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.     

Sustained good glycaemic control in NIDDM patients by implementation of structured care in general practice: 2-year follow-up study

Summary In primary care it is difficult to treat the growing number of non-insulin-dependent diabetic (NIDDM) patients according to (inter)national guidelines. A prospective, controlled cohort study was designed to assess the intermediate term (2 years) effect of structured NIDDM care in general practice with and without ’diabetes service' support on glycaemic control, cardiovascular risk factors, general well-being and treatment satisfaction. The ’diabetes service', supervised by a diabetologist, included a patient registration system, consultation facilities of a dietitian and diabetes nurse educator, and protocolized blood glucose lowering therapy advice which included home blood glucose monitoring and insulin therapy. In the study group (SG; 22 general practices), 350 known NIDDM patients over 40 years of age (206 women; mean age 65.3 ± SD 11.9; diabetes duration 5.9 ± 5.4 years) were followed for 2 years. The control group (CG; 6 general practices) consisted of 68 patients (28 women; age 64.6 ± 10.3; diabetes duration 6.3 ± 6.4 years). Mean HbA_{1 c} (reference 4.3–6.1 %) fell from 7.4 to 7.0 % in SG and rose from 7.4 to 7.6 % in CG during follow-up (p = 0.004). The percentage of patients with poor control (HbA_{1 c} > 8.5 %) shifted from 21.4 to 11.7 % in SG, but from 23.5 to 27.9 % in CG (p = 0.008). Good control (HbA_{1 c} < 7.0 %) was achieved in 54.3 % (SG; at entry 43.4 %) and 44.1 % (CG; at entry 54.4 %) (p = 0.013). Insulin therapy was started in 29.7 % (SG) and 8.8 % (CG) of the patients (p = 0.000) with low risk of severe hypoglycaemia (0.019/patient year). Mean levels of total and HDL-cholesterol (SG), triglycerides (SG) and diastolic blood pressure (SG + CG) and the percentage of smokers (SG) declined significantly, but the prevalence of these risk factors remained high. General well-being (SG) did not change during intensified therapy. Treatment satisfaction (SG) tended to improve. Implementation of structured care, including education and therapeutic advice, results in sustained good glycaemic control in the majority of NIDDM patients in primary care, with low risk of hypoglycaemia. Lowering cardiovascular risk requires more than reporting results and referral to guidelines. [Diabetologia (1997) 40: 1334–1340] Received: 5 February 1997 and in revised form: 22 May 1997     

胰岛素泵治疗与2型糖尿病第一时相分泌的研究进展

随着对糖尿病机理研究的深入，发现胰岛β细胞第一时相分泌，对糖尿病的发生、发展有重要影响，新诊断2型糖尿病患者早期予胰岛素泵治疗，模拟生理性胰岛素分泌方式，可改善第一时相分泌，促进胰岛β细胞功能的修复，利于糖尿病的治疗及预后。     

Synthesis of JTT‐501 and its metabolite JTP‐20604 labelled with 13C

JTT‐501 specifically labelled with ¹³C was obtained via a four‐step synthesis at an isotopic enrichment level of 99% and in 14% overall chemical yield starting from 4‐hydroxy‐[ring‐U‐¹³C₆]benzaldehyde (3) . The hydrogenation of [¹³C₆]JTT‐501 over Pd/C gave [¹³C₆]JTP‐20604 in 90% chemical yield. Copyright © 2003 John Wiley & Sons, Ltd.     

胰岛素抵抗与高血压病冠心病糖尿病的关系

目的探讨中老年人高血压、冠心病、糖尿病胰岛素抵抗的状况及相关因素。方法按中老年高血压病、冠心病、糖尿病、高血压合并冠心病等类别分组、并设对照组，计体重指数、测血脂、血糖、胰岛素及胰岛素抗体浓度，并根据血糖、血胰岛素浓度计算胰岛素敏感性．结果胰岛素抵抗在冠心病、高血压病、高血压合并冠心病及糖尿病中依次递增．设对照组胰岛素相对敏感性为１，则上述各病分别为０８３、０．７９、０６１、０．３２．与之相伴随的是糖及脂质代谢紊乱及体重指数的增加。结论高血压、冠心病、糖尿病多存在胰岛素抵抗，并可能是心血管疾病的危险因子。     

The Effect of Acute and Chronic Exercise on Thyroid Hormones in Obesity

Abstract Thyroid hormones were measured before, during and after acute exercise (60 min) or physical training (3 months) in obese women. Thyroid stimulating hormone concentration increased during acute work and decreased immediately after. No changes were seen during the two following days. An increase was seen after ten days as well as after three months of physical training. Thyroxine concentrations showed no changes. 3,5,3′-Triiodothyronine decreased slightly immediately after acute exercise, and after three months of physical training, 3,3′,5′-triiodothyronine (reverse triiodothyronine) increased slowly during and after acute exercise. A negative correlation was found between changes in fasting insulin and thyroxine and a positive correlation between changes in blood pressure and triiodothyronine after training. Lack of agreement in previous reports is probably due to methodological differences such as methods more or less susceptible to fatty acid interference, and thyroid hormones changing differently during acute work and before and after physical training. The duration of the study may also be of importance, even 3 months possibly being too short for attaining equilibrium in thyroid homeostasis.     

Microalbuminuria and nerve conduction velocity in type-I diabetics during conventional therapy and during continuous I.V. insulin infusion

Summary The objective of this study was to follow the development of microalbuminuria and nerve conduction velocity under continuous i.v. insulin therapy over a limited period of 4 months. For this purpose, 8 labile type I diabetics were selected (age 33±8 years, duration of diabetes 16±9 years) and treated conventionally with two insulin injections daily over 4 months. Afterwards, the same patients were treated with continuous i.v. insulin infusion and finally again with two injections daily over 4 months each. This procedure allowed each diabetic to serve as his own control. HbA₁, microalbuminuria, nerve conduction velocity and relative refractory period of the ulnar nerve were checked at montly intervals. During the continuous i.v. infusion over 4 months, blood sugar values were significantly lower, glucosuria had disappeared almost completely and the glycosylated hemoglobin had fallen to near normal values. The mean rate of albumin excretion was 16±5 μg/min at rest and 76±26 μg/min during exercise (normal: 3.9±0.4 and 4.8±1.2 μg/min, respectively) and did not change significantly. Nerve conduction velocity in the ulnar nerve rose significantly under i.v. insulin therapy from 47.9±0.6 m/sec to 52±0.6 m/sec. Similarly, the relative refractory period of the same nerve fell significantly from 3.7±0.2 to 1.9±0.1 msec (i.e. to within normal range). It is concluded that functional disturbances of peripheral nerve can regress by improved blood sugar control with continuous i.v. insulin infusion over 4 months. On the other hand, incipient microangiopathy measured as microalbuminuria remains unchanged over the same period of time. If an improvement is at all possible, considerably longer periods of euglycemia are likely to be necessary. Supported by Grant No. 3.964-0.80 from the Swiss National Science Foundation.     

Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response

BACKGROUND: The role of inflammation in the pathogenesis of cardiovascular disease is well established. C-reactive protein (CRP) is the strongest independent predictor of myocardial infarction and stroke in women. Recent studies have indicated that CRP levels are raised during use of combined oral contraceptives (COCs). OBJECTIVES: The aim of the study was to investigate the effect of COCs on serum CRP levels and to indicate the underlying mechanisms of an expected increase. METHOD: In a prospective randomized cross over-study 35 women used two different preparations of COC, one second and one third generation. Serum levels of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), antibodies against oxidized LDL, insulin and insulin-like growth factor-I (IGF-I) along with insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 were analyzed before and during the two treatments. E-selectin, von Willebrand factor and factor VIII concentrations in plasma were also measured. RESULTS: A rise in serum CRP was observed during both treatments; the median level increased from 0.45 mg L(-1) at baseline to 1.48 mg L(-1) with second generation and to 2.02 mg L(-1) with third generation COC. The serum levels of SAA increased slightly during treatment with the third generation COC. IL-6 and TNFalpha were unaffected by treatment. Both preparations lowered IGF-I and raised IGFBP-1 and IGFBP-3 concentrations. CONCLUSION: The raised serum CRP concentration during treatment with COCs appears to be related to a direct effect on hepatocyte CRP synthesis and does not reflect IL-6 mediated inflammation, endothelial activation or induction of insulin resistance.     

大鼠颅脑外伤后胰岛素与胰岛素受体的变化

目的：探讨颅脑外伤不同伤情与伤后不同时间胰岛素和胰岛素受体结合率的变化规律。方法：雄性ＳＤ大鼠８０只，随机分为轻、中、重型颅脑伤及对照组４组，液压致伤。分别在伤后６，２４，７２ｈ处死动物，测定血液中胰岛素和红细胞膜上胰岛素受体的变化。结果：轻型和中型脑伤组红细胞胰岛素受体结合率均升高，但在重型颅脑伤大鼠，胰岛素受体结合率反而显著下降。全部颅脑伤大鼠的血液红细胞胰岛素受体结合率，在伤后６和２４ｈ均非     

白内障伴青光眼患者术后胰岛素抵抗及炎症因子水平与视觉质量的关系

目的分析白内障伴青光眼患者术后胰岛素抵抗及炎症因子水平变化与视觉质量的关系。 方法选取47例(47眼)白内障伴青光眼患者为研究对象,均接受超声乳化+小梁切除术治疗。术前、术后7天、术后3个月检测患者客观散射指数(OSI)、点扩散函数(PSF)、调制传递函数截止频率(MTF cutoff)、胰岛素敏感指数及白细胞介素(IL)-1β、IL-10、IL-2水平。采用Pearson法分析视觉质量参数与胰岛素抵抗情况及炎症因子的相关性。 结果与术前比较,术后7天和术后3个月最佳校正视力、MTF cutoff及胰岛素敏感指数升高,且术后3个月更高(P＜0.05);与术前比较,术后7天和术后3个月眼压、角膜内皮细胞计数、PSF、OSI及血清IL-1β、IL-2、IL-10水平降低,且术后3个月更低(P＜0.05)。Pearson分析显示,术前、术后7天和术后3个月,白内障伴青光眼患者OSI与胰岛素敏感指数呈负相关(P＜0.05),与血清IL-1β、IL-2、IL-10水平呈正相关(P＜0.05);MTF cutoff与胰岛素敏感指数呈正相关(P＜0.05),与血清IL-1β、IL-2、IL-10水平呈负相关(P＜0.05);PSF与血清IL-1β水平呈负相关(P＜0.05)。术后7天和3个月,PSF与胰岛素敏感指数呈正相关(P＜0.05),与血清IL-2、IL-10水平呈负相关(P＜0.05)。 结论超声乳化联合小梁切除术对视觉质量的改善可能与胰岛素抵抗及炎症因子变化密切相关。