The programmable implantable medication system (PIMS): design features and pre-clinical trials

This report describes the clinically significant design features of a variable rate implantable insulin infusion pump, the Programmable Implantable Medication System (PIMS), and its function in pre-clinical trials. PIMS has a number of unique features, including a solenoid, pulsatile pump design requiring minimal power (less than 15 microwatts) and a less-than-atmospheric pressure reservoir. Two-way communication is accomplished by radiotelemetry. The implanted device stores programs, and records its own hourly history of insulin delivery. Limits are set on total insulin delivery over time. Basal rates are adjustable, and patterned prandial insulin delivery curves can be programmed. Initial trials (3.1 dog-years) identified four problems which were corrected prior to final pre-clinical trials: microcracks in the diaphragm, a valve-seating leak, electronic failure of prototype microchips, and insulin aggregation. Sixteen dog-years of final pre-clinical trials with a single system design demonstrated that 5 pumps were still working continuously after up to 3.75 years (mean 3.3 years) without mechanical or electronic pump failure. The longest interval between reservoir refills was 5 months. Remaining potential causes of flow stoppage, however, include blockage of the peritoneal catheter by omentum (which occurred once), and air lock (which occurred two times).     

Factors Associated With Insulin Pump Discontinuation in Adults With Diabetes: A Time-to-Invent Analysis and Prediction Model

ObjectiveInsulin pump discontinuation has mostly been studied in children and adolescents living with diabetes. We aimed to assess the rate of insulin pump continuation in a population of adult patients with diabetes, at 18 months after initiation; determine the factors associated with pump discontinuation; and develop a simple prediction model.MethodsThis single-center, retrospective study included all adult patients with type 1 diabetes or type 2 diabetes who started insulin pump treatment between January 2015 and June 2018. The exclusion criteria were pregnancy, short-term pregnancy plans, and insulin pump discontinuation within the previous 6 months. The probability of insulin pump continuation after 18 months was estimated using the Kaplan-Meier method. Factors associated with insulin pump discontinuation were studied using a Cox regression model, and an exponential model was built for prediction purposes.ResultsThe study included 315 patients. The mean age was 41 years, the mean duration of diabetes was 16 years, 50% were men, 74% had type 1 diabetes, and the mean hemoglobin A1c level was 9.1% (76 mmol/mol). After 18 months, the rate of insulin pump continuation was 0.80 (95% Confidence Interval (CI), 0.76-0.85). By multivariate analysis, the occurrence of severe hypoglycemia in the previous year was associated with insulin pump discontinuation (hazard ratio, 2.42; 95% CI, 1.30-4.51), while other factors did not reach statistical significance.ConclusionInsulin pump discontinuation occurred in 20% of patients at 18 months after initiation and was mainly associated with a recent history of severe hypoglycemia. The type of diabetes and glycemic control at baseline were not associated with treatment discontinuation.     

Management of "brittle" diabetes with a preprogrammable implanted insulin pump delivering intraperitoneal insulin.

OBJECTIVE--Glycaemic control in a young woman with "brittle" diabetes. DESIGN--Use of a preprogrammable fully implanted pump (Infusaid) to deliver insulin intraperitoneally at variable rates, giving a total dose of about 60 units/24 h. SETTING--Endocrinology department in a teaching hospital. PATIENT--Thirty year old woman with 15 years'' history of "brittle" diabetes. MAIN OUTCOME MEASURES--Glycated haemoglobin concentration; plasma glucose concentration. RESULTS--After implantation of the pump there was an immediate and sustained improvement in diabetic control. The patient''s glycated haemoglobin concentration decreased from 15.2% to 9.2% over seven months. Her daily glucose concentrations were in the range 3.5-12 mmol/l. She has not been admitted to hospital since implantation of the pump, which was eight months before the time of writing. CONCLUSION--The implanted programmable intraperitoneal insulin pump may be of value in the management of patients with "brittle" diabetes in whom other attempts at glycaemic control have failed.     

High antigenicity of intraperitoneal insulin infusion via implantable devices: preliminary rat studies.

Intraperitoneal insulin infusion of Genapol stabilized insulin via implantable devices significantly improves diabetes control and hypoglycemia frequency in type 1 diabetes while it increases insulin antibody levels. Causes for this particular antigenicity remain unknown. The role of insulin modifications occurring in the reservoir on the antigenicity observed was assessed by comparing the antigenicities of the insulin coming from the vial or from the pump reservoir. Rats were injected intraperitoneally with insulin sampled either from a vial (group 1) or from a pump reservoir during a refill of a clinical trial (group 2). Two control groups, one without insulin, the second one receiving a mixture of silicone and insulin were also studied. Human insulin antibody levels were assessed by RIA 10 days after 4 weekly immunizations. AIA levels were higher in group 1 compared to group 2 (P = 0.003 for the first experiment, P = 0.04 in the second experiment). The increased antigenicity of the insulin sampled from the implanted pump might be due to the insulin modifications occurring during the storage in the device. Insulin aggregates could be involved in this antigenicity since they are known to be antigenic and their concentration was shown to be related to the amplitude of the antigenic response.     

Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: a comparison study in type 2 diabetes with conventional insulin regimen failure.

OBJECTIVE: To compare the effectiveness of two intensified insulin regimens, i.e., pump delivery versus multiple daily injections in patients with type 2 diabetes not optimally controlled with conventional insulin therapy. RESEARCH DESIGN AND METHODS: Seventeen type 2 diabetes patients uncontrolled by two daily injections of regular plus NPH were randomly assigned in a cross-over fashion to either three daily injections of lispro plus NPH or pump device delivering lispro. HbA1c, 6 points capillary blood glucose, 24-hour continuous glucose monitoring system tracings and global satisfaction score were evaluated at the end of each 12-week treatment period. RESULTS: HbA1c decreased from 9.0+/-1.6% to 8.6+/-1.6% with multiple injections and 7.7+/-0.8% with pump device (p<0.03). Capillary blood glucose was lowered at all time-points with pump, but only at morning with multiple injections (p<0.01). Compared to conventional therapy, pump reduced hyperglycemic area under curve by 73% (p<0.01), but multiple injections by only 32% (p=0.08). Rate of hypoglycemia was not increased and patient's satisfaction was comparable with both intensive treatments. CONCLUSIONS: Pump therapy provides a better metabolic control than injection regimens, and seems to be safe and convenient in patients with type 2 diabetes who fail to respond to conventional insulin therapy.     

Theoretical analysis of the effect of convective flow on solute transport and insulin release in a hollow fiber bioartificial pancreas

The bioartificial pancreas, in which transplanted pancreatic tissue or isolated cells are cultured on a hollow fiber membrane, is an attractive approach to restore physiologic insulin delivery in the treatment of diabetes. Insulin response in prototype devices has been unacceptable due to the large mass transport limitations associated with the membrane and the surrounding shell region. Although available theoretical analyses provide some insight into the combined effects of transport and reaction in the bioartificial pancreas, they cannot quantitatively account for the effects of convective recirculation flow, complex intrinsic insulin secretory kinetics, and non-uniform distribution of pancreatic cells. We have developed a detailed model for glucose and insulin transport and insulin secretion in the hollow fiber bioartificial pancreas based on the solution of the mass and momentum conservation equations describing flow and transport in the lumen, matrix, and shell. Model predictions are in good agreement with literature data obtained in a hollow fiber device with minimal radial convective flow. Although no quantitative data are available for a device with significant radial convection, model simulations demonstrate that convective recirculation flow can dramatically improve insulin response, allowing the device to accurately capture the bi-phasic insulin secretion characteristic of the normal physiologic response. Results provide fundamental insights into the coupling between kinetics and transport in the hollow fiber system and a rational basis for the design of clinical devices.     

Selection for and initiation of continuous subcutaneous insulin infusion. Proceedings from a workshop

Continuous subcutaneous insulin infusion (CSII) has been used in the paediatric age group for more than 20 years. The technique is not yet widely used in most countries but there has recently been increasing interest in pump therapy for young children and adolescents. In 1999, 7.5% of Swedish children and adolescents with diabetes used pumps, now the figure is approaching 12%. The indication for starting pump therapy has usually been a medical problem, but today quality of life issues are becoming increasingly important. One technique sometimes used is to start CSII by wearing the pump only at night. Daily insulin requirements are usually decreased compared with injection therapy. Studies have shown that it is possible to lower HbA1c when using an insulin pump and that the risk of severe hypoglycaemia can be lowered. The use of CSII has also been successful in preventing recurrent admission for diabetic ketoacidosis. While starting pump therapy does take an extra effort from both the diabetes team and the family, routine visits are generally no more time-consuming than for patients on multiple injection therapy. CSII can be initiated during admission to hospital but most pumps are started on an outpatient basis. Our department has the patients on the day care ward for 3-4 days of 'pump school'. Parents wear a saline pump for practice. The total daily insulin dose is usually lowered 15-20% compared with multiple injections; on average 40-50% (sometimes up to 60%) of the daily dose is given as basal rate. We start all pumps on rapid-acting analogues and use 40 IU/ml if the basal rate is <0.3 IU/h. In conclusion, the use of CSII in children and adolescents is well accepted and can be managed safely.     

A diaphragm delivery device for flow microcalorimetry

A diaphragm delivery device is described which allows delivery of a reagent to a flow system at a constant or variable flow rate. The device presents only a Teflon surface to the reagent and avoids direct contact with the pump. This delivery system is used to cireumvent the serious problem of reagent interaction with the working parts of pumps used in flow microcalorimetry while retaining the convenience of switching from one solution to another. The reaction of α-chymotrypsin with the nonspecific substrate 3-(2-furyl)-acryloylimidazole is used to illustrate the advantages of the diaphragm delivery device.     

Technological problems of miniaturized insulin dosing devices and some approaches to clinical trials.

With the long-term goal of developing implantable insulin dosing devices, we have since 1971 developed various types of programme-controlled units for clinical research. In the initial stage, a 24-hour, fixed-programme bed-side device has been in clinical use since 1973. The good results with even labile diabetics has supplied the basis for the further development of sensorless units. Via intermediate stages, two types of miniaturized portable devices were constructed: fixed-programme and demand-programme devices. The essential equipment components have been optimized with a view to later implantability: hermetically sealed capsule for the dosing device, refilling membrane for the insulin reservoir, bubble-free drawing off of the insulin via a wick from a collapsible silicone reservoir, the stepping motor-driven roller pump of approx. 9 cm3 volume, an energy consumption of about 50 mu W, and electronic safety and alarm circuits. Because of stability problems of the insulin, the neutral insulin U-1000 used initially was changed to acid insulin U-100 (both from Hoechst).     

Clinical Efficacy and Patient Satisfaction with U-500 Insulin Pump Therapy in Patients with Type 2 Diabetes

ObjectiveTo determine the safety and efficacy of U-500 regular insulin in pump therapy and to assess satisfaction with U-500 insulin pump therapy in patients with type 2 diabetes and severe insulin resistance.MethodsWe performed a retrospective review of medical records of 6 patients with type 2 diabetes and insulin resistance who had been using U-500 insulin pump therapy for at least 6 months. In addition, we conducted a telephone follow-up patient satisfaction survey.ResultsThe mean age of the patients was 57 ± 6 years. Of the 6 patients (3 men and 3 women), 4 were white, 1 was black, and 1 was Asian. The mean hemoglobin A1c value before continuous subcutaneous insulin infusion therapy with U-500 regular insulin was 9.1% ± 1.8%, and the mean U-100 insulin dose required was 391 ± 91 U/day. In comparison, the mean U-500 insulin dose required at 6 months was 59.2 ± 13.6 U/day, which is equivalent to 296 ± 68 U/day of U-100 insulin (P = 0.04), and the mean hemoglobin A1c value at 6 months after treatment with the insulin pump using U-500 regular insulin was 6.9% ± 0.9% (P = 0.03). In addition, our study patients lost a mean of 6.1 lb during the 6-month period, and no patient had clinically significant episodes of hypoglycemia. The majority of the patients reported a higher satisfaction with the U-500 insulin pump therapy in comparison with conventional insulin treatment.ConclusionU-500 insulin pump therapy is a novel alternative for patients with type 2 diabetes and severe insulin resistance who have not met glycemic control goals with use of standard intensive insulin regimens. (Endocr Pract. 2007;13:721-725)     

Proteomic Changes to the Updated Discovery of Engineered Insulin and Its Analogs: Pros and Cons

The destruction of β-cells of the pancreas leads to either insulin shortage or the complete absence of insulin, which in turn causes diabetes Mellitus. For treating diabetes, many trials have been conducted since the 19th century until now. In ancient times, insulin from an animal’s extract was taken to treat human beings. However, this resulted in some serious allergic reactions. Therefore, scientists and researchers have tried their best to find alternative ways for managing diabetes with progressive advancements in biotechnology. However, a lot of research trials have been conducted, and they discovered more progressed strategies and approaches to treat type I and II diabetes with satisfaction. Still, investigators are finding more appropriate ways to treat diabetes accurately. They formulated insulin analogs that mimic the naturally produced human insulin through recombinant DNA technology and devised many methods for appropriate delivery of insulin. This review will address the following questions: What is insulin preparation? How were these devised and what are the impacts (both positive and negative) of such insulin analogs against TIDM (type-I diabetes mellitus) and TIIDM (type-II diabetes mellitus)? This review article will also demonstrate approaches for the delivery of insulin analogs into the human body and some future directions for further improvement of insulin treatment.     

Substitutes for the endocrine pancreas

Since it is generally accepted that a tight metabolic control might prevent the chronic complications of diabetes mellitus, several systems have been developed in which insulin is administered in a manner that mimicks the characteristics of insulin secretion. 1) In the so-called closed-loop systems, insulin delivery is regulated by the concomitant plasma glucose level. These systems, which involve continuous measurement of plasma glucose concentration are not to date implantable and have been used so far only for short-term studies. 2) By contrast, in the "open-loop systems", no glucose sensor is needed and insulin delivery is pre-programmed to achieve a constant basal infusion with peaks of insulin delivery during the meal periods. These systems have been used in man for several months. The present achievement and limitations of both kinds of systems are discussed in this review.     

Continuous intravenous insulin therapy with a miniaturized open-loop system.

For the continuous intravenous application of insulin, a portable open-loop system was developed consisting of a delivery unit with a miniaturized pump and an insulin reservoir which is connected with an electronic control unit. The infusion rates were either preprogrammed or patient-controlled. Blood glucose control with both systems was tested in eight juvenile-type diabetics, among them two of the brittle type. Diabetic control during a 1-2-day pre-infusion period was compared with 2-3 days of continuous insulin infusion; as judged by the mean blood glucose value (MBG), the mean amplitude of glycemic excursions (MAGE), and glucosuria, all patients were significantly better controlled by the open-loop systems than by conventional therapy with subcutaneous insulin. The use of portable open-loop systems offers a promising approach to an improvement of metabolic control in insulin-requiring diabetics.     

Integrated Insulin Pump and Continuous Glucose Monitoring Technology in Diabetes Care Today: A Perspective of Real-Life Experience With the Minimed™ 670G Hybrid Closed-Loop System

Objective: Intensive glucose management with insulin pump and continuous glucose monitoring therapy in insulin-treated patients with diabetes poses many challenges in all aspects of daily life. Automated insulin delivery (AID) is the ultimate goal of insulin replacement therapy to reduce the burden of managing this condition. Many systems are being tested in the clinical research setting, and one hybrid closed-loop (HCL) system has received Food and Drug Administration (FDA) approval for use in type 1 diabetes patients above the age of 14 years.Methods: Literature review and clinical practice experience from the Diabetes and Technology Program at an academic medical center.Results: This review outlines recent advances in AID systems, focusing on the FDA-approved MiniMed™ 670G HCL system and the real-life experience 1-year post-release in an academic medical center with over 60 patients on this system. The unique challenges of adapting to this new system outside the clinical trial setting are highlighted, and a training protocol designed specifically for the onboarding of first-time users is described.Conclusion: HCL insulin therapy offers several advantages, at the same time posing unique challenges to the user. Systematic training of patients with diabetes transitioning to this system is essential for retention and success of use.Abbreviations: AID = automated insulin delivery; CGM = continuous glucose monitoring; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HCL = hybrid closed-loop; ICR = insulin to carbohydrate ratio; SAP = sensor augmented pump; T1DM = type 1 diabetes     

"Glucosensor Unitec Ulm". A portable, continuously measuring glucose sensor and monitor

The "Glucosensor Unitec Ulm" is the first commercially available, portable glucose monitor that permits continuous measurement in venous blood under ambulatory conditions for up to 256 hours. The device weights 850 g, and measures 15 x 19 x 7 cm. Depending on the flow rate of the pump, the blood requirement is 15-25 ml/24 h. The size of the built-in-memory is 32 kByte, enough to store 3180-15,900 glucose values. The "24 hour glucogram" obtained under day to day living conditions permits the detection of disturbances of carbohydrate metabolism. Thus, early abnormalities of type II diabetes can be detected as well the degree of blood glucose normalization in patients suffering from severe insulin-dependent diabetes. Moreover, the effects of glucose-lowering drugs can be analyzed objectively. Finally, this portable glucose monitor permits the recognition of hypoglycemia induced by insulin administration or endogenous insulin overproduction due to tumors.     

Biotechnological and administration innovations in insulin therapy

The importance of the intensive control of blood glucose in patients with diabetes has been well documented in several large scale studies. Attempts to attain strict glucose control when managing diabetes have traditionally utilized daily subcutaneous injections of human insulin. This strategy has offered improvements in glycaemic control but is unable to replicate fully the normal diurnal plasma profile of endogenous human insulin. Advances in protein engineering techniques have, however, resulted in the formulation of a number of insulin analogues that offer more desirable properties of absorption from the subcutaneous depot and hence improved insulin profiles in patients with diabetes. Concurrent to the development of insulin analogues, devices to deliver insulin either subcutaneously or by other routes have also advanced. These novel delivery strategies are also likely to contribute to improved glycaemic control for patients with diabetes in the future.     

A coordinated control strategy for insulin and glucagon delivery in type 1 diabetes

Type 1 diabetes is an autoimmune condition characterised by a pancreatic insulin secretion deficit, resulting in high blood glucose concentrations, which can lead to micro- and macrovascular complications. Type 1 diabetes also leads to impaired glucagon production by the pancreatic α-cells, which acts as a counter-regulatory hormone to insulin. A closed-loop system for automatic insulin and glucagon delivery, also referred to as an artificial pancreas, has the potential to reduce the self-management burden of type 1 diabetes and reduce the risk of hypo- and hyperglycemia. To date, bihormonal closed-loop systems for glucagon and insulin delivery have been based on two independent controllers. However, in physiology, the secretion of insulin and glucagon in the body is closely interconnected by paracrine and endocrine associations. In this work, we present a novel biologically-inspired glucose control strategy that accounts for such coordination. An in silico study using an FDA-accepted type 1 simulator was performed to evaluate the proposed coordinated control strategy compared to its non-coordinated counterpart, as well as an insulin-only version of the controller. The proposed coordinated strategy achieves a reduction of hyperglycemia without increasing hypoglycemia, when compared to its non-coordinated counterpart.     

Anti-Insulin Immune Responses Are Detectable in Dogs with Spontaneous Diabetes

Diabetes mellitus occurs spontaneously in dogs. Although canine diabetes shares many features with human type-1 diabetes, there are differences that have cast doubt on the immunologic origin of the canine disease. In this study, we examined whether peripheral immune responses directed against islet antigens were present in dogs with diabetes. Routine diagnostics were used to confirm diabetic status, and serum samples from dogs with (N = 15) and without (N = 15) diabetes were analyzed for the presence of antibodies against islet antigens (insulin, glutamic acid decarboxylase, insulinoma-associated protein tyrosine phosphatase, and islet beta-cell zinc cation efflux transporter) using standard radioassays. Interferon-γ production from peripheral blood T cells stimulated by porcine insulin and by human insulin was tested using Elispot assays. Anti-insulin antibodies were detectable in a subset of diabetic dogs receiving insulin therapy. Pre-activated T cells and incipient insulin-reactive T cells in response to porcine or human insulin were identified in non-diabetic dogs and in dogs with diabetes. The data show that humoral and cellular anti-insulin immune responses are detectable in dogs with diabetes. This in turn provides support for the potential to ethically use dogs with diabetes to study the therapeutic potential of antigen-specific tolerance.     

Plug flow cytometry: An automated coupling device for rapid sequential flow cytometric sample analysis.

BACKGROUND: The tools for high throughput flow cytometry have been limited in part because of the requirement that the samples must flow under pressure. We describe a simple system for sampling repetitively from an open vessel. METHODS: Under computer control, the sample is loaded into a sample loop in a reciprocating eight-way valve by the action of a syringe. When the valve position is switched, the plug of sample in the sample loop is transported to the flow cytometer by a pressure-driven fluid line. By coupling the plug-forming capability to a second multi-port valve, samples can be delivered sequentially from separate vessels. RESULTS: The valve is able to deliver samples at rates ranging up to about 9 samples per minute. Each plug of sample has uniform delivery characteristics with a reproducible coefficient of variation (CV). Even at the highest sampling rate, carryover between samples is limited. CONCLUSIONS: Plug-flow flow cytometry has the potential to automate the delivery of small samples from unpressurized sources at rates compatible with many screening and assay applications.     

Continuous Subcutaneous Insulin Infusion (Insulin Pump) Therapy can be Safely Used in the Hospital in Select Patients

ObjectiveTo analyze data on inpatient insulin pump use and examine staff compliance with hospital procedures, glycemic control, and safety.MethodsWe conducted a retrospective review of charts and bedside glucose data for patients who had been receiving outpatient insulin pump therapy and were admitted to our teaching hospital between November 1, 2005, and February 8, 2008.ResultsDuring the study period, there were 50 hospitalizations involving 35 patients who had been receiving outpatient insulin pump therapy. The mean age and duration of diabetes of the 35 patients was 55 years and 32 years, respectively. Sixty-six percent were women, and 91% had type 1 diabetes. Patients in 31 of the hospitalizations (62%) were deemed candidates for continued insulin pump therapy during their stay. Of the 31 hospitalizations, 80% had the presence of the pump documented at admission; 100% had an admission glucose value; 77% had documentation of signed patient consent; 81% had evidence of completed preprinted insulin pump orders; 77% received an endocrine consultation; and 68% had a completed bedside flow sheet. Patients continuing insulin pump therapy had mean bedside glucose levels similar to those whose pump therapy was discontinued (P = .11); however, the proportion of hypoglycemic events was lower among insulin pump users (P < .01) than among nonusers.ConclusionsInsulin pump therapy is safe for select inpatients. Overall, staff compliance with procedures was high, although we identified areas for improvement. Continued study is needed on the effectiveness of insulin pump therapy in controlling inpatient hyperglycemia. (Endocr Pract. 2009;15:24-29)