Controlled insulin release from glucose-sensitive self-assembled multilayer films based on 21-arm star polymer

A glucose-sensitive multilayer film was fabricated by the layer-by-layer (LbL) assembly method with positively charged 21-arm poly[2-(dimethylamino)ethyl methacrylate] (star PDMAEMA) and negatively charged insulin and glucose oxidase (GOD) in the form of {(Star PDMAEMA/Insulin)(4)?+?(Star PDMAEMA/GOD)(4)?+?Star PDMAEMA}. The multilayer film shows an on-off regulation of insulin release in response to stepwise glucose challenge in vitro. It is found that the unique structure of star PDMAEMA and interdiffusion of charged insulin are the main factors to control the on-off status of the film. Reversible surface morphology transitions of the multilayer film were also observed, revealing a phase separation and large-scale reorganization process. Furthermore, the multilayer film could continuously release enough insulin in vivo after being subcutaneously implanted in streptocozotin-induced diabetic rats and reduce the blood glucose level for at least two weeks. It is indicated that such system may have substantial potential as a glucose-sensitive carrier for insulin due to its distinct mechanism.     

The influence of arrangement sequence on the glucose-responsive controlled release profiles of insulin-incorporated LbL films

Insulin, glucose oxidase and positively charged star polymers were incorporated into multilayer films by the layer-by-layer (LbL) assembly method. It is interesting to find that the arrangement sequence of the three components could significantly affect the glucose-responsive controlled release behaviors. The insulin release in vitro could be tuned to linear release and obtain desired “on–off” sensitivity in response to stepwise glucose challenge, just by rearranging the assembly sequence of LbL building blocks. Further, the controlled release of insulin in vivo, as well as the hypoglycemic effect, could be obviously prolonged from 17 days to 36 days by this simple strategy without changing the dosage of all the LbL components. In addition to provide a potential glucose-responsive delivery system for insulin, the strategy described in this paper could be valuable for various drug-incorporated LbL systems with three or more components.     

Facile one-pot synthesis of glucose-sensitive nanogel via thiol-ene click chemistry for self-regulated drug delivery

A novel glucose-sensitive nanogel was conveniently prepared through one-pot thiol-ene copolymerization of pentaerythritol tetra(3-mercaptopropionate), poly(ethylene glycol) diacrylate, methoxyl poly(ethylene glycol) acrylate and N-acryloyl-3-aminophenylboronic acid. The formation of core–shell nanogel was verified by proton nuclear magnetic resonance, dynamic laser scattering (DLS) and transmission electron microscopy. The successful incorporation of phenylboronic acid (PBA) in the nanogel was confirmed through Fourier transform infrared spectroscopy, inductively coupled plasma mass spectrometry and fluorescence technology. Owing to the presence of PBA, the nanogel exhibited high glucose sensitivity in phosphate-buffered saline determined by DLS and fluorescence technology. The increased amount of glucose causes an increase in the hydrodrodynamic radius and a decrease in the fluorescence intensity of PBA–alizarin red S (ARS) complex in the nanogel at pH 7.4 because of the competitive substitution of ARS to form the hydrophilic PBA–glucose complex. ARS and insulin were loaded into this glucose-sensitive nanogel. In vitro release profiles revealed that the drug release from the nanogel could be triggered by the presence of glucose. The more glucose in the release medium, the more drug was released and the faster the release rate. Furthermore, in vitro methyl thiazolyl tetrazolium assay, lactate dehydrogenase assay and hemolysis test suggested that the nanogel was biocompatible. Therefore, the PBA-incorporated nanogel with high glucose-sensitivity and good biocompatibility may have great potential for self-regulated drug release.     

An interaction between glucose and estrogen in gastric acid secretion in the lateral hypothalamic area of female rats

Gastric acid outputs caused by glucose injection into the lateral hypothalamic area (LHA) were examined in insulin hypoglycemia with or without estradiol-17 (EST) administration in bilaterally ovariectomized (OV) female rats. The basal level of acid output was higher in OV rats without EST than in OV rats with EST. When acid response was expressed as the percentage change, glucose injection into the LHA decreased acid output in a dose-dependent fashion in OV rats, while, in OV rats with EST, glucose injection into the LHA also reduced acid output without dose dependency. It was also noted that the threshold concentration of glucose that induced an acid response was lower in OV rats without EST than in OV rats with EST. These findings suggest that glucose-sensitive neurons responsible for gastric acid secretion can be modulated by estrogen at the LHA level.     

Synthesis of Y‐Shaped Copolymers Containing Phenylborate Ester and Biodegradable Poly(lactic acid) Blocks and Their Glucose‐Sensitive Behavior for Controlled Insulin Release

This study is devoted to developing amphiphilic, biodegradable, Y‐shaped block polymers, which can self‐assemble to form nanoparticles, as a glucose‐sensitive drug carrier. Y‐shaped poly(ethylene glycol)‐block‐[poly(lactic acid)‐block‐poly (2‐phenylborate esters‐1,3‐dioxane‐5‐methyl) methylacrylate)]₂ (MPEG‐(PLA‐block‐PPBDMMA)₂) polymers are constructed via a combination of ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP) with MPEG‐(OH)₂, having double initiation endings, as starting material. These Y‐shaped block polymers can disperse in an aqueous medium and self‐assemble into micellar aggregates with a spherical core–shell structure. Dynamic laser scattering (DLS), zeta potential measurements, and transmission electron microscopy (TEM) show the solution properties of these poly­meric micelles with or without insulin loading. Compared with MPEG‐PLA‐block‐PPBDMMA linear polymer, in vitro insulin release at different glucose concentrations, revealed by the fluorescence technique, shows that the studied Y‐shaped polymers have intelligent glucose‐concentration‐dependent manner of insulin release at pH 7.4 and 37 °C. The bulk swelling phenomenon of the polymeric micelles formed from the Y‐shaped polymers is detected by DLS in the process of their glucose‐responsiveness. Such a Y‐shaped glucose‐responsive polymer is a promising candidate that holds great potential in the treatment of diabetes.

     

Design and evaluation of biodegradable, biosensitive in situ gelling system for pulsatile delivery of insulin

Biodegradable glucose-sensitive in situ gelling system based on chitosan for pulsatile delivery of insulin was developed. The sols/gels were thoroughly characterized for swelling properties, rheology, texture analysis and water content. The developed glucose-sensitive gels responded to varied glucose concentrations in vitro indicating their ability to function as environment-sensitive systems. Insulin load onto the gels was optimized and was found to affect the rheological behavior of these gels, the final preparation used for in vitro contained 1IU/200mul of the sol. These gels released the entrapped insulin in a pulsatile manner in response to the glucose concentration in vitro. Furthermore, the formulations when evaluated for their in vivo efficacy in streptozotocin-induced diabetic rats at a dose of 3IU/kg, demonstrated their ability to release insulin in response to glucose concentration and were preferred much better against subcutaneously given plain insulin formulation used as the control. Together, these preliminary results indicate that biosensitive chitosan in situ gelling systems have substantial potential as pulsatile delivery systems for insulin.     

Tailoring of multilayered core-shell nanostructure for multicomponent administration and controllable release of biologically active ions

The biomaterials that can control the active ions delivery to enhance cell activity are regarded as promising bone regenerative materials. In this study, a new approach aiming to layer-by-layer (LbL) assemble the bioavailable zinc ions in the core-shell-like silica@octacalcium phosphate (OCP) nanosphere and to analyze its efficacy on improving controlled-release was reported. Firstly, a pH-responsive electrostatic interaction was used to adsorb zinc ions on silica nanospheres with different zinc concentration, which was followed by coating silica gel layer. Then the nanospheres were LbL assembled with zinc ions and silica gel alternately until the desired multilayered nanospheres were achieved. Finally, the porous OCP shells were capped onto the outside surface of the nanospheres tailored by poly(aspartic acid) sodium molecules. The ion release tests in Tris buffers in vitro indicated that zinc release was controlled by pH and storage capacity, and silicon release was regulated by the OCP shell barrier. A temporal gradient within short times and sustained-dosage for a prolonged time toward the zinc and silicon ions could be obtained in this multilayer system. The results of this organized active ion assembly might open a promising future direction for effective delivery of trace elements in bone defect therapy.     

Insulinsekretion in vitro

Zusammenfassung 1. Es wird ein einfaches System beschrieben, an dem sich in vitro die Insulinfreisetzung aus dem Rattenpankreas studieren läßt. Insulinzerstörende Proteasen lassen sich erst nach mehreren Versuchsstunden nachweisen.2. Die Insulinabgabe des inkubierten Pankreas wird spezifisch und konzentrationsabhängig durch Glucose stimuliert. Mannose ist ebenfalls wirksam. Galactose, Fructose, Citrat und Pyruvat zeigen keinen Effekt. Aus dem Pankreas alloxandiabetischer Ratten läßt sich kein Insulin, aus dem Pankreas Tolbutamid-vorbehandelter Ratten mit degranulierten B-Zellen eine gegenüber unbehandelten Tieren verminderte Insulin-Menge freisetzen. Die Insulinabgabe ist an aerobe Inkubationsbedingungen gebunden.3. Trotz maximaler Insulinfreisetzung durch Glucose läßt sich nach der Inkubation lichtmikroskopisch keine Abnahme der B-Zellgranula erkennen, weil nur etwa 5% des gespeicherten Insulins abgegeben werden. An den degranulierten B-Zellen von Ratten, die mit Tolbutamid vorbehandelt wurden, tritt während der Inkubation keine Regranulation ein.4. Die glucoseinduzierte Insulinabgabe wird durch eine bestimmte Insulinkonzentration im Inkubationsmedium blockiert. Es wird daher diskutiert, daß die Insulinsekretion nicht nur durch den Blutglucosespiegel sondern auch durch den Blutinsulinspiegel reguliert werden kann.

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Summary 1. A simple system is described with which the insulin release in vitro can be studied. Proteases destroying the insulin can only be found after several hours.2. The insulin released from the incubated pancreas is specifically stimulated by glucose and depends on the glucose concentration. Mannose is also effective. No effect is found in the case of galactose, fructose, citrate or pyruvate. No insulin release can be induced from the pancreas of alloxandiabetic rats. From the pancreas of rats pre-medicated with tolbutamide, having B-cell degranulation, there ist less insulin released than in untreated animals. The insulin release depends on aerobic incubation conditions.3. Despite a maximum insulin release through glucose there is no decrease, light-microscopically, in B-cell granulation following incubation, as only about 5% of the stored insulin are released. The degranulated B-cells of rats premedicated with tolbutamide show no regranulation during incubation.4. The insulin release induced by glucose is inhibited by a certain insulin concentration in the incubation medium. Therefore is discussed whether the insulin secretion is not only regulated by the blood glucose level, but also by the blood insulin level.

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Ein Teil der Ergebnisse wurde erstmalig beim Wenner-Gren-Symposium über The Structure and Metabolism of the Pancreatic Islets (Stockholm, August 1963) und auf dem 5. Kongreß der Internationalen Diabetes-Vereinigung (Toronto, Juli 1964) mitgeteilt.     

Layer-by-layer assembly of liposomal nanoparticles with PEGylated polyelectrolytes enhances systemic delivery of multiple anticancer drugs

Layer-by-layer (LbL)-engineered nanoparticles (NPs) are a promising group of therapeutic carriers used in an increasing number of biomedical applications. The present study uses a controlled LbL process to create a multidrug-loaded nanoplatform capable of promoting blood circulation time, biodistribution profile and controlling drug release in the dynamic systemic environment. LbL assembly is achieved by sequential deposition of poly-l-lysine (PLL) and poly(ethylene glycol)-block-poly(l-aspartic acid) (PEG-b-PLD) on liposomal nanoparticles (LbL-LNPs). This generates spherical and stable multilayered NPs ∼240 nm in size, enabling effective systemic administration. The numerous functional groups and compartments in the polyelectrolyte shell and core facilitate loading with doxorubicin and mitoxantrone. The nanoarchitecture effectively controls burst release, providing different release kinetics for each drug. LbL-LNPs are pH-sensitive, indicating that intracellular drug release can be increased by the acidic milieu of cancer cells. We further demonstrate that the LbL nanoarchitecture significantly reduces the elimination rates of both drugs tested and markedly extends their systemic circulation times, paving the way for efficacious tumor drug delivery. Because this delivery system accommodates multiple drugs, improves drug half-life and diminishes burst release, it provides an exciting platform with remarkable potential for combination therapeutics in cancer therapy.     

The dynamics of insulin release from mouse pancreatic islet cells in suspension

Summary The overall dynamics of glucose-induced insulin release was strikingly similar in dispersed cells and intact islets perifused in parallel. Both preparations exhibited a latency of 1–2 min, after which period there was a brisk rise of insulin release followed by a sustained second phase. During the second phase, insulin release from dispersed cells attained a stable plateau rate, whereas the release from intact islets continued to rise. Epinephrine (1 M) inhibited the release in both preparations, but the return to basal rate was faster in the dispersed cells than in the intact islets. The dispersed cells oxidized glucose at a constant rate for at least 60 min; the glucose oxidation was markedly sensitive to changes of the glucose concentration in the range of 3–20 mM.     

Hypothalamic-pituitary activation does not differ during human and porcine insulin-induced hypoglycemia in insulin-dependent diabetes mellitus

Summary Although pituitary hormones play only a minor role in acute hormonal counterregulation during insulin-induced hypoglycemia, their concomitant secretion with the profound sympathoadrenal response provides an indicator of hypothalamic-pituitary activation. The release of different amounts of -endorphin, growth hormone, and adrenocorticotropin during human (HI) and porcine (PI) insulin-induced hypoglycemia would serve as a pointer to a different insulin species effect on hypothalamic-pituitary response. We performed a controlled, double-blind study with randomization to either HI or PI to compare insulin effects during developing and established hypoglycemia. The glucose clamp technique was used to lower the blood glucose concentration stepwise (3.3, 2.2, 1.7 mmol/1) over similar periods in ten patients with insulin-dependent diabetes mellitus. -endorphin, growth hormone, and adrenocorticotropin levels were determined by radioimmunoassay from arterialized blood at the above plateaus. A different action of HI or PI on peripheral glucose metabolism was not found. Pituitary hormones increased significantly during hypoglycemia (analysis of variance for hypoglycemic effects: -endorphin, P < 0.02; growth hormone, P < 0.04; adrenocorticotropin, P < 0.05). No insulin species effect was detected. Hypothalamic-pituitary activation during insulin-induced hypoglycemia is independent of the insulin species used, which supports earlier observations of an identical sympathoadrenal response during HI- and PI-induced hypoglycemia.Abbreviations HI human insulin - PI porcine insulin     

The Kallikrein-Kinin system and muscle metabolism—Clinical aspects

The influence of synthetic bradykinin (BK) on disturbed protein and carbohydrate metabolism was studied in chemical and manifest maturity-onset diabetics, in surgical patients and in alloxan diabetic rats. BK,mixed with insulin and injected subcutaneously twice daily in alloxan diabetic rats lowered the morning blood glucose concentration in a dose-dependent way, whereas in a control group treated with insulin only no decrease was seen. Accelerated local blood flow or enhanced vascular permeability as a cause of increased glucose uptake could be ruled out by control experiments using papaverine and eledoisin. Better metabolic control in the BK/insulin-treated group was also indicated by lower arterial levels of free fatty acids and of -hydroxybutyrate, normalized hepatic glycogen content and better growth of body weight. In healthy man an intravenous infusion of BK (80 g/h) did not influence normal fasting blood glucose concentrations, whereas elevated glucose levels in maturity-onset diabetics were continuously reduced within 100 min by 12.2±1.4%. A comparable diabetic group receiving saline alone showed no spontaneous drop of blood glucose concentration. An improvement of pathological carbohydrate metabolism by infusion of BK i.v. could also be demonstrated using the intravenous glucose tolerance test in chemical and manifest maturity-onset diabetics and in surgical patients: in all groupsk values of the glucose tolerance test were significantly increased by BK. This effect was neither due to stimulated insulin release nor to changed glucose pool or to increased renal glucose loss, which was even reduced by BK. Interestingly, normalk values in healthy volunteers were not further improved by BK. A stimulated protein breakdown, which occurs after surgery due to peripheral insulin resistance, can also be restricted by intravenous infusion of BK: in surgical patients urinary nitrogen excretion was reduced by 50% during infusion of BK and was accelerated again after cessation of the infusion. These results indicate that BK can improve the efficacy of exogenous insulin in insulin-deficient animals and depressed insulin sensitivity in maturity-onset diabetics and surgical patients.     

Comparative stereochemical analysis of glucose-binding proteins for rational design of glucose-specific agents

There is a need for synthesizing glucose-sensitive molecules which can be used in glucose sensors and self-regulating insulin delivery devices. Currently, glucose-sensitive proteins, such as glucose oxidase and concanavalin A (Con-A), are used for detecting glucose molecules. For long-term in vivo applications, it is necessary to synthesize non-proteineous glucose-sensitive molecules which are biocompatible, nontoxic, cost-effective, and independent of environmental factors such as pH, ionic strength, or the presence of divalent cations.

As a first step toward synthesizing glucose sensitive molecules, we have compared glucose-binding sites of four different types of glucose-binding proteins. They are human β-cell glucokinase, D-xylose isomerase, lectins (Lathyrus ochrus isolectin I and Con-A), and glucose/ galactose binding protein. Analysis of the glucose-binding sites of their 3-dimensional crystal structures showed that the hydrogen bonds between the hydroxyl groups of glucose and a few types of amino acid residues of proteins provided the main attraction. In some cases, the same atom was involved in multiple hydrogen bonds. Hydrophobic interactions between the pyranose ring of glucose and aromatic rings of hydrophobic amino acid residues also played an important role in the glucose specificity. A sandwich geometry was observed among the hydrophobic groups. This comparative stereochemical analysis suggests that a possible glucose binding site can be made by placing Asp and Asn around glucose for hydrogen bonding and Phe on both sides of glucose for hydrophobic interaction.     

Comparison between closed-loop portal and peripheral venous insulin delivery systems for an artificial endocrine pancreas

To establish the ideal insulin delivery route for an artificial endocrine pancreas, we examined the effectiveness of closed-loop portal insulin delivery. We investigated the effects of the route of insulin delivery on net hepatic glucose balance (NHGB) in dogs under pancreatic clamp conditions with somatostatin plus basal glucagon and insulin infusions. A constant rate of suprabasal insulin was infused via the portal vein or a peripheral vein, and glucose was infused into the portal vein for 180min. The mean net hepatic glucose uptake (NHGU) values in the portal insulin infusion group (PI group) were significantly greater than those in the peripheral venous insulin infusion group (VI group); the changes from the baseline values at 180min were 3.54 ± 0.66 and 2.45 ± 0.82mgkg^–1min^–1 in the PI and VI groups, respectively, P < 0.05. Furthermore, dogs under pancreatic clamp conditions were controlled after a 2-g/kg oral glucose load by applying the closed-loop intraportal (PO) or intravenous (IV) insulin infusion algorithm. There were no significant differences in glycemic control and insulin requirements between these algorithms. However, the maximum peripheral venous and arterial plasma insulin concentrations with the PO algorithm were significantly lower than those with the IV algorithm [305.1 ± 68.9 and 468.1 ± 66.9pmol/l (peripheral vein) and 305.3 ± 62.9 and 469.6 ± 85.1pmol/l (artery) with the PO and IV algorithms, respectively, P < 0.05]. On the other hand, the maximum portal plasma insulin concentration with the PO algorithm was significantly higher than that with the IV algorithm (619.9 ± 101.7 and 414.3 ± 79.9pmol/l with the PO and IV algorithms, respectively, P < 0.05). The mean NHGU values with the PO algorithm were significantly greater than those with the IV algorithm. Our results confirmed that closed-loop portal insulin delivery is feasible with regard to both insulin profiles and hepatic glucose handling in vivo, and indicated that the portal vein is the most suitable insulin delivery route for the artificial endocrine pancreas.     

Cytochalasin B: Evidence for a membrane-directed action in B-cells from rat pancreatic islets

Summary In the presence of cytochalasin B (CCB) concentrations from 50 to 200 g/ml there is a dose-dependant inhibition of insulin release from isolated rat pancreatic islets. Inhibition is unspecific with respect to glucose, leucine, tolbutamide or theophylline and is reversible. Production of¹⁴CO₂ from uniformly labeled D-glucose is decreased. Islets pretreated with an high (200 g/ml) or low (10 g/ml) CCB dose release more insulin in response to a subsequent glucose or leucine stimulus in a CCB free medium compared with controls. The data are compatible with a membrane-directed action of CCB.     

The acyl-amino-alkyl benzoic acid residue and the sulfonylurea containing residue of glibenclamide affect different aspects of beta-cell function

HB 699 is a non-sulfonylurea acyl-amino-alkyl benzoic acid derivative, corresponding to a major part of the glibenclamide molecule. Basal insulin release (3 mmol/l glucose) as well as glucose-induced release (10 mmol/l glucose) were stimulated by 25 mumol/l and 200 mumol/l HB 699. HB 699 (200 mumol/l) had no effect on the osmotic swelling induced by hypoosmolarity (180 mosm/l). The results indicate that the glibenclamide-induced insulin release can be resolved in a "high-affinity" component, which correlates with increased osmotic resistance in the beta-cells and a "low-affinity" component not associated with increased osmotic resistance. It is suggested that the latter component may be due to the part of the glibenclamide molecule that corresponds to HB 699.     

A role of thyrotropin-releasing hormone in insulin secretion by isolated rat pancreatic islets

Insulin-secreting pancreatic cells also express thyrotropin-releasing hormone (TRH). Although the physiological role of TRH in this localization is unclear, its participation in glucoregulation has been implied. To test this hypothesis, we blocked the last step of post-translational maturation of the TRH molecule by disulfiram, which is an active inhibitor of peptide -amidation (PAM) within pancreatic islet cells. The treatment of male rats with 200 mg/kg/day of disulfiram during a 5-day period resulted in a low PAM activity, a high insulin content and its basal secretion from pancreatic islets, and the inability to release insulin in response to glucose (16.7 mM) or hypo-osmotic (30%) challenge in vitro. The addition of TRH (1 nM) to the medium during incubation restored the insulin content and both basal and glucose stimulated insulin secretions to control levels. Conclusion: TRH plays an important role in the mechanism of insulin secretion and its response to glucose stimulation.     

Effects of twice-daily injections of premixed insulin analog on glycemic control in type 2 diabetic patients

Purpose

Premixed insulin is effective to improve glycemic control; however, clinicians may be less likely to know which premixed insulin is appropriate for which patients. This study aimed to evaluate the effects of twice-daily injections of premixed insulin lispro on glycemic control in type 2 diabetic patients.

Materials and Methods

Forty type 2 diabetic patients, who had been treated with twice-daily injections of human protamine mixture 30/70 insulin for at least 12 months, were divided into two groups; one group whose blood glucose 2 hours after breakfast was greater than 200 mg/dL, was switched to lispro mix50, and the other group whose blood glucose 2 hours after breakfast < 200 was switched to lispro mix25.

Results

Glycated haemoglobin (HbA1c) significantly improved in the Mix50 group from 8.3% to 7.5% (at 12 weeks; p < 0.05), and to 7.5% (at 24 weeks; p < 0.05). On the other hand, HbA1c levels in the Mix25 group were slightly decreased from 8.1% to 7.7% at 12 weeks (p < 0.05), and to 7.9% at 24 weeks (not significant). Both postprandial plasma glucose and fasting plasma glucose levels were significantly improved in the Mix50 group, but not in the Mix25 group. Overall, 95% of subjects preferred premixed lispro insulin from human insulin in the viewpoint of the timing of insulin injection by questionnaire analysis.

Conclusion

Switching from human protamine mixture 30/70 insulin to lispro mix50 twice-daily injection therapy in patients with high postprandial plasma glucose could improve their glycemic control and quality of life.     

Dual roles of hyaluronic acids in multilayer films capturing nanocarriers for drug-eluting coatings

We developed hyaluronic acid (HA)-based multilayer films capturing polymeric nanocarriers (NCs) for drug delivery. The electrostatic interactions between positively charged linear polyethylene imines (LPEI) and negatively charged HAs are the main driving forces to form multilayers based on the layer-by-layer (LbL) deposition. NCs were easily incorporated within the multilayer film due to intra- and/or inter-hydrogen bonding among HA chains. The amount of NCs captured by the HA chains was varied by the ratio between HAs and NCs as well as the length (i.e., molecular weight) and absolute number density of HAs in solution. Biocompatibility of the NC-capturing HA multilayer films was tested with the human dermal fibroblast (HDF) culture. In addition, the controlled release of paclitaxel (PTX) from the HA multilayer films successfully led to the apoptosis of human aortic smooth muscle cells (hSMC) in vitro, implying that the NC-capturing HA multilayer films would be quite useful as drug-eluting stent systems to prevent the restenosis after surgery.     

Status of pancreatic transplants and mechanical devices for blood glucose control in diabetes

Many of the long-term complications seen in insulin-dependent diabetic patients are not averted by conventional modes of insulin therapy. A commonly expressed hypothesis is that more intensive efforts directed at improved metabolic control in diabetic subjects may result in a decrease of long-term complications. Therefore, increasing attention is being devoted to development of strategies designed to achieve improved blood glucose and metabolic control in insulin-dependent diabetic subjects. The approaches can be divided into three categories: [1] Transplantation, [2] Mechanical devices, and [3] Intensive, conventional therapy. The development of the transplantation approach requires resolution of the problem of rejection and the need for immunosuppression. Recent studies indicate that islet transplantation may be performed without long-term immunosuppression. Closed-loop devices for use at the bedside are available at the present time for short-term investigational use. A device for long-term portable use is not available because of the lack of an adequate glucose sensor. Open-loop devices are currently available that enable long-term clinical studies in humans. Some patients have used these devices at Washington University for over two years. In a few, there has been reversal of some of the neuropathy with retinal vascular leakage and near normal, long-term metabolic control. Some findings in over twenty patients studied long-term include the following:

1. Reduction of postprandial hyperglycemia is possible with intravenous. subcutaneous, or intraperitoneal insulin delivery;
2. Hypoglycemia remains the most common problem seen in ambulatory patients treated with open-loop pumps and necessitates glucose monitoring by the patient at home;
3. Long term “normalization” of plasma glucose is not achieved with openloop systems;
4. Maturity onset diabetic patients are easier to control than juvenile onset diabetics;
5. Some patients tolerate hypoglycemia better than others and this may determine who does well long-term;
6. Long-term subcutaneous insulin delivery is safe, whereas other forms of insulin delivery carry a greater risk;
7. Peripheral hyperinsulinemia is frequently found in patients treated by open-loop methods and may have long-term detrimental effects;
8. Behavioral and psychosocial variables may influence long-term results and have not been studied in detail;
9. The primary clinical use of open-loop systems in diabetic patients at the present time is their use in pregnancy and in patients unresponsive to conventional therapy.

Our interest in these devices is to determine if they can avert or reverse the long-term complications of the diabetic. We do not consider them safe for routine use in clinical practice and are concerned that practitioners inexperienced in their use may employ these devices prematurely, before their safety and effectiveness are demonstrated in carefully controlled clinical studies.