Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study.

AIMS: To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). MATERIALS AND METHODS: This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. RESULTS: During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (-0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. CONCLUSIONS: Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.

AIM: The purpose of this national multicenter prospective study by the French EVADIAC group was to investigate the possibility that continuous intraperitoneal insulin infusion using an implanted pump (CIpii) increases the risk of autoimmune disease in type 1 diabetic patients as it increased anti-insulin immunogenicity. METHODS: Prevalence of clinical (Hashimoto's disease, hyperthyroidism, gastric atrophic disease and vitiligo) and subclinical (presence of anti-thyroperoxidase antibodies, anti-intrinsic factor antibodies, abnormal TSH levels) autoimmune diseases was estimated by comparing two groups of patients already treated by either CIpii (n=154) or external pump (CSII) (n=121) for an average of 6 years. Incidence of autoimmune disease was determined by comparing the same measurements one year after inclusion. RESULTS: No significant difference was observed for the total prevalence of clinical and subclinical auto-immune thyroid and gastric di-seases (35.6% and 3.2% respectively in the CIpii group versus 40.4% and 2.6% in the CSII group). No significant difference for the incidence of clinical and subclinical auto-immune diseases was observed: 7.2% and 0% in CIpii and 7.3% and 1.7% in CSII. CONCLUSION: As previously shown AIA (anti-insulin antibodies) levels were higher in CIpii than in CSII (32.9% vs 20.2%, P<0.0001) but no correlation was observed with either clinical or subclinical autoimmune disease. This large-scale study eliminates the possibility that CIpii increases the risk of autoimmune disease.

Determination of portal insulin absorption from peritoneum via novel nonisotopic method.

The absorption mechanism of insulin administered in the peritoneal cavity (IP) is of current interest because of the near availability of implantable insulin-infusion devices for the treatment of diabetes. To determine the fraction of insulin absorbed by the portal circulation after IP administration, a novel nonisotopic method is described. Conscious fasting diabetic dogs were studied at normoglycemia via the euglycemic insulin-clamp method. Posthepatic appearance of insulin and C-peptide were measured in peripheral blood during IP or intravenous (IV) equimolar infusion of insulin and C-peptide at two sequential 3-h infusion rates of 3.2 and 12.8 pmol.kg-1.min-1. Prior studies have shown that 40-60% of portal insulin is extracted at first pass by the liver, whereas C-peptide is not extracted. Thus, the fraction (F) of IP insulin not taken up by liver at first pass and consequently the fraction absorbed by the portal circulation can be derived from insulin (I) and C-peptide (C) plasma concentration values at steady state with a monocompartmental model where F = (IIP/IIV)(CIV/CIP). The mean +/- SE value of F was 49.7 +/- 8.8%. Glucose disappearance rates were lower with IP than IV infusion but similar when peripheral insulin levels were matched. We conclude that IP insulin is almost entirely absorbed by the portal circulation and induces lower glucose disappearance rates than IV insulin because of lower peripheral circulating insulin levels. Whether these properties make the IP route a more appropriate route for insulin therapy than the subcutaneous or IV routes remains to be established.

Devices for insulin administration.

There is a significant need for revised, safe, and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices, e.g., jet injectors, insulin pens, and access ports, cannot be considered as a major breakthrough in the quest for improved control, although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients, e.g., those with recurrent severe hypoglycemia, but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications, e.g., surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally, programmable implantable insulin pumps, used as an open-loop delivery system, are the most promising alternative to intensive subcutaneous insulin strategies in the short term, although clear evidence of improved safety and efficacy remains to be documented.

Clinical trial of programmable implantable insulin pump for type I diabetes.

OBJECTIVE: The first step in the evolution of an artificial pancreas is the development of a reliable implantable pump for insulin delivery. Despite recent advances, significant issues remain, including small size of studies and frequent irreversible catheter obstructions. We report safety, feasibility, and efficacy results from 56 patients, representing 73 patient-yr of pump experience, entered into a multicenter trial with a new implantable programmable pump. RESEARCH DESIGN AND METHODS: All patients had insulin-dependent (type 1) diabetes, were 38 +/- 8 yr old, and were not prone to severe hypoglycemia. The pump (Infusaid 1000) has a pulsatile mechanism powered by freon-vapor pressure. Its rate is regulated by battery-powered valves, operated via a hand-held programmer. The pump is refilled transcutaneously with 25 ml U100 insulin (Hoechst 21PH) on a monthly basis and has a second septum (side port) proximal to the catheter, which allows flushing the catheter or lavaging the pump unit. The pumps were implanted after 3 mo intensive subcutaneous insulin therapy and catheters were positioned either in the peritoneum (i.p., n = 38) or the superior vena cava (i.v., n = 18). RESULTS: All implanted pumps have functioned safely with no instance of overdelivery or stoppage. The most frequent complications were flow slow downs, presumably due to insulin precipitation within the pump, which occurred in 86% of pumps and were resolved in all but one case by lavaging the pump in situ with alkaline solution. Flow slow downs due to catheter obstruction occurred in 52% of the intravenous catheters but only 21% of the intraperitoneal catheters (P less than 0.05) and were resolved in all but two cases by diluent flushing through the sideport. Incidence of severe hypoglycemia decreased from 0.47 before implant to 0.05 episodes/patient-yr after pump implantation (P less than 0.001). Mean HbA1c fell from 7.4 +/- 1.2% after intensive subcutaneous therapy to 7.1 +/- 1.0% 12 mo after implantation. Only 2 patients withdrew from study after recurrent catheter problems, and quality-of-life questionnaires showed improvement in satisfaction with diabetes-specific quality of life when on implantable pump therapy. CONCLUSIONS: Insulin therapy with implantable pumps is effective and safe for periods up to 1.7 yr with a decreased risk of severe hypoglycemia than with intensive subcutaneous insulin therapy.

Stable insulin for implantable delivery systems: in vitro studies with different containers and solvents.

The stability of a new insulin formulation (lyophilized U100 insulin, Organon) was investigated in vitro in conditions reproducing those of in vivo implanted devices, i.e., constant horizontal agitation at 37 degrees C for 4 wk in various containers and 8 wk in different solvents. Physical stability was assessed by ultraviolet absorption, chemical stability by HPLC, and biological stability by hypoglycemia tests in mice. Insulin precipitated in glass vials but remained clear and active in polyethylene reservoirs and after passage through catheter and pumps in motion, although only 83-90% of insulin was delivered chemically intact. In acidic solvent, insulin showed a major gradual transformation into deamidized derivatives (up to 78% after 8 wk), although still fully active and clear, as expected from previously published excellent in vivo results with acidic insulins. Heparin addition to neutral insulin solution (500 IU/ml) did not alter the properties of the two compounds and might thus be tried to prevent in vivo catheter obstruction due to fibrin deposition.

Diagnostic procedures for catheter malfunction in programmable implantable intraperitoneal insulin infusion devices.

OBJECTIVE: To evaluate the roles of 1) abdominal radiography, 2) a pressure diagnostic procedure (PDP) using a standardized diluent infusion into the catheter sideport, and 3) radiocontrast imaging of the catheter lumen as procedures for diagnosing catheter malfunction in diabetic patients implanted with a programmable intraperitoneal infusion device. RESEARCH DESIGN AND METHODS: Sixteen type I diabetic patients implanted with Infusaid programmable intraperitoneal insulin pumps were studied. The ability of the above three procedures to assist diagnosis of catheter malfunction and distinguish between occlusion and catheter breakage was retrospectively analyzed. Glycated hemoglobin was measured to determine the clinical importance of catheter malfunctions and decreases in pump flow due to insulin aggregation in the pump chamber. RESULTS: Mean glycated hemoglobin levels increased significantly from 8.0 +/- 0.3 to 9.0 +/- 0.4% (P < 0.05) before and after catheter malfunction, but not during pump flow slowdowns. Mean peak pressure during PDP was 1.96 +/- 0.14 psi (P < 0.01 vs. normal) in reversibly occluded catheters and 1.86 +/- 0.35 psi (P < 0.05 vs. normal) in broken catheters, compared with 1.32 +/- 0.23 psi in normal catheters. Decay times during PDP were > 50 s for both reversibly occluded and broken catheters (P < 0.001 vs. normal of 3.6 +/- 0.82 s). Abdominal radiographs and sideport injections of contrast material were used to distinguish the types of broken catheters. CONCLUSIONS: Catheter breakage and occlusion are complications in implantable insulin infusion systems and result in metabolic deterioration. The presence of a sideport allows pressure data and radiographic procedures to assist in determining the cause of catheter malfunction. A diagnostic algorithm was generated to improve efficiency in investigating catheter problems.

Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients.

OBJECTIVE: To compare intraperitoneal implantable insulin infusion (IP) to subcutaneous (SC) intensive insulin therapy. RESEARCH DESIGN AND METHODS: Twenty-one insulin-dependent (type I) diabetic patients aged 24-61 yr underwent a 3-mo treatment optimization using multiple SC daily injections or external pumps. Patients were then randomized (time 0 mo) to IP infusion using Infusaid-programmable pumps or continuation on SC intensive insulin for 6 mo. RESULTS: No differences were noted between study and control group data. However, longitudinal within-group comparisons from baseline showed that glycosylated hemoglobin improved to near-normal in both groups: IP, 9.0 +/- 0.5 vs. 7.8 +/- 0.6% (P less than 0.05) and SC, 8.4 +/- 0.5 vs. 7.5 +/- 0.3% (P less than 0.5) at 0 and 4 mo, respectively (normal less than 6.9%). The percentage of blood glucose tests greater than 11 mM at 0 and 6 mo was 28 +/- 5 vs. 16 +/- 4% in the IP group (P less than 0.05) and 22 +/- 5 vs. 24 +/- 7% in the SC group (NS). At 0 and 6 mo, the standard deviation of blood glucose values, an index of glycemic fluctuations, was 4.3 +/- 0.4 vs. 3.2 +/- 0.5 mM in the IP group (P less than 0.05) and 3.7 +/- 0.3 vs. 4.0 +/- 0.4 mM in the SC group (NS). Weight, insulin dosages, circulating lipid levels, and the frequency of severe hypoglycemic reactions and biochemical hypoglycemias were similar and did not change in the two groups. CONCLUSIONS: IP-implantable pumps compared with SC intensive insulin therapy have similar effects on most metabolic variables and are equally effective at achieving near-normal glycemic levels. Only longitudinal data suggest that IP treatment may be more effective at limiting glycemic fluctuations.

Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To examine the long-term benefits and risks of treatment of IDDM with an implantable programmable insulin pump. RESEARCH DESIGN AND METHODS: Seventy-six patients with IDDM were studied at nine clinical centers. After 3-4 months of intensive subcutaneous therapy, the Infusaid Model 1000 pump was implanted, and insulin was delivered either intraperitoneally or intravenously for an average of 39.6 +/- 10 months (251 patient-years). Data was collected for glycemic control, lipid levels, weight gain, insulin requirements, adverse events, and quality of life. Sixty-three patients were also followed for 8.5 +/- 6.3 months (45 patient-years) after pump therapy was discontinued. RESULTS: Mean quarterly HbA1c fell with subcutaneous intensive therapy and remained stable on implantable pump therapy between 6.9 and 7.5%. Severe hypoglycemia was relatively rare, with only 4 episodes/100 patient-years of implantable pump therapy. This rate was significantly less than with subcutaneous intensive therapy before implantable pump initiation (33 episodes/100 patient-years) or after discontinuation of implantable pump therapy (36/100 patient-years) (P < 0.003). Weight did not increase significantly in the 1st year of therapy, but increased by 2.0 +/- 4.3 kg after 3 years of therapy. There were no significant differences in metabolic control or adverse events between intraperitoneal and intravenous insulin therapy except for minor differences in lipid levels and the more frequent development of catheter obstruction with intravenous delivery. Most pump slow-downs and catheter occlusions were corrected noninvasively. Quality of life, as measured by the Diabetes Control and Complications Trial instrument, showed high satisfaction and improved impact scores. CONCLUSIONS: Long-term implantable pump therapy maintained HbA1c in a range similar to intensive subcutaneous therapy, but with fewer episodes of severe hypoglycemia. Although pump and catheter occlusions remain a limitation, patient satisfaction with implantable pump therapy remains high.

Long-term ambulatory peritoneal insulin infusion of brittle diabetes with portable pumps: comparison with intravenous and subcutaneous routes.

This work compares different routes of insulin infusion via portable pumps with chronically implanted catheters and evaluates the long-term feasibility of the technique. Six severely unstable (i.e., uncontrolled by optimized intensive insulin therapy) diabetic individuals (age range: 35 +/- 4 yr; duration: 11 +/- 2 yr) were selected. Promedos pumps (Siemens A. G., Erlangen, West Germany) were exclusively used because of their portability and long-life insulin reservoir (1-mo duration with U40 acidic Hoechst insulin). Each patient underwent three randomized 1-mo periods of insulin infusion: subcutaneous (s.c.), intravenous (i.v.), and intraperitoneal (i.p.) before the catheter was left indefinitely in one of these sites. Diabetic control was improved and insulin doses reduced whatever the route of infusion, although the s.c. route gave slightly higher values. These results did not deteriorate with time: mean blood glucose was 126 +/- 3 mg/dl and HbA1 was 8.3 +/- 0.6% after 10-18 mo of constant infusion versus 237 +/- 35 mg/dl and 10.0 +/- 0.8%, respectively, under conventional therapy. From a practical point of view, the i.p. route seems preferable since all s.c. catheters provoked local reactions after less than 1 mo and the two chronic i.v. catheters obstructed after 8 and 9 mo. All other incidents were minor and curable without removal of the catheters. All patients argued improvement of both diabetes and quality of life and no one has resigned so far. Thus, the i.p. infusion technique seems beneficial to unstable diabetic individuals and adaptable to long-term therapy, although intensive education and careful follow-up are necessary.

Continuous peritoneal insulin infusion with portable pumps: factors affecting the operating life of the chronic catheter.

Fifty-nine chronic peritoneal catheters made of polyethylene covered with silastic were used to treat 43 IDDM patients peritoneally for 3-34 mo (mean 14 mo) with portable peristaltic pumps and U40 acidic insulin. The operative life of the catheters was determined by actuarial analysis. The mechanisms of catheter failure were determined by preremoval x-ray opacification, removal under laparoscopic examination, and electron microscopic analysis of the catheter. Factors such as age, sex, duration of diabetes, implantation and tunnelization procedures, length of the catheter, and rate of infusion were analyzed. The 50% survival rate of the catheters was 16 mo. Six catheters were irreversibly obstructed by intraluminal fibrin formation and/or extraluminal adhesions, although insulin precipitation was never encountered. Seven catheters had to be removed because of a persisting local infection. Other causes were negligible (misinsertion, irreparable break). The only factor significantly related to incidence of catheter failure was gender with respect to obstruction (1 obstruction among 24 women versus 5 among 19 men, P less than 0.03).

Insulin antibody responses after long-term intraperitoneal insulin administration via implantable programmable insulin delivery systems.

OBJECTIVE: To determine whether insulin antibodies are generated in diabetic patients after short- and long-term intraperitoneal insulin use and, if so, whether they are of potential clinical interest. Insulin antibodies commonly develop in diabetic patients who use subcutaneous human insulin, although their clinical significance remains controversial. Few data are available regarding insulin antibody responses to intraperitoneal insulin. RESEARCH DESIGN AND METHODS: We studied insulin antibody levels and clinical diabetes control in 25 type 1 diabetic patients treated for 3-6 years with intraperitoneal surfactant-stabilized porcine modified human insulin delivered by implantable programmable insulin delivery systems. RESULTS: All patients had preimplantation insulin antibody levels < 20 microU/ml, with a mean value of 2 +/- 2 microU/ml (1 SD). Mean antibody levels increased throughout the study period to a mean maximum of 197 +/- 326 microU/ml (P < 0.02) with 11 of 25 (44%) patients' levels exceeding 20 microU/ml (insulin responders). The mean time to significant antibody development was 21.8 +/- 4.4 months. Of the 11 responder patients, 4 had clinical syndromes that consisted of increasing daily insulin requirements and/or nocturnal hypoglycemia despite minimal nighttime basal insulin infusion rates associated with peak antibody levels > 200 microU/ml. None of the nonresponder patients (antibody levels < 20 microU/ml) had these clinical findings. CONCLUSIONS: Our results indicate that insulin antibody levels observed during intraperitoneal administration of human insulin are 1) similar to those reported during subcutaneous administration; although the rise in antibody level may be delayed compared with subcutaneous human insulin, 2) associated with a patient subset who are insulin antibody responders after switching from subcutaneous to intraperitoneal human insulin, 3) associated with a decrease in levels among responder patients regardless of whether they discontinue or continue pump use, and 4) associated with increased insulin needs and/or nocturnal hypoglycemia despite minimal basal rate insulin infusion at nighttime when antibody levels exceed 200 microU/ml.

A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes.

OBJECTIVE: To investigate if intraperitoneal (IP) insulin infusion via programmable implantable pumps is a potential alternative to subcutaneous (SC) insulin via multiple injections. RESEARCH DESIGN AND METHODS: We compared the cost-benefits of the two methods using a randomized, prospective, 6-month, crossover design in 10 adult type I diabetic patients. RESULTS: When judged on the last month of IP versus SC periods in the nine patients who completed the study, metabolic data showed better glycemic control (HbA1c: 7.2 +/- 0.2 IP vs. 8.5 +/- 0.7% SC, mean +/- SE, P = 0.02), reduced glycemic fluctuations (SD of capillary glucose values: 3.4 +/- 0.2 IP vs. 4.6 +/- 0.2 mM SC, P < 0.01), and fewer mild hypoglycemic events (5.7 +/- 2.0 IP vs. 10.0 +/- 3.1 events/month SC, P = 0.02). Quality of life, judged by Diabetes Control and Complications Trial questionnaires, was unaffected by pump therapy. Direct costs, including pump acquisition, implantation, and follow-up, were 2.6-fold higher with IP than with SC delivery. CONCLUSIONS: The implantable pump is more effective in the short term, equally accepted, but more costly than multiple injections and should be limited to patients with unsatisfactory glycemic control despite intensive diabetes management with SC insulin. In addition, longer-term, larger-scale, and comparative evaluation is required.

[Inhaled insulin, new perspective for insulin therapy]. / L'insuline inhalée, nouvelle perspective pour l'insulinothérapie.

Since the discovery of insulin and its use in diabetes care, patients, physicians and nurses dream of another way of insulin administration than the subcutaneous injections actually used. Different types of insulin administration have been evaluated and, particularly, that using the pulmonary route. The use of this alternative method to deliver insulin may result in improved patient compliance, facilitate intensified therapies and avoid the delay of initiating insulin administration because patient's reluctance. The different insulin pulmonary delivering devices actually studied will be presented. Preliminary data comparing this way of administration and the subcutaneous injection of human regular insulin are good, but sufficient data comparing inhaled insulin with the new short-acting insulin analogues are not yet available. Among various difficulties of the pulmonary insulin delivery, the finding of an effective promoter, capable of increasing the bioavailability of insulin, is a crucial issue. The cost of such insulin administration might also be a problem. Finally, careful studies concerning the safety of this kind of administration, particularly potential long-term pulmonary toxicity, are mandatory. Nevertheless, inhaled insulin is an attractive topic in which most important pharmaceutical companies are currently involved.

The use of glipizide combined with intensive insulin treatment for the induction of remissions in new onset adult type I diabetes.

To determine if glipizide could enhance remission induction in new onset type 1 diabetes compared to intensive insulin treatment alone, 27 patients with type 1 diabetes were intensively treated in an open randomized trial with subcutaneous injections for one month. The insulin was randomly either discontinued (Group A) or the insulin discontinued and glipizide begun (Group B) Three patients in Group A (22%) and 7 in Group B (54%, p < .05) underwent insulin-free remissions for 10.3 +/- 4.4 and 8.7 +/- 2.6 months, respectively (p = NS). Mean blood glucose levels during insulin treatment were lower in patients entering remissions (94 +/- 3 mg/dl versus 102 +/- 5 mg/dl, p < 0.05). C-peptide levels were performed 0, 4, 8, and 24 weeks after insulin treatment. When all patients were examined, mean stimulated C-peptide levels at 4 weeks (0.58 +/- 0.09 pm/ml) were increased compared to time 0 (0.32 +/- 0.05 pm/ml, p < 0.02). Patients not entering remission had higher 4-week stimulated values (0.67 +/- 0.12 pm/ml) compared to time 0 values (0.29 +/- 0.06 pm/ml, p < .01), whereas remission patients' mean C-peptide levels remained similar at 0, 4, 8 and 24 weeks. These data indicate that a) insulin treatment plus glipizide induces higher rates of remission compared to intensive insulin treatment alone, b) the intensity of initial metabolic control may be an important determinant for remission induction, and c) endogenous insulin secretion is not associated with remission induction, suggesting that glipizide alters insulin sensitivity or is immunomodulatory in the context of new onset type 1 diabetes.

Alterations in reverse cholesterol transport associated with programmable implantable intraperitoneal insulin delivery.

Our previous studies have suggested that intraperitoneal (IP) insulin delivery may be associated with alterations of reverse cholesterol transport (RCT). We thus studied two parameters of RCT. We performed RCT studies in 10 C-peptide-negative type I diabetic patients who were randomized into two groups. The experimental (A) and control (B) groups were studied at -3 and 0 months before and +3 and +6 months after IP pump subcutaneous (SC) insulin use. The first step in RCT was estimated by measuring patient serum-mediated 3H-cholesterol efflux from cultured fibroblasts. Cholesteryl ester transport protein (CETP) activity was assessed by a solid-phase assay. No changes in glucose control occurred during the study. Total low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, apoprotein B, and apoprotein A-I remained unchanged during the study. Cholesterol efflux from group A increased from baseline after 3 months of IP insulin by 9.5% +/- 3.4% (mean +/- SE, P < .05), whereas in group B patients it decreased negligibly by 1.5% +/- 2.9% (P = .045 for changes between groups). CETP activity increased from baseline by 25.3% +/- 7.7% (P < .05) in group A after 3 months of IP insulin, whereas in group B it changed little, -1.5% +/- 7.9%, with modest differences between groups (P = .16). These data indicate that (1) serum from patients treated long-term with IP insulin delivery may enhance cholesterol efflux from fibroblasts and CETP activity, and (2) these effects appear independent from glucose control, implying a direct effect by IP insulin.

Comparison of intraperitoneal and subcutaneous insulin administration on lipids, apolipoproteins, fuel metabolites, and hormones in type I diabetes mellitus.

The relative biologic efficacy of intraperitoneal (IP) insulin administration over peripheral routes of insulin infusion for artificial delivery devices is still poorly documented. Thus, the effects of IP insulin administration have been compared with the effects of subcutaneous (SC) insulin administration upon circulating fuel metabolites, hormones and lipoproteins. In a longitudinal study, seven type I diabetic patients, aged 33 +/- 3 years, duration 16 +/- 4 years, were studied. SC intensive insulin therapy was used for 3 months, then insulin was infused IP via an implantable pump for 6 months with a similar good blood glucose control. Lipids including high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol, apolipoproteins A-I, A-II, and B were measured every 3 months. Although all values remained in the normal range, significant changes occurred in plasma triglycerides (63 +/- 9 SC v 88 +/- 12 mg/dL IP, P less than .05) and HDL-cholesterol (57 +/- 4 SC v 42 +/- 4 mg/dL IP, P less than .05) without concomitant changes in apolipoprotein levels. In another cross-sectional study, six of the patients consumed a standardized 400 kcal breakfast after 0.15 U/kg insulin. Eight SC insulin infused age-, glucose control- and weight-matched diabetic patients also underwent the same test using SC insulin. Six normal subjects consumed the same breakfast and served as controls. Plasma glucose, B-hydroxybutyrate, lactate, alanine, free fatty acids, free insulin and glucagon were measured for five hours after the meal. All measured parameters were comparable in both groups except free insulin and lactate.(ABSTRACT TRUNCATED AT 250 WORDS)

Implantable programmable insulin pumps for the treatment of diabetes.

Implantable programmable pump systems for insulin delivery to the peritoneal cavity or for intravenous insulin delivery have been recently developed. Thirty-one pumps were implanted in 25 patients between 1987 and 1991. At this writing, 76% of patients had functioning pumps. Ninety-two percent of pumps were functioning at 1 year; 89% at 2 years; and 50% at 3 years. No life-threatening complications, either surgical or metabolic, developed. However, 18 patients required 23 outpatient procedures for maintenance of pump function or for pump removal. Metabolic improvement was evidenced by mean and standard deviation of blood glucose levels and by glycosylated hemoglobin levels.

Transfer of patients with diabetes from semisynthetic human insulin to human insulin prepared by recombinant DNA technology using baker's yeast: a double-blind, randomized study.

A multicenter, double-blind, randomized, parallel-group, 12-month study was conducted to determine if patients with diabetes could be transferred safely and effectively from semisynthetic human insulin (ssHI) to human insulin produced by recombinant DNA technology using baker's yeast as the host cell [rDNA HI (BY)]. Sixty-five patients who ranged in age from 19 to 67 years and who had been on a stable dose of NPH or Lente ssHI with or without Regular ssHI participated. Forty-three were transferred randomly to rDNA HI (BY) and 22 continued on ssHI. Evaluation at both six and 12 months of treatment indicated no statistically or clinically significant differences between the ssHI and rDNA HI (BY) groups with regard to the mean changes from baseline in glycosylated hemoglobin, total daily insulin dose, or body weight. In addition, the proportions of patients who had episodes of mild or moderate hypoglycemia, severe hypoglycemia, hyperglycemia, or other clinical experiences related to diabetes or treatment were similar in the ssHI and rDNA HI (BY) groups. No pattern of unexpected retinal changes occurred, nor were there any remarkable changes in human insulin antibody binding or in mean or individual yeast antibody values in either group. These results show that patients with diabetes can be safely and effectively transferred from semisynthetic human insulin to human insulin produced by rDNA technology from baker's yeast with no change expected in the insulin dose.