Treatment of insulin lipoatrophy with monocomponent insulin

Summary A female diabetic with severe insulininduced lipoatrophy was successfully treated with a monocomponent (MC) Lente preparation. This patient was studied for over 6 years and, during periods of treatment with various insulins of different purity, a variety of reactions was observed in the adipose tissue. Evidence is presented that lipoatrophy may be caused by insulin impurities. Lipoatrophy occurring after treatment with recrystallized, mixed species Lente insulin was substantially reduced after treatment with 10 times recrystallized porcine Lente, but recurred on 4 times recrystallized beef Lente, also in areas where beef Lente was not injected. Beef insulin impurities seem more prone to produce lipoatrophy than pork insulin impurities. It is suggested that MC-insulin is the treatment of choice for this condition.     

胰岛素的糖基化作用及其与胰岛素抵抗的关系

人胰岛素在体外与不同浓度葡萄糖溶液孵育，利用氯化硝基四唑氮蓝还原反应证实胰岛素能被糖基化；利用抗胰岛素抗体分离３３例Ⅱ型糖尿病患者血清胰岛素，比色测定糖基化胰岛素水平。结果表明：糖尿病患者糖基化胰岛素水平显著升高，且与血糖呈显著正相关，与空腹血胰岛素／血糖比值和糖负荷后曲线下胰岛素／血糖面积比值呈显著负相关。说明糖基化胰岛素水平取决于血糖控制状况。且可能参与胰岛素抵抗的形成。     

Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy

PURPOSE: To compare the effects of prandial insulin therapy focusing on postprandial glucose control vs. basal insulin therapy focusing on fasting glucose control in patients with type 2 diabetes. METHODS: This was an open-label, randomized, parallel, three-arm multicenter trial in patients with type 2 diabetes starting insulin treatment. Patients (n=159) were randomly assigned to 24-week treatment with 3x daily insulin lispro, 3x daily lispro mid mixture (MidMix; 50% lispro, 50% protaminated lispro), or 1x daily insulin glargine; oral antihyperglycemic agents were discontinued. Primary end point was the postprandial glucose excursion 2 h after breakfast at the end of study. Secondary outcomes included HbA1c, self-monitored blood glucose profiles, hypoglycemic episodes, body weight, and patient satisfaction. RESULTS: At the end of study, glucose excursions 2 h after breakfast were significantly lower with lispro and MidMix than with glargine (P<.001 for each vs. glargine): lispro, -0.6+/-2.0 mmol/l; MidMix, +0.8+/-2.4 mmol/l; glargine, +2.5+/-2.4 mmol/l. Fasting glucose decreases were significantly greater with glargine (-2.6+/-2.4 mmol/l) than with lispro or MidMix (-0.9+/-2.2 mmol/l; +0.9+/-1.8 mmol/l). Nevertheless, HbA1c decreased by 1.1% (lispro) and 1.2% (MidMix), vs. 0.3% with glargine. Hypoglycemic episodes were rare with 1-1.5 self-reported episodes per 100 patient-days. CONCLUSIONS: In patients with type 2 diabetes starting insulin, 3x daily prandial treatment with a rapid-acting analog focusing on postprandial glucose values enabled better control of postprandial and circadian blood glucose profiles than once-daily glargine, in spite suboptimal fasting glucose levels, which targets fasting glucose values. These results support studies suggesting that control of postprandial hyperglycemia plays a key role in achieving HbA1c targets.     

Severe insulin allergy successfully treated with continuous subcutaneous insulin infusion

Cervical necrotizing fasciitis and a descending mediastinal abscess of the neck following acute epiglottitis, life-threatening complications, is reported in a 43-year-old man with DM. The bacterial culture showed Peptostreptococcus anaerobius. The patient recovered after surgical debridement and broad-spectrum antibiotics therapy.     

Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling

Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance.     

The renal metabolism of insulin: urinary insulin excretion in patients with mutant insulin syndrome (insulin Wakayama)

Many studies have shown that the kidney plays an important role in the metabolism of many proteins and small peptides. To understand insulin handling in the kidney, we examined urinary insulin excretion under several conditions in patients with mutant insulin syndrome (MIS; insulin Wakayama). Urinary excretion of insulin was studied using high-performance liquid chromatography analysis in patients with MIS. In these patients, most of the insulin extracted from a 24-hour urine collection and from urine collected after stimulation of insulin secretion by glucose or glucagon was normal insulin, whereas 90% of serum insulin is structurally abnormal (Leu-A3 insulin). On the other hand, arginine, which is known as an inhibitor of renal tubular reabsorption, increased urinary excretion of Leu-A3 insulin. The ratio of Leu-A3 and normal insulin in urine after arginine was similar to that in serum. A large amount of Leu-A3 insulin is excreted in urine when reabsorption of insulin at renal tubules is inhibited by arginine. These data indicate that normal and Leu-A3 insulin are filtered through the glomerulus with relatively little restriction. Using the fact that basal urine has a high concentration of normal insulin and an extremely low concentration of Leu-A3 insulin, which has less receptor-binding affinity, we speculated some possibilities. One possibility is that both forms of insulin are reabsorbed by the tubular cells, but with different efficiencies. Leu-A3 insulin absorption in more complete, and this suggests differences in the uptake pathways that may account for the differences in response to arginine infusions. Another possibility is that only normal insulin is secreted from tubules into urine which is mediated by receptors. Our results provide new insight into renal metabolism of insulin and showed that MIS is a useful model for studying it.     

谷赖胰岛素或赖脯胰岛素联合甘精胰岛素对糖尿病的有效性及安全性

目的 比较谷赖胰岛素和赖脯胰岛素联合甘精胰岛素对糖尿病的有效性、安全性.方法 本研究为多中心、随机、对照研究,包括4周的导人期和12周的治疗期.2007年2月至2008年6月共人选糖尿病患者484例（1型34例,2型450例）,患者糖化血红蛋白（HbA1c）为6.5％～11.0％,之前已接受连续3个月的胰岛素治疗.按3：1随机给予谷赖胰岛素（363例）或赖脯胰岛素（121例）每日3次联合甘精胰岛素每日1次治疗,比较两组治疗12周后HbA1c、血糖变化及低血糖发生情况和治疗满意度.组间数据比较采用ANOVA方法.结果 治疗12周后,谷赖胰岛素和赖脯胰岛素组HbA1c分别由8.7％±1.2％降至7.9％±1.0％及由8.8％±1.2％降至7.9％±1.0％（组内治疗前后比较,t=- 12.55、-8.88,均P＜0.05）.两组空腹血糖（FPG）分别由（8.6±2.8）mmol/L降至（7.7±2.5）mmol/L及由（8.6±2.5） mmol/L降至（7.8±2.2）mmol/L（组内治疗前后比较,t=-6.55、-2.98,均P＜0.05）.谷赖胰岛素组标准餐后2h血糖（2 h PPG）由（10.6±3.8） mmol/L降至（ 10.2±3.7） mmol/L（t=-2.07,P＜0.05）;赖脯胰岛素组2 h PPG治疗前后差异无统计学意义[由（ 10.9±4.0）mmol/L降至（10.4±3.5） mmol/L,t=-1.37,P＞0.05].治疗12周期间,谷赖胰岛素组和赖脯胰岛素组低血糖事件发生率分别为33.9％ （123/363）和34.7％ （42/121）.治疗前后谷赖胰岛素组和赖脯胰岛素组治疗满意度总评分分别由29±5升至31±5及由29±5升至31±4（组内治疗前后比较,t =6.81、4.21,均P＜0.05）.结论 谷赖胰岛素和赖脯胰岛素联合甘精胰岛素治疗糖尿病的临床疗效、安全性及治疗满意度相似.     

Controlled study comparing treatment with monocomponent insulin and conventional insulin in patients with lipoatrophy

Summary Twenty-one patients with evident lipoatrophy treated with conventional (Conv.) insulin were either allocated to continuation of treatment with previously used insulin (Conv. group, n=10) or were transferred to Lente? MC (monocomponent) insulin with or without supplementary Actrapid? MC insulin (MC group, n=11). On entry and after 3, 6 and 12 months of follow-up, serum insulin-, pancreatic polypeptide- and proinsulin-binding IgGs were determined by radioimmunoelectrophoresis according to the method of Christiansen. Prior to determination of proinsulin-binding IgG, the insulin-binding IgG was removed by means of sepharose-bound insulin according to the method of Heding. In both groups a slight decrease in the titer of insulinbinding IgG was observed: in the Conv. group from 5.33±0.92 (SEM) to 4.66±1.17 mU/ml after 12 months, and in the MC group from 3.22±0.64 to 2.66±0.46 mU/ml, respectively. Due to the small number of patients with pancreatic polypeptide antibody titers above the detection limit no statistical evaluation was carried out. The level of serum proinsulin-binding IgG decreased in the MC group only (from 9.3±2.2 to 1.9±0.6 ng/ml after 12 months), and even showed a slight increase in the Conv. group (the respective titers were: 14.0±4.6 and 14.9±4.6 ng/ml). In the MC group 10 patients (91%) showed improvement and 7 (64%) complete regression of their lipoatrophy corresponding to 6 (60%) and 2 (20%) in the Conv. group. This finding suggests a possible role of proinsulin-binding antibodies in the pathogenesis of insulin lipoatrophy.     

Intensifying insulin therapy with insulin analog premixes: transitioning from basal insulin in type 2 diabetes

Because of the progressive nature of type 2 diabetes, basal insulin alone may not be able to provide sufficient glycemic control over the long term, and thus insulin regimens will typically need to be intensified--especially for controlling postprandial glucose excursions. In patients with type 2 diabetes requiring more intensive intervention, insulin analog premix formulations can offer a simple, effective, and convenient option for tighter management of hyperglycemia in lieu of a traditional basal-bolus regimen.