Genetically engineered insulin: five years of experience.

Genetically engineered insulin is the first application of recombinant DNA technology which has gone into industrial production and wide clinical use. Four years after the first clinical trials, it appears that there are only minor pharmacokinetic differences from purified pork insulin; in particular, a faster subcutaneous absorption for both regular and NPH forms. The hypoglycaemic potency of genetically engineered insulin is identical to that of purified pork insulin but a weaker effect on counterregulatory hormones has been reported. However, the main advantage of biosynthetic human insulin is its species specificity, which reduces its immunogenicity. Convincing results were obtained in patients suffering from insulin-produced adverse reactions such as insulin resistance or allergy, although biosynthetic human insulin does have some immunological properties and crossreacts with beef or pork insulin antibodies.

[Malnutrition and deficiency of insulin secretion in alcoholic cirrhosis. Study by the assay of urinary C-peptide]. / Dénutrition et déficit de l'insulinosécrétion au cours de la cirrhose alcoolique. Exploration par le dosage du peptide C urinaire.

In order to evaluate the relationship between nutritional status and insulin secretion in cirrhosis, the following parameters of caloric (tricipital skin fold, prealbumin) and proteic (arm muscle size, transferrin, 24 h-urinary creatinine excretion) nutritional status were compared in 20 alcoholic cirrhotics and 10 normal subjects. Insulin secretion was evaluated in both groups by insulin and C-peptide response to an intravenous glucose tolerance test and by 24 h urinary excretion of C-peptide. When compared to normals, cirrhotics have lower values for all nutritional status parameters and individually for at least three of those in 14 (70 p. 100) patients. In cirrhotics there is a significant decrease of the 4-min poststimulative response of insulin and C-peptide, contrasting with higher basal and late poststimulative values than in normals. This contrast could be explained by a reduced metabolic clearance rate of insulin (consistent with insulin resistance) and of C-peptide (the urinary clearance of which is 2.5 times lower in cirrhotics than in normals). The 24-h urinary excretion of C-peptide, probably weakly dependent of this reduced clearance, is 50 p. 100 lower in cirrhotics: 12.9 +/- 1.6 nM/24 h than in normals: 26.0 +/- 2.4 nM/24 h (p less than 0.001). In cirrhotics there is a significant linear correlation between 24 h urinary C-peptide excretion and all the nutritional status parameters but one (prealbumin). These results indicate that in cirrhosis: 1) urinary C-peptide excretion rate is a good index of insulin secretion; 2) urinary C-peptide indicates a marked deficit in insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

[Current trends in dietetics in diabetology and their experimental bases]. / Les tendances actuelles de la diététique en diabétologie et leurs bases expérimentales.

The last decade has witnessed drastic changes in our views on diet for diabetics, whether insulin-dependent or not. To bring blood glucose levels down to normal values, thereby preventing diabetic microangiopathy or alleviating its course, remains the compelling purpose of treatment, but the modalities and constraints of the dietetic measures which contribute to this result have been radically revised. Leaving aside fashions and controversies, three tendencies have emerged: the low carbohydrate diet does not improve the glycaemic balance but implies an excessive fat intake which may aggravate the microangiopathy. Of course, an hypocaloric diet remains fundamental in the management of obese non-insulin dependent diabetics; the effects on glycaemia of the carbohydrate ration constituents must be reconsidered. The classical distinction between "fast" and "slow" sugars seems to be excessive and insufficient, if not erroneous. Food replacements must take into account the glycaemic index; a minimal dietary fibre intake has a favourable effect on post-prandial glycaemia and lipid metabolism and is to be recommended, notably to diabetics.

[Evaluation of bile diffusion of piperacillin]. / Evaluation de la diffusion biliaire de la pipéracilline.

In 10 patients undergoing cholecystectomy peroperative samples of serum, bile and gall bladder tissue were obtained one hour after intravenous injection of 2 g of piperacillin. Measurements were made by high performance liquid chromatography. Mean concentrations of piperacillin were 81.7 +/- 13.6 micrograms/ml in serum (S), 382 +/- 110 micrograms/ml in choledochal bile (CB), 30.8 +/- 8.5 micrograms/ml in gall bladder bile and 10.5 +/- 2.6 micrograms/g of gall bladder tissue. With a CB/S ratio of 4.7, piperacillin may be classified among beta-lactams showing good distribution in the biliary tract. This property would make piperacillin useful against the pathogens usually responsible for biliary tract infections.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

[Calcifications of the mitral annulus mimicking rheumatic mitral valve disease. A case]. / Calcifications de l'anneau mitral simulant une maladie mitrale rhumatismale. Une observation.

Long neglected, the significance of mitral annulus calcification had now been re-evaluated with the help of echocardiography. An unusual case with clinical symptoms mimicking rheumatic mitral valve disease has enabled the authors to discuss the acoustic manifestations of this entity, its evolutive potential and its causative factors. It is concluded that mitral annulus calcification should no longer be considered as a benign feature of the ageing heart.

[Breakfast tolerance test: application to the detection of gestational diabetes]. / Le test de tolérance au petit déjeuner: application au dépistage du diabète gestationnel.

There is general agreement that diagnosis of diabetes mellitus in pregnancy is requisite but the means of achieving it are still under discussion. The plasma glucose, insulin and C peptide responses to an oral glucose tolerance test were compared with the intravenous glucose tolerance test and a standardized breakfast tolerance test in 26 pregnant women, in order to define a simple diagnostic criterion for gestational glucose intolerance. The results of the oral glucose tolerance test distinguished between a group of 19 normal women and a group of 7 diabetic women with abnormal glucose tolerance tests. The breakfast tolerance test used (84 g carbohydrates, 22,6 g protein, 9,4 g fat, 690 calories) was followed by blood glucose modifications very similar to those observed with the oral glucose tolerance test, but the insulin response was significantly greater. The consistency between the breakfast tolerance and intravenous glucose tolerance tests was confirmed by the existence of correlations between the glucose area of the breakfast tolerance test and the coefficient K in the two groups studied. Our results suggest that the breakfast tolerance test could be as sensitive as the oral glucose tolerance test for detecting glucose intolerance; the most discriminative glycemic value appeared to be that at the 180 th minute, usually under 1 g/l in the normal pregnant women. This test could be proposed as an easy and economic method for diagnosing gestational diabetes. These preliminary results require confirmation by a study in a larger population.

Biliary elimination of ceftazidime.

When five normal subjects were given ceftazidime 2 g iv, antibiotic concentrations in aspirated duodenal fluid increased progressively during 4 h to a value of 21.2 +/- 9.2 mg/l (mean +/- S.E.M.); 0.05% of the dose given was recovered in duodenal fluid. The same dose was given to 12 patients with an external biliary drain. The mean peak ceftazidime concentration of 36.3 +/- 4.0 mg/l was reached in the collected bile during the second hour after administration. The 12-h biliary recovery was 0.21% of the dose. The respective ceftazidime concentrations in choledochal and gallbladder bile sampled peroperatively in ten patients 1 h after ceftazidime 2 g iv were 78.3 +/- 12.0 and 17.9 +/- 7.5 mg/l. These data compare favourably with the results achieved with other beta-lactam compounds.

Semisynthetic human insulin: biological and pharmacokinetic effects in normal subjects.

The assessment of pharmacokinetic and pharmacodynamic properties of semisynthetic human insulin produced by enzymatic conversion was done in normal subjects, and compared to those of highly purified pork insulin. Ten healthy volunteers were submitted to an intravenous injection of 0.06 U/kg of regular insulin, semisynthetic (Actrapid HM) and monocomponent pork insulin (Actrapid MC) in succession. No significant differences were pointed out as far as the pharmacokinetic parameters, immunoreactivity and hypoglycemic effect of both types of insulin are concerned. Only a stronger inhibition of endogenous insulin secretion, expressed by a significantly lower plasma-C-peptide levels, was observed after PPI. Stimulation of glucagon secretion was similar with both types of insulin.

[Ceftriaxone, a cephalosporin with high hepatic elimination. Evaluation of its biliary clearance in man. Therapeutic value]. / La ceftriaxone, céphalosporine à forte élimination hépatique. Evaluation de son passage biliaire chez l'homme. Intérêt thérapeutique.

The biliary elimination of ceftriaxone, a cephalosporin derivative, was quantitatively studied in man with the help of high pressure liquid chromatography (HPLC). In 6 healthy volunteers a mean peak concentration of 565 +/- 347 (SEM) micrograms/ml was observed in the aspirated duodenal fluid within the first hour after i.v. administration of 2 g ceftriaxone, and 1.4 +/- 0.5% of the dose was recovered during the 4 hours investigation period. In 10 cholecystectomized patients provided with a T-drain, the biliary concentration peak (1078 +/- 158 micrograms/ml) was reached within 1 hour after administration and the total 24 hours recovery amounted to 9.5 +/- 2.9% of the dose given. In 12 patients undergoing cholecystectomy, serum, and choledochal (CB) and gallbladder bile (GB) were peroperatively collected 1 hour after i.v. administration of 2 g ceftriaxone; the respective concentrations were: 199 +/- 10 (serum), 5259 +/- 1085 (CB), and 4533 +/- 809 (GB) micrograms/ml. These data point to excellent biliary elimination of ceftriaxone compared with the other beta-lactams previously studied, and afford evidence of its high therapeutic potential in biliary tract infections.

High biliary elimination of ceftriaxone in man.

Biliary elimination of ceftriaxone was studied in man using chromatography (HPLC). After a single i.v. administration of 2 g of ceftriaxone to 6 normal subjects, a peak concentration of 565 +/- s.e.m. 347 micrograms/ml was reached during the 1st h in the collected duodenal fluid, and 1.4 +/- 0.5% of the given dose was recovered within 4 h. In 10 cholecystectomized patients provided with a T-drain, a maximal biliary concentration of 1,078 +/- 158 micrograms/ml was measured during the 2nd h after i.v. injection of 2 g of ceftriaxone and the 24-h recovery was 9.5 +/- 2.9%. Intraoperative samples obtained in 12 patients undergoing cholecystectomy 1 h after i.v. administration of 2 g of the antibiotic, gave the following results: serum concentration 199 +/- 10 micrograms/ml, choledochal bile = 5,259 +/- 1,085 micrograms/ml, gallbladder bile 4,533 +/- 809 micrograms/ml. These data indicate an excellent biliary elimination of ceftriaxone in comparison with other beta-lactams previously studied under the same conditions and point to be a promising therapeutic potential in biliary tract infections.