Glucokinase gene mutation and impaired glucose uptake by liver

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NUMBER OF PERSON-YEARS OF FOLLOW-UP AND EVENTS FOR WOMEN 40-49 YEARS AT RANDOMISATION BY INVITED (IG) AND CONTROL GROUP (CG) FOR BREAST CANCER AS UNDERLYING CAUSE OF DEATH* AND FOR BREAST CANCER PRESENT AT DEATH*

*According to the end-point committee. Follow-up model. Standardised RR and 95% CI.

cumulative breast cancer mortality, we think that this is the best method for comparing the invited group and the control group because the development since randomisation can be followed yearly. We did not present relative risks (RR) and/or the cumulative breast cancer mortality for the 40-49 year group because each trial was too small to warrant stratified analysis. However, to meet the demand of complete material description, we report RRs for this group for each trial and for the end-points breast cancer as underlying cause of death and breast cancer present at death, with the follow-up method (table). The trials in Ostergodand and Stockholm had RRs above 1 and in Malino, Kopparberg, and Gothenburg, RR was below 1. It is noted that the CIs are wide and far from being statistically significant, but they are somewhat narrower than in earlier publications,s-7 As emphasised in our report we used exact age instead of year of birth, implying that we had to exclude some women younger than 40 in the WE-study and the trials in Stockholm and Gothenburg. Further, earlier presented data for the group 40-49 years at randomisation for the WE-study and the trials in Maimo and Stockholm included deaths to 1986, and in the overview we extended the time for follow-up to 1989. Finally, there might be differences resulting from reviewing by the local EPC compared with our EPC. We believe that the influence of these differences on RR was probably marginal. Dr Skrabanek questions the wisdom of offering mammography on a mass scale, on the basis that the RR for total mortality was 1 00 and of his calculation of crude ratios. In fact the number of observed deaths in the invited group was 15 695, compared with 15 710 expected deaths, resulting in a standardised RR of 100. Furthermore, RRs for total mortality in the individual trials were 0-98,0 98,0-99,11 00, and 1 00, and thus none exceeded 1 00. The number of deaths with breast cancer and the total number of deaths among women in Sweden in 1988 in the age group 45-79 were 1095 and 29 448, respectively, and in the age group 50-74, these figures were 1192 and 37531. Thus, breast cancer was responsible for 3 71% and 3 18% of all deaths. According to our overview the reduction in breast cancer mortality was 24%, implying that the effect on total mortality should be 0 89 % and 0-76%, respectively. Since the cohort was 40-74 years at randomisation and followed for 5 and 13 years, the age at death was between 40 and 87 years, with most in the older age groups, which means that a reduction of the total mortality of about 0-8%-ie, RR of 0-99-was what could be expected (see also ref 7, p 112). This finding is within the 95% CI for the estimate we gave, and it is not difficult to show that "as many as 25 million women-years fail to show a net benefit in survival". However, the trials were not designed to show a reduction in the total mortality, but a reduction of the mortality among breast cancer cases, which our overview

proved. To answer Dr Hakama’s criticism, of the 282 777 women in the cohort, 89 314 were between 40 and 49 years at randomisation, and the trials in Stockholm and Gothenburg, which focused on the younger women, account for more than half these (46 046). The trial in Stockholm started in March, 1981, and ended in May, 1983, with a screening interval of 28 months, and the trial in Gothenburg started in December, 1982, until April, 1984, with a screening

interval of 18 months, implying that in Stockholm they had not at the time of follow-up completed the third round for all women and that in Gothenburg they had completed four rounds. Thus, because some women in the trials in Stockholm and Gothenburg were not followed for more than 65 and 5-5 years, respectively, we have to undertake a new follow-up after about 3-4 years to ensure the potential contribution from these trials in the age group 40-49 years. Besides, the trial in Gothenburg, especially, used a more modem mammographic technique, with two views and shorter screening intervals. In time we might also be able to answer Hakama’s question whether the three first screening rounds roughly at follow-up years 0, 2, and 4 years were ineffective. We agree that a more detailed stratification by age before and around the menopause and a large number of women screened are needed to decide the best age at which to start screening for breast cancer, but none of the trials we examined was designed to answer that question. Departments of Epidemiology and Public Health and Oncology, Umeå University, Umeå, Sweden

LENNARTH NYSTRÖM LARS-GUNNAR LARSSON, behalf of the Overview of Swedish Randomised Trial Researchers

on

1. Chalmers TC, Levin H, Sacks HS, Reitman D, Berrier J, Nagalingam R. Meta-analysis of clinical trials as a scientific discipline. I: Control of bias and comparison with large co-operative trials. Stat Med 1987; 6: 315-25. 2. Elwood JM, Cox B, Richardson AK. The effectiveness of breast cancer screening by mammography in younger women. Online J Curr Clin Trials 1993; document 32, para 1-195. 3. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. Can Med Assoc J 1992; 147: 1459-76. 4. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. Can Med

Assoc J 1992; 147: 1477-88. 5. Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. BMJ 1988; 297: 943-48. 6. Frisell J, Eklund G, Hellström L, Lidbrink E, Ruqvist LE, Somell A. Randomized study of mammography screening-preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 1991; 18: 49-56. 7. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Comm Health 1989; 43: 107-14.

Glucokinase gene mutation and impaired glucose uptake by liver SiR,—Mutation of the glucokinase gene was first reported last year in maturity-onset diabetes of the young (MODY),1 and more than 20 families with mutated glucokinase have now been reported,2 The diabetes is usually mild, and only a few patients need insulin therapy or have diabetic complications. We have identified a Japanese family with a mutation in the exon 7 of the glucokinase gene.3 This mutation coincides with 2 of the French families, and the clinical characteristics of our family are similar to those of the French families. The mechanism whereby patients having a mutation in the glucokinase gene develop diabetes is of great interest. Matschinsky" originally proposed the concept that glucokinase acts as the glucose sensor of pancreatic beta cells, and a recent study of insulin secretion

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Euglycaemic hyperinsulinaemic clamp with oral glucose load. After overnight fasting, insulin was infused at constant rate (2-24 mU/kg per min) to achieve desired steady-state in plasma (150 )iU/mL), and exogenous glucose was infused to maintain euglycaemia (95 mg/dL). Glucose infusion rate (GIR, 93 mg/kg per min) before oral glucose load reflects glucose disposal by peripheral tissues, mainly by muscles. After oral glucose loading (17 g, 0-5 g/kg), GIR required to maintain euglycaemia decreased, since some fractions of orally administered glucose that are not taken up by splanchnic tissues, mainly liver, enter systemic circulation. Therefore, splanchnic glucose disposal can be calculated from difference between amount of oral glucose load (170 g) and summation of GIR decreases (E AGIR, 168 g). Glucose uptake by splanchnic tissue (tiver)=(17 0-16-8) x 100/17-0=118%. in patients with mutation in the glucokinase gene supported the concept of a raised set-point for the secretion of insulin.s However, glucokinase is also expressed in the liver as well as in beta cells, and we should consider the role of the liver. Glucose tolerance testing in our patients showed insufficient insulin response to the increase in glucose concentration.3 This result cannot distinguish between the dysfunction of glucokinase in the pancreatic beta cells and that in the liver or both. A newly developed method called euglycaemic hyperinsulinaemic clamp combined with oral glucose load enabled us to measure separately glucose uptake by the peripheral tissues (mainly muscles) and splanchnic tissues (mainly liver), and we used this method in our patient. As shown in the figure, although glucose uptake by the peripheral tissues was normal (93 mg/kg per min, normal range 10[2 x SD 44]), glucose uptake by splanchnic tissues was decreased (1 18%, normal 35 8 [24’0]). The impaired glucose uptake by the liver will contribute to an increase in

postprandial plasma glucose. We propose that dysfunction of both the pancreatic beta cells and the liver are responsible for the development of diabetes due to glucokinase mutation. Third

Department of Internal Medicine, University of Tokyo

H. SAKURA

First Department of Internal Medicine, Osaka University School of Medicine

R. KAWAMORI M. KUBOTA T. MORISHIMA T. KAMADA

Institute for Diabetes Care and Research, Asahi Life Foundation,

Tokyo

Y. AKANUMA

Third

Y. YAZAKI T. KADOWAKI

Department of Internal Medicine, University of Tokyo,

Tokyo 113, Japan 1. Vionnet

N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene early-onset non-insulin-dependent diabetes mellitus. Nature 1992; 356:

causes

721-22. 2.

Frogual P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutation in glucokinase—definition of a subtype of diabetes mellitus. N Engl J Med 1993; 328: 697-702.

3. Sakura H, Eto

K, Shimokawa K, et al. Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1992; 75: 1571-73. 4. Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes 1990; 39: 647-52. 5. Velho G, Froguel P, Clement K, et al. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 1992; 340: 444-48. 6. Kawamori R, Kubota M, Ikeda M, et al. Quantitative determination of hepatic glucose uptake using an innovative approach: effect of strict glycemic regulation and exercise in diabetic subjects. J Nutr Sci Vitaminol 1991; 37: S35-42.

SIR,-Professor Knipschild (May 1, p 1135) expresses his astonishment that his meta-analysis showed "beneficial effects for homoeopathy in many (but not all) well-performed trials". I am not surprised, since positive findings in clinical research may often be explained solely by bias. Further, as previously pointed out/ Knipschild did not do a meta-analysis, but a review. Rather than accepting the absurd idea that placebo can be better than itself, or that water can remember what was once in it, it seems more realistic to assume that the positive results in the homoeopathy trials were caused by bias. An example from rheumatology may be illustrative. In 196 double-blind trials comparing a new non-steroidal, anti-inflammatory drug (NSAID) with a control NSAID, a total of 1545 effect variables were identified.2 Significant results in favour of the control drug were claimed for 1 -9% of the variables, or close to the expected 25%, assuming equally effective drugs.3 By contrast, significant results were claimed for 11 -9% of the variables in favour of the new NSAID, or five times more often than expected. Significant differences in side-effects were reported in 39 trials; in all cases the new drug was favoured.2 Thus new drugs seemed on average to be both more effective and better tolerated than control

drugs. Meta-analyses have nullified this optimism. In crossover trials, patients preferred indomethacin, the commonest control drug, equally often as they did the new drugs.4 No differences were shown between new and control drugs in a meta-analysis of grip strength, the commonest used effect variable,5 or in a number of tender joints6which is one of the most sensitive effect variables in NSAID trials .77

Obviously, the massive bias in these trials seems to have been produced during data analysis and report writing: bias in the conclusion or abstract favoured the control drug in only one report, and the new drug in 81 .2 Usually, it was not possible to follow the track of the researchers, but sufficient detail was presented in a few papers that allowed a reanalysis of the p values. In 12 trials, significant differences in effect proved to be wrong; in all 12 trials, the erroneous results favoured the new drugs.2 I wonder how often we are presented with only the lowest of several possible p values in medical research articles? Probably this happens most of the time, when the choice favours the innovation. Department of Rheumatology, Hvidovre Hospital, 2650 Hvidovre, Denmark

PETER C. GØTZSCHE

1. Baum M. Trials of homeopathy. BMJ 1991; 302: 529. 2. Gøtzsche PC. Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal, antiinflammatory drugs in rheumatoid arthritis. Contr Clin Trials 1989; 10: 31-56 (erratum: 356). 3. Gøtzsche PC. Bias in double-blind trials (thesis). Dan Med Bull 1990; 37: 329-36. 4. Gøtzsche PC. Patients’ preference in indomethacin trials: an overview. Lancet 1989; i: 88-91. 5. Gøtzsche PC. Meta-analysis of grip strength: most common, but superfluous variable in comparative NSAID trials Dan Med Bull 1989; 36: 493-95. 6. Gøtzsche PC. Meta-analysis of NSAIDs: contribution of drugs, doses, trial designs, and meta-analytic techniques. Scand J Rheumatol (in press). 7. Gøtzsche PC. Sensitivity of effect variables in rheumatoid arthritis: a meta-analysis of 130 placebo controlled NSAID trials J Clin Epidemiol 1990; 43: 1313-18.

SiR,—Professor Knipschild states that the lack of acceptance of alternative treatment partly results from an incomplete knowledge of results of published trials. He found in less accessible journals convincing evidence for the effects of ginseng and Ginkgo biloba. He ends with the proposal to traditionalist acupuncturists and the Union Against Quackery to agree on a well-designed trial to get a final answer: they should bet and the loser should pay for the study. Knipschild is a biostatistician and he is fond of the controlled trial. However, as stated earlier by Skrabanek,l "Extraordinary claims require extraordinary evidence, and randomised clinical trials, applied to absurd claims, are more likely to mislead than illuminate". Many useful and effective forms of treatment became standard medical practice long before the introduction of the randomised trial. Many of them are, at face value, so evidently beneficial that doing a trial would seem absurd to anyone. For instance, the impact of treatments such as caesarean section in cephalopelvic disproportion, insulin in diabetes, morphine for pain