Search

The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation 303 (PREDICTIVE 303) Study (n = 5604) evaluated the effectiveness of insulin detemir, a long-acting basal insulin analogue, using a simplified patient self-adjusted dosing algorithm (303 Algorithm group) compared with standard-of-care physician-driven adjustments (Standard-of-care group) in a predominantly primary care setting, over a period of 6 months. Insulin detemir was to be started once-daily as add-on therapy to any other glucose-lowering regimens or as a replacement of prestudy basal insulin in patients with type 2 diabetes. Investigator sites rather than individual patients were randomized to either the 303 Algorithm group or the Standard-of-care group. Patients from the 303 Algorithm group sites were instructed to adjust their insulin detemir dose every 3 days based on the mean of three 'adjusted' fasting plasma glucose (aFPG) values (capillary blood glucose calibrated to equivalent plasma glucose values) using a simple algorithm: mean aFPG < 80 mg/dl (<4.4 mmol/l), reduce dose by 3 U; aFPG between 80 and 110 mg/dl (4.4-6.1 mmol/l), no change; and aFPG > 110 mg/dl (>1.1 mmol/l), increase dose by 3 U. The insulin detemir dose for patients in the Standard-of-care group was adjusted by the investigator according to the standard of care. Mean A1C decreased from 8.5% at baseline to 7.9% at 26 weeks for the 303 Algorithm group and from 8.5 to 8.0% for the Standard-of-care group (p = 0.0106 for difference in A1C reduction between the two groups). Mean FPG values decreased from 175 mg/dl (9.7 mmol/l) at baseline to 141 mg/dl (7.8 mmol/l) for the 303 Algorithm group and decreased from 174 mg/dl (9.7 mmol/l) to 152 mg/dl (8.4 mmol/l) for the Standard-of-care group (p < 0.0001 for difference in FPG reduction between the two groups). Mean body weight remained the same at 26 weeks in both groups (change from baseline 0.1 and -0.2 kg for the 303 Algorithm group and the Standard-of-care group respectively). At 26 weeks, 91% of the patients in the 303 Algorithm group and 85% of the patients in the Standard-of-care group remained on once-daily insulin detemir administration. The rates of overall hypoglycaemia (events/patient/year) decreased significantly from baseline in both groups [from 9.05 to 6.44 for the 303 Algorithm group (p = 0.0039) and from 9.53 to 4.95 for the Standard-of-care group (p < 0.0001)]. Major hypoglycaemic events were rare in both groups (0.26 events/patient/year for the 303 Algorithm group and 0.20 events/patient/year for the Standard-of-care group; p = 0.2395). In conclusion, patients in the 303 Algorithm group achieved comparable glycaemic control with higher rate of hypoglycaemia as compared with patients in the Standard-of-care group, possibly because of more aggressive insulin dose adjustments. The vast majority of the patients in both groups were effectively treated with once-daily insulin detemir therapy. The use of insulin detemir in this predominantly primary care setting achieved significant improvements in glycaemic control with minimal risk of hypoglycaemia and no weight gain.

Aim: The aim of this study was to compare the long-term safety and efficacy of twice-daily insulin detemir or NPH insulin as the basal component of basal-bolus therapy in people with type 1 diabetes., Methods: A multicentre, open-label, parallel-group study was conducted over 12 months and completed by 308 people (from an original randomized cohort of 428). Patients were randomized in a 2:1 ratio to receive insulin detemir or NPH insulin before breakfast and dinner, with insulin aspart at mealtimes., Results: Glycaemic control improved in both groups with HbA(1c) decreasing by 0.64 and 0.56% point in the insulin detemir and NPH insulin groups, reaching baseline-adjusted final values of 7.53 +/- 0.10% and 7.59 +/- 0.13%, respectively. No significant difference was apparent between treatments in terms of HbA(1c), fasting plasma glucose or 9-point blood glucose profiles. Fewer hypoglycaemic events (major and minor) occurred in association with insulin detemir compared with NPH insulin, but the overall hypoglycaemic risk did not differ statistically significantly (RR for detemir, 0.78 [0.56-1.08]). However, the risk of nocturnal hypoglycaemia during the maintenance phase (month 2-12) was 32% lower in the detemir group (p = 0.02) and lower in every month. This risk reduction remained statistically significant after correction for HbA(1c). After 12 months, baseline-adjusted mean body weight was significantly lower in the insulin detemir group than in the NPH insulin group (p < 0.001)., Conclusions: In long-term basal-bolus therapy, insulin detemir with insulin aspart as mealtime insulin is well tolerated and reduces the risks of nocturnal hypoglycaemia and weight gain compared to NPH insulin.

French type 2 diabetic patients are underinsulinised mainly because of fear of injections. Among all alternatives to the subcutaneous route, only the lung has a sufficient bioavailability of 10% without addition of promoters. This is made possible by the large surface and thinness of the alveolo-capillary barrier, and only if insulin particles have an ideal size (2-3 microns). The Pfizer-Aventis-Inhale project utilises powder aerosolisation, whether the Novo-Aradigm project utilises liquid nebulization. In the former project, phase 1 studies have shown plasma kinetics similar to subcutaneous lispro, and intrasubject reproducibility non significantly different from rapid and lispro insulins. Phase 2 studies, performed on more than 200 insulin-treated and non insulin-treated subjects have shown an efficacy similar to subcutaneous insulin, with no difference in terms of side-effects (hypoglycaemia, weight gain) and a satisfactory 1-year local tolerance, as evaluated by functional tests. Phase 3 studies, performed on 1400 subjects have just been completed and are not published yet. Though results are promising, some important questions remain to be clarified: long term tolerance, miniaturisation of the inhaler, overcost, and long-term acceptability, especially in type 2 patients. It already appears that the major potential indications may be "functional" (flexible) insulin therapy of type 1 diabetes and early insulinisation of type 2 patients with oral drugs failure.

Background and Aims: Secondary failure to oral hypoglycaemic agents, a common evolution of long-standing Type 2 diabetes, is usually assessed by non-standardized indices requiring fine clinical assessment, including hyperglycaemia resistant to maximum doses of sulphonylureas despite appropriate diet and follow-up. The goal of this study was to evaluate if HOMA, a modelized plasma insulin/glucose ratio allowing simple evaluation of residual insulin secretion and sensitivity, is a better predictor of the insulin requiring stage than clinical indices., Materials and Methods: HOMA was measured in 84 Type 2 diabetic patients aged 58 +/- SD 6 years, with diabetes duration 11 +/- 4 years, hospitalized because of hyperglycaemia resistant to maximal doses of sulphonylureas (e.g. glibenclamide > or = 15 mg/day), with no apparent external reason for hyperglycaemia. Despite reinforced appropriate diet recommendations, 62 of these patients remained hyperglycaemic (insulin-requiring group)., Results: Age, duration of diabetes, body mass index (BMI) and HOMA value for insulin sensitivity (71 +/- 6% vs. 76 +/- 7%, normal values 59-161%) were comparable in the two groups. HbA(1c) was higher (10.0 +/- 0.2% vs. 8.3 +/- 0.3%, P < 0.001) and HOMA insulin secretion values lower (25 +/- 2% vs. 43 +/- 6%, normal values 70-150%, P < 0.01) in the insulin-requiring group. Of the following potential predictors: HbA(1c) > 8%, duration of diabetes > or = 10 years, HbA(1c) combined with diabetes duration, insulin sensitivity < or = 40%, insulin secretion < or = 20%, the latter showed the best positive predictivity (86% patients with low insulin secretion were insulin-requiring)., Conclusions: (i) HOMA is a simple and good predictor of the insulin-requiring stage in Type 2 diabetes mellitus; (ii) this stage of diabetes is characterized by a further decline of insulin secretion rather than of insulin sensitivity. Diabet. Med. 18, 584-588 (2001)

External insulin infusion (CSII) pumps have regained interest since DCCT, the number of patients approaching 100,000 in the USA. Only 2 manufacturers (Minimed, Disetronic) and 2 insulins (lispro, insuman) are sharing the market. The major advantages over multiple s.c. injections (MDI) are a reduction of nightly instability and hypoglycemia, and time flexibility. Patients poorly controlled under MDI and/or with recurrent hypoglycemias thus represent the best indications. Pumps are predicted to expand in some european countries e.g. France with changes in reimbursement regulations. Implantable insulin pumps are still not commercialized except in few countries e.g. France. Therefore only 1065 pumps have been implanted worldwide so far. The only material available is the Minimed 2007 pump, with the Aventis Genapol insulin. The catheter is intraperitoneal for portal insulin absorption. Metabolic results are better than CSII in terms of glycemic fluctuations and hypoglycemias. Adverse events are limited to catheter obstructions (15% per patient-year). Ideally, indications should be restricted only to patients with recurrent severe hypoglycemias and/or poor control with CSII because of high cost of the pump ($ 15,000).

Management of very high insulin requirements in rare extreme insulin resistance syndromes is difficult and poorly documented. We report a case of a type B insulin-resistant patient requiring approximately 10,000 units of insulin per day, i.e. beyond the possibilities of current insulin formulations and delivery devices. Only the Panomat C10 portable pump model (Disetronic) and U500 Humulin (Lilly) allowed the required rate of 400 units per hour to be attained only when the reservoir was changed twice daily and the site and catheter were changed once daily. Three months after discharge, the patient was in good general and local condition, but with only fair diabetes control (glycated haemoglobin 9.5%).

The difficulties of achieving good glycaemic control in insulin-dependent diabetes are due in large part to the inadequacies of subcutaneously administered insulin. In particular, resorption with the long acting form is variable from one subject to another and from one day to another and irregular over time, whereas the action of the rapid acting form is too late and prolonged. The slowness of absorption of the rapid acting form is attributable to the need for hexamer dissociation. The Lilly Laboratories, by inverting the amino acids lysine and proline in positions 28 and 29 in the B chain, have created an insulin (Lispro) which more rapidly dissociates into monomers after injection. The stability of Lispro is good, probably because of its phosphate buffer. In our experience, in conditions simulating use in portable insulin pumps, Lispro proved to be more stable than insulins specially intended for this use. The affinity in vitro was identical to that of insulin for its receptor. The affinity for insulin-like growth factor-I (IGF-I) receptor has been found to be 1.5 times as high as that of fast insulin in some models and comparable in others, and nearly 1,000 times less than that of IGF-1. Studies on in vivo potency and ex vivo cell growth, as well as of tolerance in the animal (mutagenicity, toxicity and carcinogenicity), have not shown a different effect from regular insulin (contrary to results for analogue Asp B10). The pharmacokinetics has shown an earlier and higher insulinaemic peak and a more rapid return to baseline values than regular insulin. On the basis of pharmacokinetic studies in normal subjects and diabetic patients, the characteristics retained by the licensing authorities are onset of action at 15 min, insulinemic peak between 30 and 70 min, and duration of action 2 to 5 h. Some clinical studies have shown a shortened action period of 1 to 3 h as compared to regular insulin and less influence of dose and injection site, notably with a return to normal insulin levels. The time required for normalisation is increased by 1 h if the injection is made in the thigh rather than the abdomen, as compared to 2 to 3 h for conventional insulin. This suggests that Lispro should be administered just before the meal (0 to 15 min). In some patients, an insulin with prolonged action can be added if the interval between injections is prolonged, i.e. always at the evening meal but possibly also at the noon meal. Lispro can be mixed with Umuline NPH or Umuline zinc without any alteration in its pharmacokinetics and potency if the injection is performed immediately. The few studies that have considered glycaemic stability and reproducibility have shown a tendency toward improvement in glycaemic excursions during the day, as measured by MAGE, and in insulinaemia variability expressed in area under the curve, which was reduced by half in the same individual or from one individual to another, with less marked impact on the variability from one day to another of glycaemic excursions. On the whole, Lispro provides faster kinetics, greater stability and possibly better reproducibility than fast insulin. These advantages, if confirmed by clinical experience, should allow an improvement in the comfort and glycaemic stability of diabetic patients.

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.

The aim of this study was to develop a diagnostic procedure for pumping unit malfunction by radionuclide imaging (RI) and to validate the method by comparing the results with those obtained using more conventional methods. Fifteen radionuclide investigations were performed in 11 patients with intraperitoneal implantable insulin pumps. One mCi of 99 mTc in 1 ml isotonic sodium chloride was injected into the reservoir. The results based on catheter visualization and peritoneal accumulation were compared blindly to the efficacy of alkaline rinses and laparoscopic findings. In all RI stoppage cases except one alkaline rinses failed to restore flow. Where laparoscopy was performed, comparisons were concordant i.e. no outflow from the tip of the catheter. The RI images obtained were reproduced in vitro using a pump under normal flow conditions and complete proximal and distal catheter obstruction. RI is a safe, quick non invasive method which allows the location of the site of pump/catheter malfunction within a one step procedure and the prediction of the efficacy of sodium hydroxide rinses.

Intraperitoneal (IP) insulin infusion with programmable implantable pumps is associated with a reduction in hypoglycaemic events when compared to intensive diabetes management with subcutaneous insulin in patients with Type 1 diabetes mellitus. The mechanism may involve more physiological insulin kinetics, lower peripheral insulin levels or a specific hepatic action of portal insulin on hypoglycaemic counter regulation. To investigate the latter two hypotheses, we performed two hypoglycaemic clamps (controlled blood glucose decrement to 2.2 mmol l-1) in random order in 12 Type 1 diabetic patients. Insulin was infused either IP or IV for 150 min, at rates chosen to generate similar peripheral insulin levels (1 mU/kg-1 min-1 IV or 2 mU/kg-1 min-1 IP, n = 6) to evaluate direct hepatic action, or at similar rates (1 mU/kg-1 min-1 IV and IP, n = 6) to evaluate IP indirect effects via lower peripheral insulinaemia. Hepatic glucose production and glucose utilization were measured by [6.6 2H] glucose dilution technique. Glucose production was lower (1.7 +/- 0.4 vs 0.5 +/- 0.4 mg kg-1 min-1, p < 0.05), and utilization was similar at the end of the matched-insulinaemia IV and IP clamps, respectively. By contrast, glucose production was higher (1.7 +/- 0.5 IV vs 2.7 +/- 0.3 IP mg kg-1 min-1, p < 0.01) and glucose utilization lower (4.4 +/- 1.0 IV vs 3.3 +/- 0.2 IP mg kg-1 min-1, p < 0.05) with IP delivery at the end of the matched-dose clamps. Counterregulatory hormones and hypoglycaemic symptoms increased similarly in all clamps. In summary, IP insulin, when compared to IV insulin at similar delivery rates, but not at similar insulinaemia, is associated with a less negative glucose balance (glucose production-glucose utilization) during hypoglycaemia. Such a mechanism may play a role in the reduced hypoglycaemic risk seen with IP implantable pumps.

The DCCT study confirmed the importance of optimizing insulin therapy to reduce the microvascular risks of diabetes mellitus. Optimization requires improving the methods already in use. Recent results must be used to improve patient motivation. Control of blood glucose levels must include improving the frequency and/or the quality of follow-up (pluridisciplinary consultations). Follow-up must be improved, taking advantage of the recent developments such as rapid glycosylated haemoglobin assay and computerized glucose meters. Of course, improvement in blood glucose must aim at normal levels, accepting the increased risk of hypoglycaemia. The insulin-tool itself must be improved on the basis of recent developments including ultra-rapid analogues and external and implantable insulin pumps. Finally, a major challenge is to develop these improvements without increasing too greatly the patient's short-term costs and without causing further discomfort.

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.

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.

Since feasibility is now proven, cost-efficacy of external sub-cutaneous (EXT) and implantable programmable (IMP) insulin pumps needs to be compared to those of intensified conventional insulin therapy (CONV). Only metabolic efficacy and short-term direct costs are easily evaluable. We (WHO-CSII Study) and others have shown that glycemic control and severe hypoglycemia risk are slightly improved, while ketoacidosis risk and costs are aggravated with EXT vs CONV. We (CEDIT Study) and others have shown that glycemic control, mild and severe hypoglycemic risks are improved, with no increase in ketoacidosis rates although a doubling in costs with IMP vs CONV. Rigid interpretation of the above data would limit indications of insulin pumps to patients experiencing frequent hypoglycemias while on intensified conventional insulin therapy.

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.

Conventional insulin therapy, particularly when intensive, dose not provide all the comfort and effectiveness desired. The new insulin therapy methods that are, or will soon be, available are described in this review paper. The new types of subcutaneous insulin administration include the so-called "fountain-pens"--in fact ready-to-use syringes--and portable insulin pumps, which are helpful to some patients. Pancreas and islets transplantations are limited by the problem of tissue harvesting and by the necessity of chronic immunosuppression. Nasal insulin sprays will replace rapid insulin injections when the problem of bioavailability is solved and the lack of toxicity is demonstrated. The implantable artificial pancreas is still awaiting the development of long-term reliable glucose sensors, but one of its elements, the implantable insulin pump, is already operational; its safety and reliability have now been proven; its effectiveness seems to result from a better stabilization of blood glucose level variations; it will not supersede conventional injections, but it is the only alternative for patients with poor glycaemia control and notably for those at high risk of hypoglycaemia.

Insulin therapy by subcutaneous injection is not satisfactory: it rarely brings down glycaemia to its normal level, exposes to the risk of hypoglycaemia and hyperinsulinism, is difficult to endure for a long period and requires full patient's involvement. Improvements are being achieved in the route of insulin administration (intraperitoneal and nasal routes), the type of insulin (analogues) and the material used to administer the hormone (insulin pens and implantable pumps).

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.

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.

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.

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.

Circulating lymphocytes from 39 juvenile insulin dependent diabetics of recent onset were studied by six membrane marker techniques and mitogen stimulation. Well controlled (n = 14) were grouped separately from poorly controlled (n = 25) patients. The total lymphocyte counts were not different from 50 control subjects. The percentage of T-cells detected by erythrocyte rosettes and B-cells detected by erythrocytes--antibody--complement rosettes was significantly decreased only in poorly-controlled diabetics (64.1 +/- 1.3 and 9.7 +/- 1.8, vs 71.0 +/- 1.0 and 15.3 +/- 0.6 in controls). Cells bearing receptors for the Fc fragment of IgG immunoglobulins were decreased in both groups. Mitogen stimulation was not different from controls but was significantly lower in poorly controlled than in well controlled diabetics. Optimal blood glucose control for 5 +/- 2 days using an external artificial pancreas led to a rapid normalisation of membrane marker values and mitogen responsiveness of lymphocytes from previously poorly controlled diabetics. Separate in vitro experiments showed that glucose had an inhibitory effect on mitogen stimulation at concentrations greater than or equal to 8.3 mmol/l and on T- and B-lymphocyte numbers at concentrations greater than or equal to 55.6 mmol/l. DL 3-hydroxybutyrate tested at 17.1 and 34.2 mmol/l only depressed mitogen responsiveness. Such results suggest a rapidly reversible T-cell defect closely linked to the existing metabolic disturbances.

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.

With the artificial pancreas used by the authors, insulin was delivered through a venous infusion and the rate of delivery was adjusted according to data provided by a continuous blood glucose monitor. After different trials we selected control algorithms integrating two parameters: instantaneous blood glucose concentration and increasing or decreasing patterns of blood glucose. A constant basal insulin infusion rate was added and improved the control of glycaemic excursions. Different parameters concerning exogenous insulin homoeostasis were determined. The delay to reach an insulin effect was 18+/-2 min and was shortened by a priming-dose at the beginning of the infusion. The insulin effect remained for 28+/-2 min after the infusion had been stopped, but differences were noted in the morning (21+/-2 min), in the afternoon (32+/-2 min) and during the night (25+/-3 min). Insulin needs were evaluated during meals. Related to the amount of carbohydrates, the doses fell from 0.53 units/hr/g of carbohydrate for breakfast to 0.15 for dinner. From these data, it appears that the efficiency of exogenous insulin exhibits a circadian rhythm.

To evaluate the immunogenicity of human insulin preparations, the treatment of 10 insulin-dependent diabetic patients was changed from purified porcine insulins to lente and regular semisynthetic human insulin (SSHI, N = 5) or NPH and regular biosynthetic human insulin (BHI, N = 5). Circulating levels of T lymphocyte subsets, in vitro responses of enriched mononuclear cells to mitogens and circulating insulin antibody measurements were performed before and during the 24 weeks of treatment. Insulin antibody levels did not change significantly in either human insulin treatment group. Circulating levels of Leu 1 and Leu 3 positive cells, identifying total and helper/inducer T lymphocyte populations respectively, and the Leu 3:Leu 2 (helper/inducer: suppressor/cytotoxic) T cell ration were all reduced (p less than 0.025) at eight weeks in the BHI treatment group. Cells identified with murine monoclonal antibody, Leu 7 defining a natural killer cell phenotype, were increased in the SSHI group at four weeks of study (p less than 0.05). There was a decreased pokeweed mitogen-induced proliferation of mononuclear cells in SSHI treated patients (p less than 0.01) at 12 weeks and both insulin treatment groups had increased responses to phytohemagglutinin (p less than 0.05) but not concanavalin A at 24 weeks. These data indicate that changes in the cellular immune system without associated changes in circulating anti-insulin antibody levels can be observed in patients whose treatment was changed from purified porcine to human insulin preparations. Thus, cellular immune responses may be more sensitive than humoral immune responses as indicators of immunological alterations to insulin preparations.

Recent studies have suggested that optimal glucose control fails to arrest or even worsens background retinopathy possibly by aggravating retinal ischaemia. Fourteen insulin-dependent diabetic patients, aged 34 +/- 11 years (mean +/- SD) treated by long-term intraperitoneal insulin infusion using portable pumps, were followed for 3 years. Preproliferative or proliferative lesions on ophthalmoscopy and large non-perfused areas on fluorescein angiography were exclusion criteria. Six patients were found to have minimal and 8 mild background retinopathy. The patients were retrospectively assigned to two comparable groups except for their glycaemic equilibrium under insulin infusion: average control (n = 6) and excellent control (n = 8), although glycaemic control was significantly improved in all cases when compared to previous conventional therapy. Fluorescein changes were scored blindly and independently by 3 ophthalmologists according to modifications of fluorescein diffusion and capillary abnormalities. The two types of retinal lesions improved gradually in 10 patients and deteriorated in only 1 patient, although not progressing to proliferative retinopathy. Structural improvements were significantly more frequent in the excellently controlled group. We conclude that non-ischaemic lesions may still be arrested and even improved by tight metabolic control.

Five insulin treated diabetics were studied on three consecutive days. Overnight variable intravenous insulin infusions were used before each study to maintain normoglycaemia and to calculate the optimal basal insulin infusion rate (1.1 +/- 0.1 U/h) which ws then kept constant throughout the study day. A standard 400 kCal breakfast with 25 g xylose was given at 0800 h. When the blood glucose rose above 4.1 mmol/l, an external artificial pancreas was used to infuse either extra insulin (day INS) or somatostatin for either 3h (day som) or the entire 8h experimental period (day SOM). Peak post-prandial blood glucose values were similar on all three days. The blood glucose rebounded after the cessation of the somatostatin infusion on day som. Post-prandial blood xylose peaks were lowered by somatostatin on both days but rebounded after the cessation of the somatostatin infusion on day som. The area under the plasma and urinary xylose curves was lowered by somatostatin only on day SOM. Growth hormone and glucagon levels were not statistically different on all 3 days. Thus somatostatin, when added to an optimal insulin infusion, minimised the insulin requirements by slowing intestinal absorption, but led to rebound hyperglycaemia if not feed-back controlled.

Presented are results obtained with a continuous intravenous infusion of regular insulin in 13 cases of diabetic ketoacidosis. A bolus of 10 units of insulin followed by an average of 15 units delivered via an infusion pomp induce an immediate and regular decrease of blood glucose levels (1.63 +/- 0.15 g/h). A large quantity of glucose (25 g per hour) shortens duration of ketosis (7.0 +/- 1.2 h).

Remission of diabetes was attempted in 12 recent acute onset ketosis-prone juvenile diabetes after short term (5 +/- 1 days) but excellent blood glucose control by the external artificial beta-cell. The comparison group comrised patients undergoing traditional treatment (n = 28). Nine (75%) persistent (over 3-14 months of duration) although partial (oral drugs required) remissions were obtained in the former group as compared to 3 (11%) in the latter group (p less than 0.05). Cases which showed remissions after insulin infusion had a plasma insulin response to IV glucagon still present before insulin infusion, and a daily urinary C-peptide excretion significantly enhanced after (p less than 0.01). Urinary C-peptide/blood glucose remained improved during the remission period. Thus, early effective treatment by means of the artificial pancreas may break the vicious circle hyperglycaemia-insulin depletion-hyperglycaemia and lead to frequent and sustained remissions of juvenile diabetes.

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.

The vitamin D status of IDDs was studied in 3 groups of patients who were treated for several months with (i) conventional insulin therapy (group I, n = 17, HbA1 = 10.1 +/- 0.5%); (ii) continuous subcutaneous insulin infusion (CSII, group II, n = 11, HbA1 = 8.9 +/- 0.6%); and (iii) continuous intraperitoneal insulin infusion (CPII, group III, n = 13, HbA1 = 8.0 +/- 0.4%). In all patient groups the plasma concentration of vitamin D metabolites were within normal range. However plasma 25 OH D (ng/ml) was significantly lower in groups I (13.0 +/- 0.8, P less than 0.01) and II (12.5 +/- 1.5, P less than 0.02) than in group III: 22.1 +/- 2.3 (normal range 7-27). Plasma 24,25-(OH)2D (ng/ml) was positively correlated to plasma 25 OH D and was significantly decreased in groups I (1.5 +/- 0.2, P less than 0.05) and II (1.4 +/- 0.2, P less than 0.05) compared with group III: 2.3 +/- 0.3. No significant differences were found in plasma 1,25-(OH)2D between the three groups of diabetics. Plasma PTH was similar in the three groups. The same differences in plasma 25 OH D were observed between the patients treated with CPII and 15 subcutaneously treated patients matched for diabetic control (HbA1 less than 10 per cent). The present results seem to indicate that insulin might have a stimulatory effect on the hepatic 25 hydroxylase activity.

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)