow Springs glucose analyser YSI 23A (Yellow Springs Instruments, OH, USA). Insulin was measured by double-antibody radioimmunoassay (sensitivity 2 m U/l; intra-assay coefficient of variation of 7 ?&) using human insulin as standard [ 111. C-peptide was measured by radioimmunoassay with ethanol precipitation (sensitivity 0.02 nmol/l, with intra-assay coefficient of variation of 3 9~) [ 121. HbA, was measured using electroendosmosis [ 131. Samples for total cholesterol, HDL-cholesterol and triglycerides were centrifuged, aliquotted and frozen at -70 “C until analysis. Lipid analyses were performed by standard
133
enzymatic techniques on an automated analyser.
at first, 74% (n = 14) remained so, while 25% (n = 5) were IGT, but none had normal OGTTs on retesting. All eight subjects who were IGT on the first test remained so on rechallenge. Patients with diabetic tolerance curves were significantly older than those with normal glucose tolerance, (64 k 11 vs. 56 k 9 years; P-K0.05) (Table 2). Not surprisingly, mean fasting blood glucose and HbA, were significantly lower in patients who had normal glucose tolerance compared to those with persistent diabetes (PC0.05) (Table 2). Weight loss since diagnosis of diabetes mellitus was greater 13.5 + 10.9 kg (range 1.4-3 1.9) in patients who had reverted to normal glucose tolerance compared to those who showed IGT or diabetes; 5.7 k 4.1 kg (range 0.3-10.7) and 5.4 + 3.8 kg (range 0.9-9.0), respectively (both P-c 0.001). There were no significant differences in the cholesterol and triglyceride levels, fasting insulin and C-peptide levels or known duration of diabetes in the three groups. Of those who remained diabetic, 35% had gained weight since diagnosis compared to only one patient in the group with normal glucose tolerance. More patients had a positive family history of diabetes mellitus in both the IGT and the
chemistry
Statistical analysis Descriptive and Student’s paired t-test statistics were calculated with the Statworks software programme (Apple Computers, Cupertino, CA, USA); PcO.05was taken as significant. Results are shown as mean + SD except where otherwise stated.
Results In the first OGTT, 5 1% of subjects (n = 19) continued to show diabetic glucose tolerance; 22% (n = 8) showed impaired glucose tolerance (IGT) and 27% (n = 10) had normal tolerance. Of those who showed diabetic tolerance, seven (37%) had fasting blood glucose concentrations < 6.7 mmol/ 1 (Table 2). On repeat OGTT testing on the following day, 382, (n = 14) showed diabetic curves, 38% (n = 14) IGT and 24% (n = 9) had normal tolerance. Of the subjects who were normal at first testing, one subject became IGT, but none were diabetic on retesting. Of those who were diabetic TABLE 2 Characteristics
of patients according to degree of glucose intolerance
Number Age (years) BMI at diagnosis (kg/m2) BMI at test (kg/m2) Duration of diabetes (years) Fasting blood glucose (mmol/l) HbA, at diagnosis (‘,b) HbA, at test (y&) Mean weight loss (kg) Fasting serum insulin (mu/l) Serum cholesterol (mmol/l) Serum triglycerides (mmol/l) Weight gainers (R) Family history of DM (7; positive)
Normal
IGT
Diabetic
10 **56 + 9 30.0 ; 2.4 27.8 T 1.1 423 **4.9 + 0.6 **8.1 T 0.6 **5.8 ; 0.2 *13.5 I 10.9 10.2 * 5.7 6.4 T 0.9 1.6 f 0.6 10 20
8 61& 12 28.8 f 6.6 27.0 & 5.8 3+2 6.1 +0.7 8.6 + 1.2 6.4 & 0.5 5.7k4.1 10.4 & 7.0 5.6 + 0.7 1.7 f 0.6 12.5 50
19 64k 11 29.3 * 4.3 28.1 + 3.8 5+3 6.6 2 0.7 10.1 & 0.7 7.0 + 0.2 5.4 & 3.8 10.3 k 8.0 5.6 f 1.3 1.8 f 0.6 35 36
* P<:O.OOl (normal vs. IGT; normal vs. diabetic), ** PcO.05
(normal vs. diabetic). Results expressed as mean + SD.
134
diabetic group (50 and 36%, respectively) compared to the 2O’;b found in patients with normal glucose tolerance. Discussion The diagnosis of diabetes is generally based on the demonstration of abnormal fasting or random blood glucose levels [4,5]. In cases where these tests are not diagnostic, the oral glucose tolerance test (OGTT) is then performed to reach a diagnosis [5,6]. The OGTT has a poor reproducibility, having a coefficient of variation of up to 404; depending on the population studied [ 6,141. However, it remains an invaluable tool in the diagnosis of IGT and in subjects with lesser degrees of hyperglycaemia. Although severity of diabetes may fluctuate from time to time in an individual with mild cases becoming severe and vice versa, most clinicians agree that diabetes is incurable. As pointed out in previous studies [ 15,161, the closest to recovery once the diagnosis is made is return to normal glucose tolerance in the obese subjects following weight loss. This was, however, referred to as remission as diabetes would probably return with increase in weight. Various degrees of abnormality of glucose intolerance are frequently found in association with obesity. More than 40’& of the type 2 diabetic patients attending our diabetic clinic are overweight. The metabolic relationship between obesity and diabetes mellitus has been well documented [ 17-211. It is generally agreed that increased adiposity especially of the android type is a risk factor for the development and perpetuation of type 2 diabetes [22]. What is not clear however is the critical amount of adiposity necessary for the development of diabetes mellitus, and the genetic component required. It is not surprising, therefore, that the diagnosis of diabetes mellitus is made independent of the degree of adiposity and, indeed, of the dietary background of the individual concerned. It has been suggested that following institution of a suitable diet, maximum responses in terms of
blood glucose control are usually observed within days or weeks [ 23-251, this giving the impression that improved glycaemic control may be related to calorie restriction or dietary composition rather than weight loss. Weight loss and weight maintenance have both been shown by several studies as important factors in achieving and maintaining normal glucose tolerance [21,23,24,26-301. Nonetheless, the possibility of regression of diabetes mellitus is usually not addressed in practice; hence patients who are diagnosed as having diabetes will carry this label for the rest of their lives. The suggestion that a high-sugar diet may play a role in the development of diabetes has been based on the assumption that sucrose presents a powerful challenge to B-cells and generates higher blood glucose levels than complex carbohydrates. It is also suggested that diabetes is commoner among some populations with a high sugar intake [31,32], although these assumptions have been heavily criticised [33,34]. A recent extensive review. for example, found no evidence that sugar intake in England was related to glucose intolerance [ 351. Consumption of sugars may, however, be important in causation and perpetuation of obesity due to the easily consumed excess calories. This is likely to be the link between sugar consumption and diabetes. In our study, 359; of those who remain diabetic following a period of supposed dietary restriction had gained weight as opposed to only IO”, of those with normal glucose tolerance. Although it has been argued that non-responders to dietary regimens may have problems with insulin secretion, this is not the case in this study. There was no significant difference in the fasting insulin levels in the three categories of patients. One could argue rather that reversibility of diabetes in these patients was related to improved insulin sensitivity following caloric restriction and weight loss. In the present study, we have shown that a quarter of the patients studied showed normal glucose tolerance for a mean of 4 years following institution of a conventional sugar-free diet with caloric content designed to attain body weight.
135 This obviously poses epidemiological as well as clinical problems. Do these people still have diabetes? Would these subjects with now normal glucose tolerance develop diabetes if changed to a free sugar-rich diet with increase in weight? There are no straightforward answers to these questions at the present time. However, our results suggest that obese middle-aged persons diagnosed and managed as true diabetes mellitus can regain and retain normal glucose tolerance by reduction of weight towards normal. This again confirms the favourable prognosis in terms of reversibility to normal glucose tolerance which may be expected in diabetes associated with obesity. This should give hope and encouragement. It could also suggest, perhaps, that the diagnosis of diabetes mellitus should not be totally abandoned in such individuals as this may lead to self-neglect and ultimately the potential for late complications. This study also identifies factors such as age, fasting blood glucose level, HbA,, weight gain and positive family history of diabetes mellitus as important predictive factors for regression or otherwise of diabetes mellitus in the clinic population Normal fasting blood glucose, a modest elevation of HbA, and a higher initial BMI makes regression of previous diabetes a possibility. It is also noteworthy that patients who reverted back to normal glucose tolerance were relatively younger, suggesting that perpetuation of diabetes mellitus in the obese patient may be related to duration of obesity, although age is an important risk factor. This requires further clarification. In conclusion, it may be suggested that the diagnosis of diabetes mellitus should not be based solely on the results of initial investigations at presentation. Subjects who develop consistently normal glucose and HbA, levels with lifestyle changes alone should be reassessed periodically to determine their glucose tolerance status. If found to be consistently normal, this could have wide implications, especially from the point of view of employment, insurance and social status of the individual concerned. We also suggest a review of the definition of the disease to allow people to escape the diagnosis where, for exam-
ple, a permanent lished.
change in dietary habit is estab-
Acknowledgements We aret the Ltd.
are grateful to Sisters M. Brown and MargMiller, Ms. L. Ashworth and her staff and to British Diabetic Association and Hoechst for financial support.
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