THE QUEST FOR NORMOGLYCEMIA - A HISTORICAL-PERSPECTIVE

One of the longest-running controversies in medicine concerns the aims of diabetes treatment. The question debated for 80 years has been whether the clinician should just relieve symptoms, or try to achieve the much more difficult objective of near-physiological normality as measured by an absence of glycosuria and/or normal blood sugar levels. At the beginning of World War One, most clinicians and physiologists thought the severity of diabetes was inversely proportional to the number of functioning islets of Langerhans. Hyperglycaemia, it was hypothesized, stressed the surviving islets and led to a downward spiral of increasing glandular fatigue and hyperglycaemia. The aim of undernutrition was to rest the damaged tissue in the hope of promoting a return of functional efficiency and possibly regeneration. Most experts stressed that rest of the islets could only be achieved by abolishing glycosuria and restoring normal blood sugar levels. The first clinical use of insulin in 1922 led to astonishing improvements in the health and strength of patients with diabetes and the concept of pancreatic rest seemed to be confirmed when some regained such carbohydrate tolerance that after weeks or months they could reduce the dose of insulin without developing glycosuria. Initially there were expectations that insulin would allow the islets of Langerhans to recover completely, so that diabetes was cured. Most physicians insisted that the best chance of preserving what pancreatic function remained was biochemical normality. It was also contended that patients who had normal blood sugar levels were more healthy than those without and had fewer 'complications'. The complications in question were mainly infective, since specific diabetic tissue damage was not recognized until the late 1930s. The toll of microvascular complications (retinopathy and nephropathy) in those whose lives had been saved by insulin did not become apparent until the late 1930s and early 1940s, when it generated an often acrimonious debate bout whether they were due to the metabolic disorder or an associated phenomenon. Liberalization of diet in patients taking insulin began in 1926 and by 1930 it was clear that patients who were prescribed 200 g of carbohydrate per day felt better and more energetic than those on the old regimens of 50 g or less per day. Even these more liberal diets were measured but, in the early 1930s some paediatricians, feeling that a strict measured diet was psychologically damaging, experimented with 'free' or unmeasured diets. Most still tried to achieve the best possible metabolic control whereas the New York physician, Edward Tolstoi, allowed his patients to have any degree of hyperglycaemia provided they felt well and did not lose weight. He claimed that in units which aimed for 'chemical control' microvascular complications were as, or even more, frequent than in patients on a free diet. The debate remained unresolved because, as one expert put it, 'one deals perforce with individuals whose diabetes has been under varying degrees of inadequate control and speaks of the bset of them as having good control'. Indeed, until the introduction of haemoglobin A1 in 1976 there was no way of assessing long-term glycaemic control except by relatively subjective criteria and repeated random blood glucose measurements. In 1960 an attempt was made, in patients with newly diagnosed maturity onset diabetes, to find out whether treatment with tolbutamide or phenformin was better or worse than insulin. This study of over 1000 patients in 12 university clinics (the University Group Diabetes Program or UGDP) produced its first report in 1970 and led to what the Lancet described as 'a storm of controversy without parallel in modern medicine'. Initial results appeared to show that treatment with tolbutamide or phenformin was actively harmful and the mortality of patients on insulin, either a fixed or variable dose, was no lower than in the placebo group. Every aspect of the design, execution, analysis and interpretation of the trial was minutely criticized by clinicians and statisticians. The UGDP was eventually 'buried' in 1980 when reanalysis of the data led to conclusions which were the direct opposite of those reached by the UGDP investigators. Coterminous with the UGDP study was the basement membrane controversy. Using the surrogate endpoint of quadriceps basement membrane thickness, Siperstein reported that it could be found in 'prediabetes', was unrelated to the duration of diabetes and was not found in patients with non-genetic forms of the disease. The implication was that the changes were inherited independent of the metabolic abnormality or that a common unknown factor caused the vascular and endocrine abnormalities. Others could not confirm Siperstein's results and eventually the protagonists in this controversy resorted to an argument about methodology which was eventually resolved (against Siperstein) by a collaborative study sponsored by the National Institutes of Health. In 1976 the American Diabetes Association attempted to squash once and for all the heresy that control was unimportant in preventing late complications. They reviewed the literature and concluded that good control was beneficial and that the goals of therapy should include 'a serious attempt to achieve blood glucose levels as close to those in the non-diabetic state as feasible'. Opponents claimed that no one would disagree with this aim if it could be achieved safely but that there was a serious risk of hypoglycaemia. Neither side had data to support their position. The most recent, and possibly definitive, contribution has been the Diabetes Control and Complications Trial (DCCT), a randomized controlled multicentre trial in which 1441 young adults with insulin-dependent diabetes were randomly allocated to either intensive or conventional treatment. In 1993 after an average follow up of 6.5 years the study was terminated by the data monitoring committee. Intensive treatment (resulting in a mean blood glucose concentration of 8.6 compared to 12.8 mmol l-1 in the conventionally treated group) delayed the onset of and slowed the progression of clinically important retinopathy by up to 70 %. Complications of intensive therapy were a threefold increase in the rate of severe hypoglycaemia and an average weight gain of 4.6 kg. On the basis of these results the DCCT investigators recommend that most patients with insulin-dependent diabetes be treated with closely monitored intensive regimens with the goal of maintaining their glyaemic status as close to the normal range as safely possible. The targets they advocate in 1993 are identical with those recommended in 1923!