In the Diabetes Control and Complications Trial (DCCT) intensification of insulin therapy was associated with a threefold increase in the incidence of severe hypoglycaemia when compared to conventional insulin therapy, and there was a strong inverse exponential association between the frequency of severe hypoglycaemia and HbA 1 c levels [1]. This is in accordance with a recent meta-analysis of randomized controlled studies on intensified insulin therapy [2]. However, among the 29 centres participating in the DCCT there was a substantial variation by clinic in the risk of severe hypoglycaemia associated with intensification of insulin therapy (between 0 and 150 episodes per 100 patient-years) despite a narrow range of variation in the median HbA 1 c values (between 6.7 and 7.2 %) [3]. In addition, apart from the DCCT, there are diabetes centres with patients Diabetologia (1997) 40: 926-932 Intensified insulin therapy and the risk of severe hypoglycaemia Summary The objectives of the present analyses were to assess the association between HbA 1 c levels and severe hypoglycaemia (SH, treatment with glucose i. v. or glucagon injection) and to identify predictors of SH in a prospective multicentre trial. The study population consisted of 636 insulin-dependent diabetic patients who had participated in a structured 5-day in-patient group treatment and teaching programme for intensification of insulin therapy (ITTP) in one of 10 hospitals and who were re-examined after 1, 2, 3, and 6 years including assessment of demographic, disease and treatment related parameters, diabetes-related knowledge, behaviour, and emotional coping. At baseline, age (mean ± SD) was 27 ± 7 years, diabetes duration 9 ± 7 years and HbA 1 c 8.3 ± 1.9 %. During the 6-year follow-up, the mean HbA 1 c value improved to 7.6 %, and in patients with a diabetes duration of more than 1 year at entry into the study (n = 538) the incidence of SH decreased from 0.28 cases/patient/year during the year preceding the ITTP to 0.17 cases/patient/year. The patient group was divided into decile groups according to mean follow-up HbA 1 c values. In each group more than 230 patient years could be analysed. Groups with mean HbA 1 c values of 5.7, 7.0, 7.4, 7.7 and 8.9 % had comparable risks of SH (0.15-0.19 cases/ patient/year). In a logistic regression analysis, mean HbA 1 c during follow-up, a history of SH during the year preceding the ITTP, C-peptide level, emotional coping, carrying emergency carbohydrates (as assessed at the 1-year follow-up), and age at onset of diabetes were significant independent predictors of SH. The incidence of SH between centres varied between 0.05 and 0.27 cases/patient/year. In conclusion, in the present analyses no linear or exponential relationship between HbA 1 c and severe hypoglycaemia could be identified by using simple group comparisons. Applying complex regression analyses, various patient-related predictors of severe hypoglycaemia were identified. [Diabetologia (1997) 40: 926-932]
De novo lipogenesis increases after overfeeding with glucose and sucrose to the same extent in lean and obese women but does not contribute greatly to total fat balance.
OBJECTIVE -This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS-In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. CONCLUSIONS -INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes. RESULTS Diabetes Care 28:1077-1082, 2005T he pulmonary delivery of insulin is currently being studied as an alternative method of insulin administration. Early studies have shown promising results, and it has been demonstrated that the onset of action of inhaled insulin is faster than that of regular human insulin (RHI), resembling that of rapid-acting insulin analogs (1-5). RHI has several disadvantages when its use for controlling prandial glycemia is considered. A relatively slow onset of action and a prolonged duration of action results in a suboptimal time-action profile (6). In addition, subcutaneous insulin injections are often considered inconvenient and cause anxiety for many patients (7).Inhaled insulin may be a viable alternative to prandial insulin administration for patients with diabetes because of its more favorable pharmacokinetic profile and less invasive route of administration. However, a direct comparison of the pharmacodynamic properties of INH and subcutaneously injected rapid-acting insulin analogs has not yet been performed. The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of human insulin administered to the lung using a novel drypowder inhaled insulin delivery system with those of subcutaneously injected RHI and the rapid-acting insulin analog insulin lispro (ILP). RESEARCH DESIGN ANDMETHODS -Eighteen healthy, nonsmoking male volunteers (age 28 Ϯ 4 years, BMI 23.6 Ϯ 2.0 kg/m 2 ) participated in this open-label, randomized, three-way, crossover study. Seventeen participants completed the study; one withdrew after receiving his first study treatment (INH) due to an adverse event (sepsis) attributed to the testing procedure and not the study treatment.Subjects gave written informed consent and underwent a physical examinat i o n , 1 2 -l e a d e l e c t r o c a r d i o g r a m recording, and clinical laboratory tests. All subjects had normal lung function (mean forced expiratory volume in 1 s [FEV 1 ] Ͼ80% of predicted normal value; FEV 1 -to-forced vital capacity ratio Ͼ0.80) as measured in a standing position using a Spirovit Baar, Switzerland). Nonsmoking status was verified using a negative urine cotinine excretion test (LCMS method, API 3ϩ; Perkin-Elmer, Weiterstadt, Ger-
There is no evidence that insulin glargine accumulates after multiple injections over 12 days. These results indicate that the predetermined dose of insulin glargine will not need to be reduced after commencing treatment because of a risk of accumulation.
The programme improved glycaemic control mainly as a result of a substantial reduction in the incidence of severe hypoglycaemia. Patients with persistent poor glycaemic control may benefit from structured follow-up care focusing on motivational aspects of self-management and psychosocial support.
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