Aims In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment. Methods The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases and controls. Results The proportion of D-allele carriers was higher amongst cases than controls (83 vs. 73%; P=0.032). In contrast, AT2R genotype distribution was similar in cases and controls. In a multiple regression analysis, D-allele carriage remained a significant risk factor for being a case [odds ratio: 1.9 (1.0–3.6)] together with male sex, impaired symptomatic awareness of hypoglycaemia and presence of nephropathy. Conclusion The D-allele of the ACE gene is associated with severe hypoglycaemia requiring emergency treatment in type 1 diabetic patients with preserved spontaneous ACE activity. This supports the association between high ACE activity and occurrence of severe hypoglycaemia.

Recommendations for self-monitoring of blood glucose (SMBG) from the DCCT have not been implemented with the same rigour as recommendations for intensifying insulin therapy. We assessed the frequency of and motives for SMBG and compared SMBG behaviour with clinical, behavioural and demographic characteristics.Cross-sectional Danish-British multicentre survey of 1076 consecutive patients with type 1 diabetes, who completed a detailed questionnaire on SMBG and related issues. The key variables were test frequency and motive.SMBG was performed daily by 39% of the patients and less than weekly by 24%. Sixty-seven percent reported to perform routine testing, while the remaining 33% only tested when hypo- or hyperglycaemia was suspected. Age, gender, and level of diabetes-related concern were associated with test pattern. Reported frequencies of mild and severe hypoglycaemia and awareness of hypoglycaemia were independently associated with testing behaviour, whereas the presence of late diabetic complications was not. Lower HbA1c was associated with more frequent testing.Patient compliance regarding SMBG is limited. Thus, almost two thirds of the patients do not perform daily SMBG and one third do not perform routine tests.

Background The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. Methods Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. Results Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. Conclusions High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

Introduction: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia.Methods: Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests.Results: Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031). There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups.Conclusion: Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.

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The diabetes and obesity epidemics are closely intertwined. International randomized controlled trials demonstrate that, in high-risk individuals, type 2 diabetes can be prevented or at least delayed through lifestyle modification and, to a lesser degree, medication. We explored the relative roles of science, surgery, service delivery, and social policy in preventing diabetes. Although it is clear that there is a role for all, diabetes is a complex problem that demands commitment across a range of government and nongovernment agencies to be effectively controlled. Accordingly, we argue that social policy is the key to achieving and sustaining social and physical environments required to achieve widespread reductions in both the incidence and prevalence of diabetes.

Alcohol consumption is a well-known risk factor for severe hypoglycemia in insulin-treated diabetes. 1 Kerr D. Drugs and alcohol. in: Frier B.M. Fisher B.M. Hypoglycaemia and Diabetes. Edward Arnold, London, United Kingdom1993: 328-336 Google Scholar Studies based on interviews have implicated alcohol use in up to 19% of severe hypoglycemic episodes. 2 Potter J. Clarke P. Gale E.A. et al. Insulin-induced hypoglycaemia in an accident and emergency department The tip of an iceberg?. BMJ. 1982; 285: 1180-1182 Crossref PubMed Scopus (114) Google Scholar , 3 Moses R.G. Hubert P.A. Lewis-Driver D.J. Severe hypoglycaemia. A one-year prospective study in Wollongong. Med J Aust. 1985; 142: 294-296 PubMed Google Scholar , 4 Feher M.D. Grout P. Kennedy A. et al. Hypoglycaemia in an inner-city accident and emergency department A 12-month survey. Arch Emerg Med. 1989; 6: 183-188 Crossref PubMed Scopus (29) Google Scholar , 5 Hart S.P. Frier B.M. Causes, management and morbidity of acute hypoglycaemia in adults requiring hospital admission. QJM. 1998; 91: 505-510 Crossref PubMed Scopus (73) Google Scholar Alcohol may promote the risk of severe hypoglycemia by interfering with cognitive function and self-care, compromising awareness of hypoglycemic symptoms, 6 Kerr D. Macdonald I.A. Heller S.R. Tattersall R.B. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia. 1990; 33: 216-221 Crossref PubMed Scopus (117) Google Scholar and reducing the mobilization of carbohydrates during hypoglycemia. 7 Avogaro A. Beltramello P. Gnudi L. et al. Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients. Evidence for a critical role of free fatty acids. Diabetes. 1993; 42: 1626-1634 Crossref PubMed Google Scholar , 8 Turner B.C. Jenkins E. Kerr D. et al. The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care. 2001; 24: 1888-1893 Crossref PubMed Scopus (145) Google Scholar

BACKGROUND:Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. METHODS:Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. RESULTS:The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. CONCLUSION:Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia.

In their overview of globalisation and the prevention and control of non-communicable disease (Sept 13, p 903),1Beaglehole R Yach D Globalisation and the prevention and control of non-communicable disease: the neglected chronic diseases of adults.Lancet. 2003; 362: 903-908Summary Full Text Full Text PDF PubMed Scopus (363) Google Scholar R Beaglehole and D Yach correctly draw attention to the importance of ischaemic heart disease and cerebrovascular disease. Their tabulations place these as ranking first and second, respectively, in both developed and developing countries. By contrast, diabetes—generally regarded as one of the most serious pandemics affecting all societies today2King H Aubert RE Herman WH Global burden of diabetes 1995–2025: prevalence, numerical estimates and projections.Diabetes Care. 1998; 21: 1414-1431Crossref PubMed Scopus (5109) Google Scholar—ranks ninth as cause of death in developed countries, and does not appear at all in the top ten causes of death in the year 2000 in developing countries. The reason is unfortunately clear from previous publications on reporting bias in death certification. Events tend to be recorded preferentially, whereas underlying causes of such events can often be neglected. Even if underlying causes are recorded, these are sometimes ignored in statistical analysis in favour of event codes. Thus with coding according to the International Classification of Diseases revision 9, myocardial infarction (410) is more likely to be recorded as the underlying cause of death than diabetes mellitus (250), even though the antecedent cause for accelerated atherosclerosis will have been the diabetes. Fuller3Fuller JH Elford J Goldblatt P Adelstein AM Diabetes mortality: new light on an underestimated public health problem.Diabetologial. 1983; 24: 336-341Crossref PubMed Scopus (172) Google Scholar described this deficiency of reportage as early as 1983. The UK Prospective Diabetes Study recorded 981 deaths in a prospective study of median duration 10 years. Of these deaths in the UK, only 42% of the certificates mentioned diabetes overall, and even in the case of cardiovascular death (for which there is a prima facie case for regarding diabetes as antecedent) the mention was made in only 46% of cases. Nor is this bias confined to the UK: estimates from Denmark suggest that only half the diabetes-associated mortality is registered in the national statistics. Does the under-reporting matter? We think it does, because diabetes is treatable and intensive treatment reduces risk.4UKPDS GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Summary Full Text Full Text PDF PubMed Scopus (19345) Google Scholar If governments and health-care providers believe that diabetes does not even rank in the top ten causes of early death, then resources will not be appropriately allocated and the 150 million people with diabetes (rising to 300 million in 2025)5Zimmet P Alberti KG Shaw J Global and social implications of the diabetes epidemic.Nature. 2001; 414: 782-787Crossref PubMed Scopus (4659) Google Scholar will find themselves struggling with a burden of morbidity and mortality that could have been avoided.