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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.

Objectives-To study prevalence and incidence of diabetes mellitus in patients with cystic fibrosis.Design-Five year prospective study with annual oral glucose tolerance tests.Setting-CF Center Copenhagen, Denmark. Subjects-191 patients with cystic fibrosis aged above 2 years.Main outcome measures-Glucose tolerance, plasma glucose concentrations after fasting and after glucose loading, and haemoglobin Al, levels.Results-Prevalence of diabetes increased from 11% (n=21) to 24% (n=46) during study, with annual age dependent incidence of 4-9V/.. Diabetes was diagnosed at median age of 21 (range 3-40). At diagnosis of diabetes, symptoms of hyperglycaemia were present in 33% of patients, fasting hyperglycaemia (>7.8 mmol/l) was seen in 16'!%, and increased haemoglobin A,, levels (> 6.4%/6) were seen in 16'/!. Impaired glucose tolerance implied higher risk for development ofdiabetes than normal glucose tolerance (odds ratio 5.6). In 58%1. of cases with impaired glucose tolerance, however, glucose tolerance was normal at next annual test. Normal glucose tolerance was found in only 37%. of patients at all five tests. Within this group of patients, median plasma glucose concentrations after fasting and after glucose loading and haemoglobin Alc levels increased by 6-8"/! during study.Conclusions-Prevalence and incidence of diabetes in cystic fibrosis patients was high and increased with age. Since hyperglycaemic symptoms, fasting hyperglycaemia, and increased levels of glycated haemoglobin did not reliably identify diabetes mellitus, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients aged over 10 years.

The frequency of symptomatic hypoglycaemic episodes was studied in 411 randomly selected conventionally treated Type 1 diabetic out-patients. Between two consecutive visits to the out-patient clinic each patient filled in a questionnaire at home. The number of hypoglycaemic episodes was then recorded prospectively in a diary for 1 week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycaemia were 1.6 and 0.029 episodes patient-1 week-1. From the diaries, the (prospective) frequencies of mild and severe hypoglycaemic episodes were 1.8 and 0.027 patient-1 week-1. Symptomatic hypoglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The symptoms of hypoglycaemia were non-specific, heterogeneous, and weakened with increasing duration of diabetes. During their diabetic life, 36% of the patients had experienced hypoglycaemic coma. The frequency of hypoglycaemia was positively, but only weakly, correlated with insulin dose, number of injections, percentage unmodified insulin of the total dose, and HbA1c (mild hypoglycaemia only). The frequency was also negatively, but weakly, correlated with age and HbA1c (episodes with coma only), but not correlated with sex, duration of diabetes, or patients' ratings of worries about mild and severe hypoglycaemia.

The E23K polymorphism of the pancreatic ␤-cell ATPsensitive K ؉ (K ATP ) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucosetolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P ‫؍‬ 0.022) and serum insulin levels under the response curve during an OGTT (0 -120 min) (P ‫؍‬ 0.014) as well as with an increase in BMI (P ‫؍‬ 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P ‫؍‬ 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n ‫؍‬ 2,824, odds ratio [OR] 1.49, P ‫؍‬ 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.

The impact of pre-diabetes on clinical status was retrospectively studied in 38 cystic fibrosis (CF) patients with diabetes mellitus (DM) and 38 non-diabetic CF patients (control patients), matched in pairs for age, sex, and chronic Pseudomonas aeruginosa lung infection. Quarterly parameters of CF clinical status were collected for 6 years prior to the diagnosis of DM in the index case. Compared to the control patients, decreases in body weight, body mass index (BMI), forced expiratory volume in 1s (FEV1), and forced vital capacity (FVC) and an increase in the daily intake of pancreatic enzyme capsules were found in the pre-diabetic patients. Statistically significant differences in body weight, BMI, FEV1, FVC, and intake of pancreatic enzyme capsules between pre-diabetic and control patients emerged 4, 4, 1.25, 3 and 4.5 years prior to the diagnosis of DM, respectively. The number of lung infections did not differ between the two groups of patients. Thus, when DM develops in CF patients, an insidious decline in overall clinical status is observed for years prior to its diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is presently unknown. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in CF.

People with type 1 diabetes generally remember severe hypoglycaemic episodes during a one-year period. A simple method is proposed for classifying the state of awareness of hypoglycaemia in clinical practice.

OBJECTIVE -In pregnancy with type 1 diabetes, we evaluated occurrence of mild and severe hypoglycemia and analyzed the influence of strict metabolic control, nausea, vomiting, and other potential predictors of occurrence of severe hypoglycemia. RESEARCH DESIGN AND METHODS-A prospective observational study of 108 consecutive pregnant women with type 1 diabetes was conducted. At 8,14,21, 27, and 33 weeks of gestation, patients performed self-monitored plasma glucose (SMPG) (eight/day) for 3 days and completed a questionnaire on nausea, vomiting, hypoglycemia awareness, and history of mild (managed by the patient) and severe (requiring assistance from others) hypoglycemia.RESULTS -Forty-nine (45%) women experienced 178 severe hypoglycemic events, corresponding to 5.3, 2.4, and 0.5 events/patient-year in the first, second, and third trimesters, respectively. The incidence of mild hypoglycemia was 5.5 events/patient-week in early pregnancy and decreased throughout pregnancy (P Ͻ 0.0001), regardless of presence of severe hypoglycemia. Prevalence of nausea and vomiting, mild hypoglycemia, and fraction of SMPG readings Յ3.9 mmol/l did not differ between women with and without severe hypoglycemia. A1C, median SMPG, and fluctuations in SMPG decreased during pregnancy, with no differences between women with and without severe hypoglycemia. Logistic regression analysis identified history of severe hypoglycemia the year preceding pregnancy (odds ratio 3.3 [95% CI 1.2-9.2]) and impaired awareness or unawareness (3.2 [1.2-8.2]) as independent predictors for severe hypoglycemia.CONCLUSIONS -In pregnancy with type 1 diabetes, the incidence of mild and severe hypoglycemia was highest in early pregnancy, although metabolic control was tighter in the last part of pregnancy. Predictors for severe hypoglycemia were history of severe hypoglycemia and impaired awareness. Diabetes Care 31:9-14, 2008P regnancy outcome among women with type 1 diabetes is still significantly poorer than in the background population (1). Optimal glycemic control is crucial in order to reduce the risk of congenital malformations, stillbirth, macrosomia, preeclampsia, and preterm delivery (2-5). However, striving for near normoglycemia increases the risk of severe hypoglycemia (6), which is the major limiting factor for achieving optimal blood glucose control in pregnant women with type 1 diabetes (7).Severe hypoglycemia is three times as frequent in early pregnancy compared with the period before pregnancy (8), and the incidence is highest in gestational week 8 -16 and lower in the second part of pregnancy (7). Traffic accidents (9) and death (10) due to severe hypoglycemia in pregnancy are rare but significant problems. Pregnancy-induced nausea and vomiting have been proposed to be contributing factors for severe hypoglycemia in early pregnancy (7,8). Hypoglycemia unawareness is a major predictor for severe hypoglycemia in nonpregnant patients with type 1 diabetes (11), but its significance during pregnancy in type 1 diabetes is not known. It is not known w...