Chronic continuous intraperitoneal insulin infusion (CIPII) in type I diabetic patients non-satisfactorily responsive to continuous subcutaneous insulin infusion (CSII)

Summary Six unstable C-peptide negative type I diabetic patients who had been previously treated with continuous subcutaneous insulin infusion (CSII) for at least one year without achieving satisfactory metabolic control, were admitted to this study and switched to continuous intraperitoneal insulin infusion (CIPII). The results obtained with the two treatments have been compared from the metabolic and clinical points of view. CIPII produced a decrease in HbA_1c (p<0.05), in MAGE value (p<0.005), in the percentage of blood glucose determinations above 14 mmol/l (p<0.05) and below 3.9 mmol/l (p<0.05); an increase in serum cholesterol, and a decrease in HDL-cholesterol (p<0.05) due to a reduction of the HDL₂ fraction (p<0.01). A mean body weight reduction of 3 kg was observed during CIPII (p<0.01), not related to dietary changes or to a reduction of the daily insulin dose. Twenty-four hour metabolic profiles during CIPII showed lower mean plasma glucose (p<0.001), serum free insulin (p<0.001), blood β-OH-butyrate (p<0.001), and higher serum glycerol (p<0.001) as compared to CSII. It is concluded that CIPII may be of clinical value in the out-patient management of unstable type I diabetic patients, and that metabolic modifications induced by CIPII are not limited to changes in glucose utilization and production, but include changes in triglyceride, cholesterol and lipid metabolism which may have clinical relevance. Supported by the National Research Council (CNR), Target Project ‘Preventive Medicine and Rehabilitation’, Subproject ‘4’ and by the Juvenile Diabetes Foundation, U.S.A., file No. 184066.     

A nationwide study of continuous subcutaneous insulin infusion (CSII) in Denmark.

AIMS: To record the number of patients treated with continuous subcutaneous insulin infusion (CSII), the attitude to CSII treatment among diabetes care providers and the characteristics of pump users in Denmark. METHODS: A questionnaire was mailed to all departments of endocrinology, internal medicine and paediatrics in Denmark (n = 73) to determine the number of diabetic patients treated with CSII and the attitudes of chief consultants to it. All patients using CSII were identified and data from their records collected. RESULTS: Primarily Type 1 diabetic patients (n = 142) were treated with CSII, approx. 0.5% of patients in Denmark. The explanations given for this low frequency varied for non-CSII and CSII-using diabetologists. Both found lack of funding important. In addition, the non-CSII-using group had a perception that CSII was dangerous. The CSII-using diabetologists found that no more patients were interested and that it did not significantly improve metabolic control. The mean age of pump users was 48.1 +/- 10.5 years and the mean time wearing a pump 14.1 +/- 6.3 years. Mean HbA1c was 7.9 +/- 1.2% during CSII, with a significant difference among the 15 centres (P < 0.05) and a tendency to be lower in females (P = 0.07). CONCLUSIONS: CSII is infrequently used in Denmark despite pump users showing reasonably good metabolic control. The most common explanations for these low figures are lack of expertise and funding for CSII. If more patients in Denmark were to be offered pumps, education of healthcare providers would be needed and the funding would have to be clarified.     

Continuous subcutaneous insulin infusion (CSII) and insulin antibodies in rabbits.

Using prepubertal male New Zealand White rabbits, continuous subcutaneous insulin infusion (CSII), delivered by either an external or an implantable infusion device, resulted in significantly higher insulin antibody (I-Ab) production than bolus injection (BII). We tested the influence during CSII of (1) the insulin species, (2) the insulin diluent, (3) the materials of which the infusion devices were made and (4) the incubation of insulin in a syringe on the backs of rabbits ('sham-infusion'), with the following results: (1) beef and sulphated beef insulins produced high levels of I-Abs, while porcine and human insulins produced moderate levels; (2) with all insulins used, 0.9% NaCl and 0.9% NaCl with 24-26 mmol NaHCO3 added, produced high levels of I-Ab. A buffer containing 0.7% NaCl, 0.136% sodium acetate trihydrate and 0.1% methyl-p-hydroxybenzoate and a buffer containing 16 mg/ml glycerol and 2 mg/ml phenol, produced highly significantly lower I-Abs (P less than 0.001); (3) insulin glass syringes produced much lower I-Ab levels than in standard polypropylene syringes and (4) polypropylene syringes in a 'sham-infusion' technique, resulted in intermediate levels of insulin antibodies [(P less than 0.02) vs CSII; (P less than 0.005) vs BII]. Our data suggest that insulin immunogenicity is influenced by all four factors tested. We suggest that benefits of CSII therapy may be attenuated unless a best possible control of these factors is achieved.     

Modern technologies in diabetology. CSII (continuous subcutaneous insulin infusion) and CGM (continuous glucose monitoring) in clinical practice

Modern diabetology is closely associated with the use of modern technologies; glucometres are now widely clinically used and it is difficult to envisage diabetology without these devices. At present, CSII and CGM are less frequently used but they certainly are equally exciting. The author discusses both methods individually as well their interrelationship, mainly from the perspective of their optimal use.     

Continuous subcutaneous insulin infusion (CSII) in children with type 1 diabetes

Recent studies have shown that continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, provides a treatment option that can assist in the attainment of current goals of treatment in children and adolescents with type 1 diabetes (T1DM). In pediatric patients, CSII has been demonstrated to reduce both glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or excessive weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children are reviewed.     

An observational study comparing continuous subcutaneous insulin infusion (CSII) and insulin glargine in children with type 1 diabetes

OBJECTIVE: The advantages of continuous subcutaneous insulin infusion (CSII) or insulin glargine have been demonstrated both in adult and paediatric diabetic patients; however, as no data comparing these two approaches during childhood are available, we have examined the efficacy of these two intensive approaches. RESEARCH DESIGN AND METHODS: We retrospectively evaluated data from 36 diabetic children, who had changed their previous insulin regimen [with isophane insulin (NPH) at bedtime] because of HbA1c levels >8.0%. Twenty patients underwent CSII, while the other 16 (significantly younger for age) started insulin glargine at bedtime. RESULTS: At 6 and 12 months, CSII-treated patients showed a significant reduction in HbA1c values from 8.5 +/- 1.8 to 7.4 +/- 1.1% and to 7.6 +/- 1.2%, respectively. The insulin requirement significantly decreased from 0.93 +/- 0.2 IU/kg to 0.73 +/- 0.2 IU/kg of body weight and to 0.74 +/- 0.15 IU/kg of body weight, respectively, while no significant differences were observed for BMI SDS, fructosamine and severe hypoglycaemic events. The patients treated with glargine showed a small decline in HbA1c values from 8.9 +/- 1.7 to 8.3 +/- 0.9% (not significant) in the first 6 months of treatment and to 8.2 +/- 0.9% after 12 months. CONCLUSION: The basal insulin supplementation can be supplied effectively in children with type 1 diabetes by either CSII or insulin glargine. As previously reported for adults, it is confirmed that CSII is the best current intensive approach aimed to the improvement of glycaemic control.     

Retrospective analysis of daily glucose profile in type 1 diabetic patients with continuous subcutaneous insulin infusion (CSII).

A retrospective analysis of blood glucose control was performed in 17 type 1 diabetic patients who regularly monitored their blood glucose concentration by visual strips over a period of 3-83 months. Analysis was performed by a patient management software loaded on a personal computer. In this cohort of patients the average daily blood glucose reading was 1.6 +/- 0.3. Blood glucose readings were collected more frequently following meal ingestion (40.3%) than in the post-absorptive state (24.6%; P less than 0.05). Blood glucose concentration fluctuated from a basal level of 146 +/- 5 mg/dl to 167 +/- 4 mg/dl in the post-prandial phases with an average daily value of 156 +/- 2 mg/dl. Blood glucose values below 80 mg/dl were evenly distributed throughout the day, while hyperglycemia (greater than 300 mg/dl) occurred more commonly after meals (42%). Daily blood glucose was higher during weekends (164 +/- 5 mg/dl) than during weekdays (155 +/- 2 mg/dl; P less than 0.05). A weak correlation was found between the number of blood glucose readings/day and daily blood glucose level. These results suggest that long-term maintenance of satisfactory metabolic control is attainable in type 1 diabetic patients and that this is mainly dependent upon subject self awareness.     

Influence of continuous subcutaneous insulin infusion (CSII) treatment on diabetic somatic and autonomic neuropathy

Near-normal plasma daily glucose profile was induced by Continuous Subcutaneous Insulin Infusion (CSII) treatment in order to evaluate its influence on diabetic somatic and autonomic neuropathy. Twelve insulin-dependent diabetic subjects with somatic neuropathy were studied before and after a short term CSII treatment of 10 days. Four out of these subjects, all affected by autonomic neuropathy, were followed for 1 yr with controls every four months. Metabolic equilibrium was monitored by mean daily plasma glucose (MPDG) profile and by Glycosylated Hemoglobin (GHb) evaluation. Somatic neuropathy was studied assessing conduction velocity at peroneal motor (PMCV) nerve, ulnar motor (UMCV), ulnar sensory (USCV) and sural sensory (SSCV) nerves. Autonomic neuropathy was assessed by means of a battery of five cardiovascular autonomic tests: Valsalva Manoeuvre (VR), Deep Breathing (DB), Lying-to-Standing (LS), Sustained HandGrip (SHG) and Postural Hypotension (PH). Short-term CSII treatment induced a near normalization of metabolic parameters, a significant improvement in VR (p less than 0.05) and DB (p less than 0.01) values, but no changes in NCV. The prolongation of CSII treatment in 4 subjects induced a significant (p less than 0.05) improvement in VR, DB and LS values and in PMCV and UMCV after 4 months. This improvement did not increase with the longer CSII treatment (1 yr).(ABSTRACT TRUNCATED AT 250 WORDS)     

Position Statement on the management of continuous subcutaneous insulin infusion (CSII): The Italian Lazio experience

This document has been developed by a group of Italian diabetologists with extensive experience in continuous subcutaneous insulin infusion (CSII) therapy to provide indications for the clinical management of CSII in diabetic patients (both type 1 and type 2) based on delivery mode operating in Italy. Although the potential benefits of pump therapy in achieving glycemic goals is now accepted, such results cannot be obtained without specific knowledge and skills being conveyed to patients during ad hoc educational training. To ensure that these new technologies reach their full effectiveness, as demonstrated theoretically and clinically, a careful assessment of the overall therapeutic and educational process is required, in both qualitative and quantitative terms. Therefore, to ensure the cost‐effectiveness of insulin pump therapy and to justify reimbursement of therapy costs by the National Health System in Italy, in this article we present a model for diabetes and healthcare centers to follow that provides for different levels of expertise in the field of CSII therapy. This model will guarantee the provision of excellent care during insulin pump therapies, thus representing the basis for a successful outcome and expansion of this form of insulin treatment in patients with diabetes while also keeping costs under control.     

甘精胰岛素加三餐前短效胰岛素和胰岛素泵短期强化治疗对2型糖尿病疗效比较

目的探讨甘精胰岛素联合三餐前短效胰岛素和胰岛素泵治疗对口服降糖药效果不佳的2型糖尿病的疗效、安全性及性价比。方法60例T2DM患者分为甘精胰岛素注射（甘精组）和胰岛素泵（CSII组）,两组的年龄、BMI、FDP、FPG、2hC-P、2hPG、HbA1C差异无统计学意义（P〉O．05）。结果甘精组和CSII组治疗均有效,FPG、2hPG均较治疗前明显下降,FC-P、2hC-P均较治疗前明显升高（P〈0．05）。两组达到相同血糖水平所需的治疗时间以及低血糖发生率无统计学差异（P〉O．05）,但甘精组的胰岛素用量明显低于CSII组（P〈0．05）。结论甘精胰岛素配合三餐前短效胰岛素能有效模拟人生理胰岛素分泌,有效控制高血糖,且效价比高于胰岛素泵。     

Glucose disposal and intermediary metabolism during one year of continuous subcutaneous insulin infusion (CSII).

To study the effects of CSII on insulin action and intermediary metabolism, seven type 1 diabetic patients (duration 17 +/- 4 (SEM) years), underwent sequential euglycemic clamps 1/4, 6 and 12 months after changing from conventional insulin treatment to continuous subcutaneous insulin infusion (CSII); seven healthy subjects served as controls. For at least 14 h before the study, blood glucose was maintained between 4-10 mmol/l in the patients by intravenous insulin infusion, to avoid negatively biased clamp measures. A metabolite profile was taken in the basal state and during euglycemic hyperinsulinemia. At 1/4 month insulin sensitivity was decreased in the patients (ED50 82 +/- 14 vs 52 +/- 4 mU/l in controls, P less than 0.02), whereas insulin responsiveness was normal. During the course of one year, no change towards control values was found for insulin-stimulated glucose disposal. Concomitantly, HbA1 did not change either, and remained elevated (1/4 month 11.1 +/- 0.7%, 12 months 10.0 +/- 0.9% vs 6.5 +/- 0.3% in controls, P less than 0.01). Regarding basal intermediary metabolism, triglycerides became significantly improved (1/4 month 1.32 +/- 0.13 mmol/l, 12 months 0.70 +/- 0.05 mmol/l, P less than 0.05, vs 0.70 +/- 0.08 mmol/l in controls). The acetoacetate/3-OH-butyric acid ratio increased from 0.10 at 3 to 0.26 at 12 months, which was similar to controls. The absolute levels of acetoacetate and 3-OH-butyric acid remained elevated 2-3 fold. For other basal metabolite levels no systematic trend for improvement was found for 1/4 to 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Continuous subcutaneous insulin infusion (CSII) in inpatient setting: unmet needs and the proposal of a CSII unit

Continuous subcutaneous insulin infusion (CSII) represents an increasingly popular method of treating diabetes. Patients with diabetes are often hospitalized, and current data indicate that inpatient hyperglycemia results in poorer outcomes. When patients on insulin pump therapy require hospitalization, practitioners caring for them face the issue of how to manage the inpatient care of these patients. We believe that patients using insulin pumps can safely have their therapy transitioned when hospitalized. Moreover, CSII during hospitalization should be regarded not only as a fundamental tool in patients already on insulin pump therapy, but also as an effective method to obtain euglycemia, in critically ill patients. However, a standard policy on CSII use during hospitalization is still lacking, and literature data are inconclusive about the benefits of insulin pump on glycemic homeostasis, in hospitalized patients. We suggest that a CSII unit should be activated inside the hospital, in order to increase compliance with required procedures and to properly address the unmet needs of CSII in inpatient setting.     

Exercise in Type 1 (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion

Summary The study was performed to investigate the effects of mild to moderate exercise on blood glucose levels, metabolite concentrations and responses of counterregulatory hormones in tightly controlled Type 1 (insulin-dependent) diabetic patients treated by continuous subcutaneous insulin infusion, and to quantify the measures necessary to prevent acute and late exercise-induced hypoglycaemia. Seven male patients started a 60 min exercise period 90 min after an insulin bolus and a standard breakfast; they were monitored during a post-exercise resting period of 5 h 30 min. Different basal and premeal insulin infusion rates were applied. (Near)normoglycaemia prevailed throughout the study during the control protocol when the subjects did not exercise and received their usual insulin dose. When they exercised without changing the insulin dose, four patients were forced to stop due to hypoglycaemia. This effect of exercise could be attenuated but not completely avoided if the basal infusion rate of insulin was discontinued during the exercise period. The pronounced increase in catecholamine and growth hormone concentrations during exercise were not sufficient to prevent hypoglycaemic reactions. Hypoglycaemia during exercise could only be prevented when the premeal insulin bolus was reduced by 50% in addition to the discontinuation of the basal insulin infusion during exercise. In order to reduce late hypoglycaemic reactions after exercise the best measure proved to be a reduction of the basal insulin infusion rate by 25% during post-exercise hours. Administration of only 50% of the basal insulin infusion rate during this time was associated with blood glucose levels being raised up to 8 mmol/l. In conclusion, Type 1 diabetic patients treated with continuous subcutaneous insulin infusion at (near)normoglycaemia need to reduce their insulin dosage before, during, and after mild to moderate endurance exercise in order to minimize the risk of acute and late hypoglycaemia.     

Variation of insulin absorption during subcutaneous and peritoneal infusion in insulin-dependent diabetic patients with unsatisfactory long-term glycaemic response to continuous subcutaneous insulin infusion.

The aim of present study was to analyse the reproducibility of plasma-free insulin profiles of subcutaneously (CSII) and intraperitoneally (CIPII) administered insulin in 6 C-peptide-negative, type 1, diabetic patients. The patients were selected for CIPII because of unsatisfactory, long-term, metabolic response to CSII. Plasma-free insulin was measured repeatedly, twice during subcutaneous infusion and twice during intraperitoneal infusion, for 4 hours, following a standard breakfast. In the CSII experiment, insulin was given as a meal-dose of 0.1 U per kg body weight, and in the CIPII experiment the meal-dose was 0.05 U per kg body weight. The dose-induced peak occurred earlier after the CIPII than with the CSII (60.0 +/- 8.0 vs 133.6 +/- 16.3 min). In conclusion, the intra-patient coefficient of variation (C.V.) of plasma-free-insulin profiles at 0-60 min and 0.240 min, as well as the peak time, were markedly lower for CIPII insulin than for CSII, indicating a more reproducible way of insulin administration with CIPII in this selected group of patients.     

Pharmacokinetics of continuous subcutaneous insulin infusion

Summary One of the reasons for the variability of blood glucose regulation in Type 1 (insulin-dependent) diabetic patients is the huge variation in subcutaneous absorption of intermediate-acting insulin. We have investigated the variation in insulin absorption during continuous subcutaneous insulin infusion in eight such patients. The content of insulin in the subcutaneous tissue was measured using ¹²⁵I-labelled insulin. The concentration of free serum insulin and blood glucose was followed from 1 h before and from 7 h after breakfast on two consecutive days. The amount of insulin absorbed during 24 h differed in all cases by less than 3% from the daily insulin dose given by the pumps. Mean insulin absorption rates and mean free insulin concentration showed peak values 30–90 min after meal bolus injections; this was sufficient to maintain near-normal blood glucose. Mean free serum insulin correlated strongly with disappearance of insulin from the subcutaneous tissue (r=0.98). From the insulin absorption rates and free insulin concentrations during basal constant insulin infusion, the half-time of serum insulin was calculated as 6 min. Compared with the known large variability in the absorption of intermediate-acting insulin, continuous subcutaneous insulin infusion offers a precise and reproducible way of insulin administration resulting in post-prandial serum insulin peaks sufficient to maintain near-normal blood glucose levels. The half-time of serum insulin during subcutaneous infusion corresponds to values for intravenous infusion given in the literature, indicating that local degradation of insulin in subcutaneous tissue is of minor importance.     

Feasibility of continuous subcutaneous insulin infusion in young diabetic patients

Seven diabetic children (age: 8-12 y.) participated in a study comparing CSII and conventional treatment (CT) under the same monitoring and supervision for a year. The aim of the study was to explore the feasibility, the risks and the results on the glycemic control of CSII. Mean HbAlC fell from 9.3 +/- 2.1% to 7.3 +/- 1.4% (p less than 0.001) after the first month of CSII, remaining stable thereafter and with marginally lower, daily insulin requirements. There was a trend for HbAlc to increase, (HbAlC = 8.6 +/- 1.8%) under conventional treatment. The individual means of premeal capillary blood glucose concentrations were lower under CSII than under CT, but exhibited large variability under both treatments. Symptomatic hypoglycemia was as frequent under CSII as under CT. Ketonuria occurred frequently after the night basal infusion, but was of moderate clinical relevance and mainly due to technical problems. All seven children completed the trial; 4 of them chose to return to pump treatment. No psychologically adverse effects were noted. They all liked the flexibility of lifestyle afforded by CSII, and were generally compliant with the guidelines of this regimen. The pump itself was a valuable educational tool for the children and their families. However, CSII was recognized as individually demanding. This study demonstrates the feasibility of CSII in prepubertal children, and its impact on the glycemic control. The risks of this form of intensified treatment were limited by the strict monitoring and medical supervision provided by a specialized team.