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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.

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.

The porcine-extracted monocomponent insulins and human insulin (Novo) obtained by enzymatic conversion of porcine insulin had similar effects on glycemia balance when compared by means of an artificial pancreas during two 48-h studies 2 or 3 days apart. There was no significant difference between the maximum and minimum blood glucose circadian variations, the glycemic drops, and the Schlichtkrull coefficient. The speed of increase and decrease of glycemia during meals was slightly slower with human insulins than with porcine insulins, but the difference was not significant. Although comparable, the insulin requirements (per gram of ingested carbohydrate) were proportionately greater in the morning than during the rest of the day; the baseline requirements were also similar, but showed a trend toward increase during the day with both insulins.

Insulin infusions given by portable pumps constitute a recent therapeutic advance in those difficult cases of diabetes mellitus which cannot be stabilized by repeated conventional injections. The different varieties of pumps, catheters and insulins used are described. The intravenous and intraperitoneal routes of administration have given results superior to those of the subcutaneous route. Short-term results are evaluated by change in blood glucose levels, medium-term results by glycosylated haemoglobin levels and various metabolic and hormonal abnormalities, and long-term results mostly by the influence of treatment on degenerative complications of diabetes. The metabolic and infectious incidents and accidents of the method as well as its psychological advantages and drawbacks are discussed.

Long term experience with the use of sulfonylurea and/or biguanide oral hypoglycemic agents in patients under the age of 30 years shows the following results: 1) Oral treatment under 30 years of age is effective only for a limited period of time, in the large majority less than 24 months;--2) The success of oral treatment of diabetics and the period of effectiveness is increased if the subject is overweight at the time of discovery of the diabetes mellitus;--3) The type of antidiabetic treatment, i.e., insulin only, oral only, or oral and insulin, does not influence the susceptibility to the complications likely to appear in this age group, such as retinopathy, coronary disease, neuropathies and urinary and dental infections;--4) Poteinuria, peripheral vascular disease and various abnormalities of plasma lipids involving cholesterol and triglycerides, are significantly more common in patients under oral therapy than in those receiving insulin. These findings suggest the necessity for serious reconsideration of therapy as soon as any of these pathological events appear, especially the proteinuria or the lipid anomalies;--5) The duration of the oral treatment preceding therapeutic insulin does not have influence on the subsequent metabolic disturbance (hypoglycemia, deto-acidosis) and thus on the ultimate control of the diabetic state;--6) The somatic growth of the diabetic child is maintained regardless of the type of treatment as long as it is effective. Growth is interrupted however very early if oral treatment becomes ineffective with regard to control of the diabetes. Monitoring of somatic growth during oral antidiabetic treatment is of obvious importance. An interruption in growth is an indication for insulin therapy even if the diabetic control appears satisfactory;--7) The course and the outcome of pregnancy do not appear to be affected by the use of oral therapy at the time of conception. This holds true also for cases in which oral treatment precedes the use of insulin, the pregnancy having commenced during the course of insulin therapy.

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.

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.

Porcine extracted monocomponent insulins and human semi-synthetic insulins obtained by enzymatic conversion of porcine insulin had exactly the same clinical effectiveness on blood glucose balance when compared with an artificial pancreas during two 48-hour studies 2 or 3 days apart. There was no significant difference between maximum and minimum blood glucose variations, glycaemic falls and Schlichtkrull coefficient. Glycaemia increased and decreased during meals at a slightly slower rate with human insulin than with porcine insulin, but the differences were not significant. With both types of insulin therapy, insulin requirements per gram of ingested carbohydrates were proportionally more important in the morning than during the rest of the day, dans baseline requirements tended to increase during the day.

HLA antigen typing by lymphocytotoxicity was performed for 2 groups of unrelated caucasian subjects. The first group was composed of 100 subjects with insulin-dependent diabetes mellitus. The second group was composed of 270 healthy subjects without diabetes. Our study has shown that for the inhabitants of Languedoc the BW15 antigen is not the most frequently found (11% of the diabetics, 10% of the healthy subjects) contrary to findings reported by others. The B8 antigen was the most frequently found (20% of the diabetics, 16,3% of the healthy subjects), in agreement with the findings of the same authors. The frequency of BW15 and B8 found simultaneously was increased (observed 3%, expected 1.38%). The principal findings of our study were a significantly increased frequency of Da25 and B18 (23% and 25% for the diabetic subjects, 11.26% and 12.22% for the healthy subjects), and a significantly decreased frequency of A11 and B12 (6% and 18% for the healthy subjects). The association of Da25 and B18 was observed for HLA phenotypes, suggesting a higher incidence of the Da25-B18 haplotype. For the diabetics, the types BW15, BW40 and Da25-B18 have little hereditary character, and are rapidly insulin dependent individuals.

With the external artificial pancreas used by the authors, blood glucose is continuously controlled by insulin delivered through an IV infusion and adjusted to two parameters: instantaneous blood glucose levels and increasing or decreasing patterns of blood glucose. The artificial pancreas can be used to treat acute diabetic disorders an to evaluate insulin needs. Furthermore, exogenous insulin homeostasis can be studied: the delay to reach an insulin effect is 18 mm +/- 2 and it remains within 28 mm +/- 2 after the infusion has been stopped; fractional insulin needs are evaluated. From these data, it appears that the efficiency of exogenous insulin exhibits a circadian rhythm.

We report our personal experience of chronic ambulatory insulin therapy via portable and implantable pumps in insulin-dependent diabetics. Fifteen patients, poorly controlled on conventional insulin injections, were equipped with portable Siemens pumps. These pumps offer compactness, safety means, portability, one-month insulin reservoir and variable insulin rates. The pump catheter was chronically inserted in the peritoneal space using a non-surgical personal technique. Our present experience, representing six patient-years of treatment (range 1 to 16 months), shows excellent steady blood glucose control (mean blood glucose is 115 +/- 5 mg/dl v. 187 +/- 21 mg/dl with conventional therapy). All incidents were minor and most were catheter related. However, there was no catheter removal or discontinuation of pump treatment. All patients declared that there was a marked improvement in their quality of life. One of the pump-treated patients agreed to be transferred to a totally implantable Siemens prototype. The pump was inserted in the muscular wall of abdomen, and the delivery catheter terminated in the peritoneal space. Refills are made percutaneously approximately every 20 days. Rates and functions of the pump are remotely controlled. Five months after implantation, results, compared with those of a portable pump, show similar excellent blood glucose control and pump precision with a further improvement in the patient's quality of life. Thus, although further miniaturization and longer autonomy are expected in the forthcoming devices, our present experience shows that, with careful patient instruction and follow up, insulin pumps could represent in the next years an alternative to conventional insulin therapy for poorly controlled diabetics.

Plasma Antithrombin III (At III), a natural inhibitor of coagulation, was determined using a single radial immunodiffusion technique. In 116 diabetics, plasma At III levels were significantly decreased (26.6 +/- 0.4 mg/100 ml) compared with those in 64 controls (31.0 +/- 0.3 mg/100 ml, P less than 0.001). An elevation of plasma fibrinogen degradation products in 42 per cent of our patients, and a positive linear relationship between platelet counts and At III levels ( r = 0.29, P less than 0.01), provided additional evidence for chronic disseminated intravascular clotting in diabetes mellitus. Diabetic retinal complications were more frequent in patient with low plasma At III levels (50.6 per cent of cases) than in those exhibiting At III concentrations within a normal range: 32.4 per cent of cases (X2 = 6.09, P less than 0.02). It is postulated that the low levels of At III encountered in diabetes result from excessive consumption, and that the deficiency may be responsible for the onset and/or aggravation of intravascular clotting. At III deficiency may therefore contribute to vascular degenerative complications, particularly those leading to diabetic retinopathy.

The choice of a contraceptive method for diabetic women must take into account metabolic and vascular risks. Combined oestrogen-progestogen contraception is not contra-indicated in insulin-dependent diabetes but requires close supervision. Progestogens alone for nulliparous women and mechanical devices for multiparous women appear to be preferable. Oral contraceptives have a more limited use in insulin-independent overt or chemical diabetes. In such patients combined oestrogen-progestogen contraception is absolutely contra-indicated and progestogens should be given under strict metabolic monitoring. The potential risks incurred by these women already liable to vascular and metabolic complications make male contraception even more desirable.

The authors analyzed the effects of obesity/non-obesity in 162 epidoses of severe metabolic disturbances. Ketoacidosis and hypoglycaemics comas were more frequent in the non-obese group of diabetics, who were often insulin treated; whereas hyperosmolar coma and lactic acidosis were frequent in the obese group of diabetics, usually not treated with insulin. In the obese group both advanced age as well as a higher frequency of degenerative complications impaired the prognosis of these metabolic accidents. However the mortality rate was not significantly different in the two groups of patients. Despite the importance of the weight balance in the natural history of diabetes mellitus, it did not seem to influence the clinical aspects nor did it modify the therapeutic management of the major metabolic disturbances which occur in diabetes.

The urinary excretion of 3-methylhistidine (3 MH) is considered an easy and reliable method to quantify muscle protein catabolism in man. The 3 MH/creatinine (Cr) ratio is thought to be a good index of fractional degradation of muscle fibre protein. In the present article, the stress is placed on the limitations of 3 MH assays an- on their clinical applications. In thyroid diseases and in malnutrition (anorexia nervosa), the 3 MH/Cr ratio differentiates clearly marasmic malnutrition without increase in protein catabolism from hypercatabolic states, such as hyperthyroidism, with excessive protein degradation. 3 MH measurements therefore appear to be useful to determine the contribution of protein catabolism to lean mass reduction.

Nineteen patients suffering from chemical diabetes either with (group A, ten cases) or without (group B, nine cases) reactive hypoglycaemia were included in the study and compared with seven control (group C). The following variables were measured over a 5 hour period during a standard oral glucose tolerance test (OGTT): (i) blood glucose by continuous monitoring; (ii) plasma insulin and glucagon levels by radioimmunoassay. Furthermore, in five diabetics of group A, the data from the standard OGTT were compared with those from a pectin-supplemented OGTT (9 g per square meter of body surface). Although the insulin response was similar glucagon levels were significantly higher (45.1 +/- 11.8 pmol/l) (p less than 0.01) in group B than in group A (9.6 +/- 1.3) and C (8.1 +/- 1.4 at 30 minutes). The high glucagon levels noted in group B may explain the absence of reactive hypoglycaemia. The pectin supplementation improved the OGTT pattern by blunting the blood glucose peak (p less than 0.05), and avoiding the reactive hypoglycaemia (p less than 0.01). The addition of pectin did not produce any significant effect on the insulin response while a significant increase in glucagon concentrations (p less than 0.05) was observed beyond the 150th minute. Therefore, the data suggest that pectin may improve the OGTT pattern by increasing the glucagon response in the late period of the test. The development of postprandial reactive hypoglycaemia seldom coincides with a plasma glucagon peak, while the absence of reactive hypoglycaemia tends to be associated with high levels of glucagon, as is the case in overt diabetes mellitus.

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were simultaneously measured by obtaining an isotopic steady state during a continuous infusion of 125I orthoiodohippurate (OIHA). A good correlation was found between the clearances of Ioth (y) and of inulin or polyfructosan (x) : y = 1.18 X (x) + 8.43 (r = 0.96; P less than 0.001) and between the clearances of OIHA (y') and of PAH (x') : y' = 0.62 X (x') + 21.2 (r = 0.93; P less than 0.001). When renal functions were impaired the use of Ioth was not convenient since the infusion time necessary to reach a radioactive plateau was longer than 3 hours. On the contrary, excellent results were obtained by using OIHA. In this case, the main advantages were the absence of urine collection and the rapid obtention of an isotopic equilibrium. The repeated determination of renal clearances in hypertensive or diabetic patients appears to be useful in the study of changes induced by antihypertensive drugs or insulin. Clearances were slightly improved by clonidine, claimed to be useful in hypertension associated with chronic renal failure. GFR and ERPF were rapidly increased by insure on the metabolic and hemodynamic changes induced by insulin than on the return to normal of glomerular basement membrane permeability.

Among 28 patients with acute diabetes mellitus of recent onset, long-term remission (25-48 months) was obtained in 14 and medium-term remission (10-24 months) in the other 14. At the onset of the disease these two groups were very similar: remissions were longer in the older patients and shorter in the leaner ones. In patients seen at an early stage, there is no hormonal or immunological data to differentiate between those who will be in remission and those who will not. In our series, insulin secretion was the same in all patients at the onset of diabetes and at the end of the remission period. Further explorations suggested some degree of resistance to insulin, but this was easily overcome by the initial intravenous insulin treatment and by the conventional subcutaneous insulin treatment after the remission had ceased. Our data show the weakness of arguments which separate insulin-dependent from non insulin-dependent patients in acute diabetes mellitus of recent onset.

In eight patients exhibiting chemical diabetes mellitus with a poststimulative hypoglycemia, we observed that the pattern of the oral glucose tolerance test (OGTT) was improved when indigestible fiber was added to the oral glucose load. As compared with a standard OGTT, the peak blood glucose, expressed as per cent change from baseline, was particularly blunted by pectin or by cellulose phosphate but remained unchanged with cellulose supplementation. The time interval required to reach the blood glucose peak was significantly prolonged with pectin. The rate of blood glucose rise was reduced to a greater extent by pectin than by cellulose phosphate, which in turn was more efficient than cellulose. The blood glucose nadir expressed as per cent change from baseline was blunted by pectin, while the results were not significantly different after addition of either cellulose phosphate or cellulose. On the other hand, the plasma immunoreactive insulin did not show any significant change whether the glucose was given with or without one of the aforementioned types of fiber. From these results, it is concluded that an additional fiber intake may be of interest in the management of chemical diabetes. The use of pectin may diminish the poststimulative hypoglycemia.