Nocturnal hypoglycaemia in Type 1 diabetic patients,assessed with continuous glucose monitoring: frequency,duration and associations

Aims We quantified the occurrence and duration of nocturnal hypoglycaemia in individuals with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) or multiple‐injection therapy (MIT) using a continuous subcutaneous glucose sensor. Methods A microdialysis sensor was worn at home by 24 patients on CSII (mean HbA_1c 7.8 ± 0.9%) and 33 patients on MIT (HbA_1c 8.7 ± 1.3%) for 48 h. Occurrence and duration of nocturnal hypoglycaemia were assessed and using multivariate regression analysis, the association between HbA_1c, diabetes duration, treatment type (CSII vs. MIT), fasting and bedtime blood glucose values, total daily insulin dose and mean nocturnal glucose concentrations, and hypoglycaemia occurrence and duration was investigated. Results Nocturnal hypoglycaemia ≤ 3.9 mmol/l occurred in 33.3% of both the CSII‐ (8/24) and MIT‐treated patients (11/33). Mean (± sd ; median, interquartile range) duration of hypoglycaemia ≤ 3.9 mmol/l was 78 (± 76; 57, 23–120) min per night for the CSII‐ and 98 (± 80; 81, 32–158) min per night for the MIT‐treated group. Multivariate regression analysis showed that bedtime glucose value had the strongest association with the occurrence (P = 0.026) and duration (P = 0.032) of nocturnal hypoglycaemia. Conclusions Microdialysis continuous glucose monitoring has enabled more precise quantification of nocturnal hypoglycaemia occurrence and duration in Type 1 diabetic patients. Occurrence and duration of nocturnal hypoglycaemia were mainly associated with bedtime glucose value.     

危重病患者血浆胰岛素水平与细胞因子含量的关系

目的探讨危重病患者是否存在高胰岛素血症、胰岛素抵抗(IR)及与肿瘤坏死因子(TNF-α)、白细胞介素-6(IL-6)的关系.方法测定危重病患者123例和对照组30例的空腹血糖(FBG)、空腹胰岛素(FINS)、TNF-α、IL-6的水平,并计算胰岛素敏感性指数(IAI),以评估危重病患者IR的严重程度,并分析各参数之间的相关性.结果危重病组与对照组的IAi分别为-1.95±0.38和-1.5±0.29,两者差异显著(P＜0.01).危重病按病因分组后各组IAI相比无显著差异(P＞0.05).IAI与危重病严重程度、TNF-α及IL-6的直线回归分析,直线关系r分别为0.86,-0.89,-0.87,差异有显著性(P＜0.01).结论危重病患者存在高胰岛素血症及IR.IR的程度与危重病程度、TNF-α、IL-6的水平有显著相关性.危重病患者的IR与TNF-α的升高有关,提示IAI可作为危重病患者病情严重程度的预测指标.     

Efficacy of continuous subcutaneous insulin infusion in Type 1 diabetes: a 2-year perspective using the established criteria for funding from a National Health Service.

AIM: To determine the 2-year efficacy of continuous subcutaneous insulin infusion (CSII) following the current established criteria for funding of a National Health Service. METHODS: Longitudinal, prospective, observational unicentre study. Included in the study were 153 Type 1 diabetes (T1D) subjects, previously treated with multiple daily injections (MDI) of insulin, in whom CSII was started in accordance with the criteria for reimbursement of the Catalan National Health Service. At baseline, we recorded data on age, gender, duration of the disease, body mass index (BMI), insulin dose and indications for CSII. Glycated haemoglobin (HbA(1c)) and the frequency of hypoglycaemic events were used to assess glycaemic control. Quality of life was assessed using three different self-report questionnaires. After 24 months, these same items were remeasured in all subjects. Serious adverse events and injection-site complications were also recorded. RESULTS: In 96% of subjects, CSII indication included less than optimal glycaemic control using MDI. HbA(1c) fell from 7.9 +/- 1.3 to 7.3 +/- 1.1% (P < or = 0.001) after 24 months of CSII. Insulin requirements were significantly lower at the end of follow-up (0.55 +/- 0.21 U/kg body weight) in comparison with before use of CSII (0.70 +/- 0.20, P < or = 0.001). BMI increased from 24.0 +/- 3.1 to 24.4 +/- 3.2 kg/m(2) after 24 months (P < or = 0.025). The rate of episodes of diabetic ketoacidosis per year remained unchanged. Mild and severe hypoglycaemic episodes were significantly reduced. The scores in all subsets of the Diabetes Quality-of-Life (DQoL) questionnaire significantly improved after 24 months of CSII. CONCLUSIONS: CSII, commenced according to the criteria for a nationally funded clinical programme, improves glycaemic control and quality-of-life outcomes with fewer hypoglycaemic episodes in T1D subjects previously conventionally treated with MDI.     

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.     

胰岛素对糖尿病大鼠阴茎内nNOS神经纤维的影响

目的探讨糖尿病性阴茎勃起功能障碍（ED）的发病机制及胰岛素的治疗作用。方法注射链脲佐菌素建立糖尿病（DM）大鼠模型，胰岛素治疗组于成模后注射胰岛素。7周和12周后注射阿扑吗啡（APO）进行大鼠阴茎勃起功能实验，取大鼠阴茎和血浆，用ABC免疫组织化学法观察nNOS神经纤维的变化。测定血浆NOS活性。结果（1）与对照组相比，DM组大鼠阴茎勃起次数明显减少;胰岛素治疗后症状缓解;（2）与对照组相比，DM组血浆NOS活性明显增高;DM组血浆NOS活性与病程延长呈负相关;与DM组比较，胰岛素治疗组血浆NOS活性明显降低;（3）与对照组相比，DM组阴茎内nNOS阳性神经纤维明显减少;与DM组比较，胰岛素治疗组nNOS阳性神经纤维表达增加。结论糖尿病性ED阴茎内nNOS阳性纤维的数量及光密度随DM病程的延长而下降;早期给予胰岛素治疗可预防糖尿病大鼠ED的出现及阴茎内nNOS含量的下降。     

甘糖酯和胰岛素对体外孵育红细胞变形性的影响

目的：观察甘糖酯及胰岛素对体外孵育红细胞变形性（ＥＤ）的影响。方法：对１２例ＩＩ型糖尿病（ＮＩＤＤＭ）病人（男性６例，女性６例，年龄６０±ｓ１０ａ）取血观察其ＥＤ，并与正常人比较。将红细胞分别与甘糖酯和胰岛素共同孵育２４ｈ观察ＥＤ变化。结果：病人的ＥＤ明显低于正常人。孵育２４ｈ后，ＥＤ进一步降低。但与甘糖酯孵育后ＥＤ较孵育前改善。与胰岛素共同孵育后，ＥＤ较孵育前降低，但较不加药物孵育者降低程度小。结论：甘糖酯在体外可使ＮＩＤＤＭ病人ＥＤ改善。胰岛素的作用较弱。     

胰岛素对数种缩血管物质作用的影响

目的 观察胰岛素对去甲肾上腺素、内皮素-１、氯化钾（ＫＣＩ）、血管紧张素Ⅱ和５－羟色胺缩血管作用的影响。方法 用ＳＤ大鼠的离体动脉血管观察缩血管物质的作用。结果 在含有１ｍＵ／ｍｌ胰岛素环境中，胰岛素对数种缩血管作用机制不同的物质有程度不同的血管增敏作用。对去甲肾上腺素、内皮素－１和ＫＣＩ有明显的增敏效果；对血管紧张素Ⅱ有增敏趋势，但无显著性差异；对5－羟色胺无增敏效应。结论 胰岛素在高血压的发病过程中可能起重要作用。     

Reversible Adsorption of Soluble Hexameric Insulin onto the Surface of Insulin Crystals Cocrystallized with Protamine: An Electrostatic Interaction

Mixing pharmaceutical preparations of soluble neutral regular insulin solution (NRI) and neutral protamine Hagedorn (NPH) crystalline insulin suspension leads to a reduction in the measurable amount of soluble insulin in the formulation supernatant. However in spite of the loss in soluble insulin, the time-actions of these components have been shown, in clinical trials, to be unaffected. The interaction between these different physical forms of insulin has been studied using reversed-phase HPLC, isothermal titrating calorimetry, and Doppler electrophoretic light scattering analysis. Sorbent surface and solution perturbation studies revealed that the NRI adsorbs to the surface of the NPH crystal with an equilibrium constant ranging from 10⁴ M^–1 to 10⁷ M^–!, depending on the protamine concentration, pH, ionic strength, and temperature. This adsorption behavior suggests that the binding is mediated by electrostatic interactions arising between the positively-charged NPH crystal and the negatively-charged NRI hexamer. Doppler electrophoretic light scattering results, used to probe the pH-dependent surface charge of NPH and soluble insulin hexamer, support the conclusion that electrostatic interactions mediate the adsorption process. Adsorption studies under physiological conditions indicate that the elevated temperature and ionic strength, in a subcutaneous depot, are sufficient to lead to the dissociation of the NRI/NPH complex that exists in these NPH mixture formulations.     

Suppression of the nocturnal free fatty acid levels by bedtime cornstarch in NIDDM subjects

The aim of the present study was to examine the effects of a large dose of slow-release carbohydrates (CHOs) at bedtime on the nocturnal glucose, insulin and free fatty acid (FFA) levels, and to assess the putative effects on morning fasting and post-prandial glucose levels in patients with moderately controlled non-insulin-dependent diabetes mellitus (NIDDM). Unheated cornstarch (106 g of CHO) or a mixed equicaloric meal (58 g of CHO) was given at 22.00 hours to 10 NIDDM patients. For comparison, the patients were also given a smaller mixed meal at 22.00 hours on a third occasion (17 g of CHO). Compared with the mixed meals, cornstarch led to a slightly elevated early-morning plasma insulin level and a suppression of the nocturnal FFA level ( P  < 0.05), as well as to a reduced incremental glucose level (IAUC) after breakfast the next morning by approximately 30% ( P  < 0.05). There was a significant and linear relationship between the nocturnal FFA level and the glucose IAUC after breakfast ( r  = 0.44, P  < 0.02), indicating that the effect may have been mediated by the suppressive effect of cornstarch on nocturnal lipolysis. In summary, bedtime intake of unheated cornstarch in NIDDM subjects is associated with a suppression of the nocturnal FFA levels and a reduced glucose IAUC after breakfast. As the treatment did not improve overall glucose control, studies of the effects of an individually titrated amount of cornstarch are proposed to further explore the putative favourable effects of bedtime cornstarch in the treatment of NIDDM.