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The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetic complications while reducing the frequency of hypoglycaemic episodes. Continuous subcutaneous insulin infusion (CSII) using an external pump is an intensive diabetes therapy recognized to improve metabolic control and glycaemic instability, and to reduce the frequency of severe hypoglycaemia. For years, the theoretical advantages of the insulin pump (constancy of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycaemic variability) have contributed to its reported superiority compared with multiple daily injections (MDI). However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII. Recently, several studies reported that children and adolescents, and patients whose blood glucose imbalance was initially the most pronounced with basal-bolus regimens, would particularly benefit from CSII. Other indications were also proposed in marginal clinical situations with highly selected patients in whom a significant improvement of blood glucose was demonstrated. Finally, the use of CSII in type 2 diabetic patients now appears to be a good alternative to the ineffective MDI regimens observed in some of these patients. However, past experience with CSII indicates that candidates for insulin pump therapy must be carefully selected and strongly motivated to improve their glucose control. Use of CSII also requires strict medical supervision by physicians and a regular programme of patient education by paramedical teams, to ensure optimal responsible use of this technique by healthcare professionals.

There are many reasons to believe that in the near future, the treatment of patients with Type 2 diabetes will be characterised by an increased use of insulin therapy. To ensure that insulin regimens are acceptable to patients, and implemented by physicians, they should be as simple and efficient as possible. Simplicity is synonymous with the regimen of once-daily basal insulin glargine given at any time of the day (at the same time each day). With such a strategy, the dose is adjusted by titrating to target fasting blood glucose values of 5.0 - 7.2 mmol/L (90 - 130 mg/dL). When these targets can no longer be achieved with reasonable doses of long-acting insulin, a rapid-acting insulin analogue should be added at meal times. A step-by-step strategy can be used; it is recommended that initially, a single daily prandial bolus of a rapid-acting insulin analogue is administered before the meal that leads to the highest post-meal blood glucose excursions. Further boluses can be added at other meal times as necessary, i.e, when post-meal blood glucose values remain above 10.0 mmol/L (180 mg/dL) and 7.8 mmol/L (140 mg/dL) at mid-morning and 2h-post-lunch or post-dinner times, respectively. This stepwise strategy may eventually lead to a standard basal-bolus regimen with 3 pre-meal injections of rapid-acting insulin analogues, a potentially small trade-off for achieving fairly-well controlled diabetes.

A case of type III (Arthus') hypersensitivity to insulin which occurred several years after insulin treatment was instituted is described. Its persistence even with highly purified insulins of bovine or porcine origin was suggestive of a direct reaction against insulin itself. The patient had no history of allergy and, contrary to most similar cases published, had not received intermittent insulin therapy. Using stimulation of lymphocyte blastogenesis, the authors were able to demonstrate the presence of specific antigen-mediated hypersensitivity to all insulins tested, including human insulins. The circulating immune complexes did not appear to be pathogenic, since the patient only had minimal retinopathy after 22 years of insulin-dependent diabetes. Human insulin was tolerated and proved effective in controlling both blood glucose levels and skin rashes in response to conventional insulins.

We have determined peripheral venous somatostatin like immunoreactivity (SLI) levels in 11 normal subjects (blood glucose--BG--: 4.4 +/- 0.1 mM; ketone bodies--KB--: 90 +/- 12 microM; plasma free fatty acids--FFA --: 340 +/- 42 microM), 4 Biostator controlled insulin dependent diabetics (BG: 5.4 +/- 0.2 mM; FFA: 418 +/- 38 microM; KB: 226 +/- 41 microM) and 7 poorly controlled ketotic diabetics (BG: 10.8 +/- 1.3 mM; FFA: 915 +/- 19 microM; KB: 2490 +/- 576 microM). SLI was determined again after 48 to 96 hours of intravenous insulin infusion for the 7 ketotic diabetics and after transient interruption of insulin infusion for the Biostator controlled diabetics. Relative to normal subjects ketotic diabetics had elevated SLI levels (29.7 +/- 5.9 vs 13.5 +/- 1.8 ng/L, p less than 0.01) whereas biostator-controlled patient had near to normal values (20.4 +/- 6.4 ng/L, p greater than 0.30). Transient arrest of insulin infusion in the Biostator controlled diabetics resulted only in a mild metabolic deterioration (BG: 12.8 +/- 2.1 mM; FFA: 640 +/- 146 microM; KB: 950 +/- 163 microM) without a significant rise of SLI. Intravenous insulin infusion in the initially ketotic patients decreased BG and KB in each subject (p less than 0.01) but decreased FFA (1097 +/- 170 to 453 +/- 74 microM, p less than 0.05) and SLI (34.0 +/- 12.0 to 9.8 +/- 2.4 ng/L, p less than 0.05) only in 4 patients whereas both FFA (737 +/- 107 to 725 +/- 25 microM) and SLI (27.6 +/- 4.7 to 20.3 +/- 4.7 ng/L) levels remained stable in the other 3. These results suggest that SLI levels in type I diabetics are dependent the degree of metabolic control and could be related to the variations of FFA concentrations.

To compare daily blood glucose and free-insulin profiles after the administration of two different mixtures of semisynthetic human insulins (soluble + lente or soluble + NPH), 8 well-controlled insulin-dependent diabetic patients with identical basal blood glucose levels were studied. At the beginning of the first daily period of study, each subject was connected to an Artificial Pancreas to achieve a standard blood glucose (100 mg/dl); after at least 4 hours of normoglycemia, feed-back control was interrupted and the insulin mixture injected, at 8 p.m. and 8 a.m., at the dose previously optimised but always in the ratio 1:2 (1/3 rapid-acting + 2/3 intermediate-acting insulin). Blood glucose and free-insulin were then monitored for a 24-hour period, starting from 8 p.m. The same observation was repeated for each patient a few days later, only changing the intermediate-acting insulin. After dinner (8.30 p.m.) and after breakfast (8.30 a.m.) mean blood glucose was lower with soluble + NPH mixture, while early in the morning and in the late afternoon better glycaemic control was achieved with soluble + lente. F-IRI showed an almost specular behaviour: lower values soon after mixture injection and higher levels 8-12 hours later were observed with soluble + lente than with soluble + NPH. These data indicate that, at the ratio 1:2, the mixture of short-acting with lente HM insulin differs from the one with NPH not only for a lower activity of soluble insulin but also for a stronger and more prolonged effect of the intermediate preparation. This difference should be carefully taken into account in clinical practice.

To determine the effect in normal subjects of small variations of insulin and glucagon on plasma aminoacids concentrations we suppressed endocrine pancreas secretion with somatostatin and measured aminoacids levels during a sequential insulin infusion in the absence (control test, low glucagon level) or in the presence (normal glucagon concentration) of a replacement glucagon infusion. Insulin infusion rates were 0.05, 0.09, 0.15 and 0.30 mU.kg-1.min-1 during the control test and 0.09, 0.15, 0.30 and 0.40 mU.kg-1.min-1 during the replacement test. During the control test, glucagon decreased (p less than 0.01) and insulin levels were successively 8.2 +/- 0.4, 10.1 +/- 0.7, 11.9 +/- 0.14 and 18.5 +/- 0.8 mU.l-1. The only effect on insulin was to decrease branched-chain aminoacids (BCAA). BCAA were inversely related to insulinemia (p less than 0.01). A significant decrease was obtained for an insulin level of 11.9 +/- 0.4 mU.l-1, a value intermediate between those decreasing glycerol (10.1 +/- 0.7 mU.l-1) and stimulating total body glucose uptake (18.5 +/- 0.8 mU.l-1). During the test with glucagon replacement glucagon was maintained at its initial value. Insulin levels were successively 8.3 +/- 0.3, 11.9 +/- 0.3, 19.7 +/- 0.6 and 26.7 +/- 0.5 mU.l-1. Insulin decreased always BCAA but also threonine, proline, tyrosine, methionine and total aminoacid levels. BCAA were always inversely related to insulin levels (p less than 0.01) but the slope of the relationship was modified and more insulin was needed to decrease BCAA concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

In this long-term prospective study, including 45 diabetic children and adolescents under the age of 20 years, insulin antibodies and other immunological factors (circulating immune complexes, autoantibodies, etc.) were compared before and during a two-year follow-up after a switch-over from monocomponent porcine insulins to monocomponent semisynthetic human insulins. IgG insulin antibodies were detected in 21 children out of 45 (47%) at a mean level of 0.96 mU/ml (0.77-1.15). A significant and important decrease of both the number of patients having insulin antibodies and the level of insulin antibodies was observed 18 months after the switch-over. After 24 months, IgG insulin antibodies were only present in 5 patients (11%) at a mean level reduced by half (0.53 mU/ml; p less than 0.05). Four patients out of the five (80%) had HLA-DR3 DR4 antigens while this phenotype was only prevalent in 26% of the initial patient cohort. On the other hand, 3 months after the transfer, there was a significant and persistent decrease (by half) of non-specific immune complexes (39% of the patients with porcine insulins) which did not appear to correlate with the level of insulin antibodies. The prevalence of autoantibodies and of antinuclear factors showed no significant variations. The practical implication of these findings is that the use of semisynthetic human insulins could be of interest in patients previously treated by porcine insulins.

An insulin suppression test performed in random order with either biosynthetic human insulin or purified pork insulin was used to compare biological activity of these two insulins in obese patients suffering from varying degrees of glucose intolerance. Blood glucose curve, steady-state blood glucose levels, insulin sensitivity indices and steady-state plasma insulin levels were identical during the two sets of tests. Furthermore endogenous insulin and glucagon secretion were similarly suppressed. The insulin suppression test is a simple and rapid procedure to compare the biological activity of fast-acting insulins. Our results confirm the insulin-resistance in obesity and clearly show that biosynthetic human and porcine insulins have similar biological potency.

The influence of the insulin concentration on its absorption from the subcutaneous tissues was studied by direct measurement of the appearance of insulin in the circulation after its subcutaneous administration. 10 units of regular insulin of semisynthetic human and porcine origin in strength of 15 units/ml, 40 units/ml, and 100/units/ml were administered as bolus to 9 healthy male volunteers, using switched-off, manually handled insulin pumps. Insulinaemia rose significantly higher (p less than 0.05) and insulin levels peaked earlier after the delivery of the 15 units/ml insulin solutions compared to the 100 units/ml insulin solutions. These findings might be of interest for type-I diabetic patients using insulin pumps that are to be loaded with regular insulin in varying concentrations.

The response of intermediary metabolite concentrations was measured in six insulin-dependent diabetic men during intravenous low-dose incremental insulin infusion. Insulin was infused during consecutive hours at rates of 0.01 u/kg/h, 0.05 u/kg/h and 0.10 u/kg/h. Each patient was studied on two occasions a month apart using either highly purified porcine or semi-synthetic human short-acting insulin. No difference was observed in the changes in blood glucose, lactate, pyruvate, glycerol, alanine, total ketone bodies or plasma non-esterified fatty acids. Thus no difference could be identified in the actions of intravenous porcine and semi-synthetic human insulin on carbohydrate, fat or ketone body metabolism in vivo.

As the use of human insulin could possibly modify the immunogenicity of insulin, the present prospective study compares complement evaluation (CH50, C3, C3d/C3, C4) as well as other immunological factors (insulin antibodies, autoantibodies, ...), metabolic control (HbA1, lipids, ...) and clinical data (insulin dose/kg, number of hypoglycaemic episodes, ...), before and after a switch-over from monocomponent porcine insulins (Actrapid MC, Monotard MC) to human semisynthetic insulins (Actrapid HM, Protaphane HM). Forty-six type I diabetic children and adolescents (mean age +/- SD: 14.3 +/- 3.8 years) participated in the trial. The duration of diabetes ranged from 1.0 to 16.9 years (mean +/- SD: 7.3 +/- 3.7). The study protocol consisted of a 9 month period during which, at monthly intervals, the subjects were assessed clinically and blood samples taken for measurement of biological data. After 3 months, porcine insulins were switched to human insulins. The main results were as follows: 1) The insulin dose/kg was increased after the switch-over (porcine insulin: 0.90 +/- 0.03 U/kg; human insulin: 0.98 +/- 0.03 U/kg; p less than 0.001). This can perhaps be explained by the different bioavailabilities of Monotard MC and Protaphane HM. 2) The objective degree of metabolic control (HbA1), as well as the HDL-cholesterol level and the apo A1/B ratio, were not statistically different before and after the switch-over. 3) IgG insulin antibody binding was not statistically different on transfer from porcine insulin to semisynthetic insulin. 4) Mean level of total IgE and IgE specific insulin antibodies, determined before and after the switch-over, were not different. 5) Autoantibodies and antinuclear factor were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe resistance to subcutaneous insulin with normal sensitivity to intravenous insulin developed in a 39 year old woman affected by type 1 diabetes mellitus. The patient had been treated for ten months with continuous intravenous or intraperitoneal insulin before undergoing pancreatic transplantation. After surgery repeated plasmapheresis were performed and immunosuppressive therapy was undertaken. When studied again, one month after surgery, the patient showed normal sensitivity to subcutaneous insulin. Our data suggest that plasmapheresis and/or immunosuppressive treatment could have played a role in reversing insulin resistance.