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Aims To identify factors associated with glucose control, as measured by HbA1c over 4 years, in people with type 2 diabetes starting insulin therapy. Methods CREDIT, an observational cohort study, collected data semi-annually over 4 years, on people with type 2 diabetes starting any insulin, in 311 centres in 12 countries; 2803 people had data on HbA1c during follow-up. Multivariable backward regression analysis selected characteristics associated with glycaemic control from a limited number of candidate variables. Results Before starting insulin therapy, HbA1c was 9.3% (78 mmol/mol) and decreased to 7.6% (60 mmol/mol) after 1 year, and changed little after that. Insulin dose increased from 0.21 U/kg to 0.36 U/kg at 1 year, and then by 0.10 U/kg over the next 3 years. Body weight increased by 2.0 kg in the first year and increased little thereafter. Poorer glycaemic control over the 4 years was mainly determined by the HbA1c before starting therapy, after accounting for the other statistically significant associated variables in multivariable analysis: higher BMI, younger age, longer diabetes duration, more glucose-lowering drugs, using basal insulin alone, higher insulin dose and female sex. At 4 years, a higher current insulin dose was the characteristic most strongly associated with a higher concurrent HbA1c. Conclusions HbA1c at the start of insulin therapy was the characteristic most predictive of later HbA1c, after accounting for other variables associated with HbA1c. This may provide some justification for earlier insulin introduction to improve glucose control to target.

Objectif Evaluer les caracteristiques, a l’instauration de l’insuline, associees a l’efficacite du controle glycemique des patients DT2 durant quatre annees. Patients et methodes Donnees recueillies dans 12 pays, 3 continents, pendant 4,0 ± 0,5 an. Controle glycemique defini par : (a) le taux moyen d’HbA1C sur quatre ans, (b) le taux d’HbA1C a quatre ans. Resultats La population etudiee (n = 2 803) etait composee de 49 % de femmes (taux initial d’HbA1C 9,5 ± 1,9 % (moyenne ± ET), âge 61 ± 10 ans, anciennete du diabete 11 ± 8 ans, IMC 29,4 ± 6,3 kg/m 2 ). Les facteurs predictifs univaries du taux moyen d’HbA1C sur quatre ans etaient l’âge, le sexe, l’IMC, l’HbA1C de base, les comorbidites, les antecedents CV familiaux, les hypoglycemiants oraux et le type d’insulinotherapie (tous p ≤ 0,01) ; l’anciennete du diabete, le tabagisme, la dose d’insuline, la pression arterielle, l’activite physique, et les maladies micro/macro-vasculaires n’etaient pas significativement correles. Le modele multivarie incluait quatre facteurs predictifs (p Conclusion Les caracteristiques cliniques sont le facteur predictif le plus puissant du controle glycemique sur quatre ans. Le taux d’HbA1C de base etait le facteur predictif le plus important, suggerant qu’il est plus approprie de debuter l’insuline avant que la deterioration du controle glycemique ne soit trop avancee. Les comorbidites sont egalement predictives, mais de maniere non independante des parametres cliniques.

Although neuropathy has long been recognized as a complication of diabetes, the impact of this condition has not been adequately established. The prevalence of diabetic neuropathy is virtually unknown because the published studies differ considerably with regard to definition, method of assessment, and patient selection. Furthermore, the determination of prevalence has been hampered by the fact that there is no generally accepted classification of the variety of manifestations of diabetic neuropathy. The introduction of new sensitive diagnostic methods aids in the detection of less severe stages of neuropathy, as compared with clinically based assessment, and renders the disease more prevalent. The prevalence of diabetic neuropathy in the few reported population-based studies was approximately 30%. We have evaluated the prevalence of cardiovascular autonomic neuropathy in a group of approximately 1000 diabetic patients randomly included from 21 hospitals in Germany, Austria, and Switzerland. The results of this study and those of a prospective study on the natural history of neural dysfunction during the first 5 years after diagnosis of type 1 diabetes will be presented.

A double blind placebo controlled trial was performed to evaluate the effects of the aldose reductase inhibitor, ponalrestat, on symptomatic diabetic neuropathy. After a 4-week placebo run-in phase, 60 patients were 2:1 randomized to receive either 600 mg ponalrestat or placebo once daily over 12 months. Forty-six patients, 30 of whom were treated with ponalrestat and 16 with placebo, completed the study. Motor and sensory nerve conduction, thermal and vibration sensation thresholds, heart rate variation at rest, E/I ratio, pupillary dilation velocity and pupillary reflex latency were determined at baseline and after 6 and 12 months. Neuropathic symptom scores were assessed every 3 months. Among the fifteen nerve function parameters studied, only trends in favour of ponalrestat were noted for heart rate variation and E/I ratio after 6 months (P = 0.06), but no significant differences between the groups could be demonstrated during the study. No adverse reactions were observed. It is concluded that one-year treatment with ponalrestat has no beneficial effects on symptoms or electrophysiological parameters in diabetic neuropathy.

Rationnel L'un des facteurs susceptibles de retarder la mise sous insuline de patients DT2 est la conviction qu'une prise de poids puisse influencer negativement le controle glycemique. Nous avons donc evalue cette eventuelle relation apres 4 ans d'insulinotherapie dans la pratique clinique courante. Patients et methodes CREDIT est une etude non interventionnelle prospective sur 4 ans chez des patients DT2 ayant debute une insulinotherapie en Europe, Amerique du Nord et Asie. Les medecins etaient libres de choisir et d'adapter les traitements conformement a leur pratique. Les donnees ont ete recueillies lors de visites de routine. Des analyses univariees et multivariees ont ete realisees pour determiner la relation entre variation de poids et HbA1c sur 4 ans. Resultats La population etudiee ( n = 1 973) etait composee de 47 % d'hommes ; taux initial d'HbA1C 9,5 ± 1,9 % (moyenne ± ET), âge 61 ± 10 ans, IMC 29,2 ± 6,1kg/m², anciennete du diabete 10 ± 8 ans. Apres 4 ans, le taux d'HbA1c a diminue de – 2,0 ± 2,1 % et le poids corporel a augmente de 2,6 ± 7,4kg. Apres ajustement par region et par centre, la variation de poids etait un facteur predictif de l'HbA1c ( p p vs HbA1c ≥ 7,0 etait de 0,97 (0,96, – 0,99, p =0,0015) pour une prise de poids d'1 kg. Conclusion Apres 4 ans d'insulinotherapie, la prise de poids des patients DT2 est associee a une tres faible augmentation d'HbA1c. Ces resultats devraient rassurer quant aux craintes qu'une prise de poids ait un fort impact sur le controle glycemique. Etude sponsorisee par Sanofi Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Sanofi a sponsorise cette etude.

Objectif Evaluer la relation entre evenements cardiovasculaires (CV) et HbA1c chez des patients DT2 ayant debute une insulinotherapie « en vie reelle » (etude Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy, CREDIT). Les donnees etant recueillies a partir des rapports des medecins. Patients et methodes 2 999 patients ont ete etudies pendant 4 ans en Europe, Amerique du Nord et Asie. Le critere de jugement principal etait compose de: deces d'origine C V, infarctus du myocarde (IM) ou AVC non mortels (evenements evalues a l'aveugle par un comite d'experts). Les risques d'evenements CV ont ete calcules a partir du modele de Cox, comprenant les facteurs de risque du patient et l'HbA1c moyenne comme variable dependante du temps. La relation entre hypoglycemie severe et symptomatique (6 derniers mois avant consultations annuelles) avec la mortalite CV et la mortalite toutes causes confondues a ete analysee. Resultats Au total, 147 evenements composant le critere principal ont ete observes pendant le suivi a 4 ans (60 deces C V, 44 IM non mortels et 57 AVC non mortels) avec 148 deces toutes causes confondues. L'analyse a montre une association positive entre le critere de jugement principal et l'HbA1c moyenne (hazard ratio (HR)=1,25, IC95 %=1,12-1,40, p p =0,0027) et d'AVC (1,36 [1,17-1,59], p Conclusion L'etude CREDIT montre qu'un mauvais controle glycemique est associe a la survenue d'evenements C V. L'hypoglycemie n'a ete associee ni a la mortalite C V, ni a la mortalite toutes causes confondues. Etude sponsorisee par Sanofi Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Sanofi a sponsorise cette etude.

Objectif Evaluer en pratique courante, la relation entre le controle glycemique et les evenements cardiovasculaires quatre ans apres l’instauration d’insuline chez des patients DT2 dans 12 pays en Europe, au Japon, et au Canada Patients et methodes Les patients DT2 ont ete suivis pendant 4 annees (± 6 mois). Des analyses multivariees de survie ont evalue les relations entre le controle glycemique pendant le suivi (une variable dependant du temps) et le MACE (Deces CV, IDM et AVC) et le MACE + (MACE plus revascularisation, amputation ou hospitalisation pour angor severe ou insuffisance cardiaque), en ajustant sur les facteurs lies a ces evenements. Resultats L’analyse portait sur 147 evenements et 2 984 patients DT2 pour le MACE et 289 evenements et 2 962 patients DT2 pour le MACE +. Le schema d’insuline et le taux d’HbA1c initiaux ne constituaient pas des facteurs predictifs. Le modele de Cox multivarie final retrouvait, comme facteurs independants pour les evenements du MACE + (p Conclusion Nous retrouvons une forte correlation entre maintien du controle glycemique et survenue d’evenements CV chez des patients DT2 debutant un traitement par insuline, apres prise en compte de certains facteurs explicatifs. Ainsi, un accroissement moyen de 1 % de HbA1c permet de predire une augmentation du risque d’evenements CV de 16–26 % chez ces patients inities a l’insuline en pratique courante.

Blood amino acid concentrations were determined in the postabsorptive state in nine patients with insulin excess (functioning insulinomas), nine juvenile-type diabetics with insulin deficiency (diabetic ketosis due to insulin withdrawal), six juvenile diabetics in moderate metabolic control, and five healthy control subjects. Blood branched-chain amino acid (BCAA) levels were elevated in diabetic ketosis and decreased in patients with insulinomas. Blood concentrations of BCAA were significantly correlated to blood glucose levels, and in diabetics they were also correlated to blood ketone bodies, serum free fatty acids, and glycerol levels. These data indicate an inverse relationship between circulating effective insulin levels and blood BCAA concentrations. It is suggested that blood levels of BCAA might represent an indicator of insulin-dependent alterations of protein metabolism.

Premature atherosclerosis in hypercholesterolemic patients may be due, in part, to increased growth of vascular cells. Therefore, the growth stimulating effect of serum and serum fractions from patients with primary hyper-LDL-cholesterolemia (LDL-cholesterol: 7.5 +/- 1.7 mmol/l) and from healthy subjects on human arterial smooth muscle cells and fibroblasts has been investigated over 5-7 days in culture. Human hypercholesterolemic sera increased the growth of both cell types up to a mean of 133% compared with normal sera (100%) (P less than 0.001). Removal of the dialyzable serum fraction (m.w. less than 3,500 daltons) reduced the growth effect of the hypercholesterolemic sera by 32% (P less than 0.001) and of the normal sera by 11% (P less than 0.01). Readdition of the hypercholesterolemic serum dialysate to its dialyzed serum restored completely the original growth effect. There was no significant difference in growth stimulation between the dialyzed hypercholesterolemic and normal sera excluding a major additional growth effect by LDL-cholesterol. The low molecular weight growth factor(s) of hypercholesterolemic serum (m.w. less than 3,500 daltons) showed a linear dependence of growth stimulation over a 20-fold concentration range. Increased amounts of this factor(s) might easily penetrate the arterial wall, thus contributing to atherogenesis.

Serum factors from non-ketotic poorly controlled diabetic patients when compared to serum factors from normal subjects, stimulate growth and protein synthesis of cultured fibroblasts from diabetic patients by 25-50%. This increased growth stimulating effect of diabetic serum is mainly related to low molecular weight components (mol. wt.12,000 daltons), but not to insulin or glucose. These low molecular weight components of diabetic serum are effective only in combination with serum factors of a molecular weight12,000 daltons which are essential for initiation and continuous stimulation of cellular growth. As the growth stimulation by diabetic serum factors with a molecular weight12,000 daltons does not differ from comparable normal serum factors, the relevance of these serum factors (e.g. growth hormone, lipoproteins) for the increased growth stimulation of mesenchymal cells in diabetes mellitus seems to be only of limited importance. In as much as these in vitro results represent the in vivo situation, chronic exposure of vascular cells from diabetics to these serum factors could be related to the increased angiopathic risk in diabetes mellitus.

1. 1. Basal and stimulated lipolysis and re-esterification were determined in tissue slices of epididymal and subcutaneous adipose tissue in four strains of mice and in subcutaneous adipose tissue slices of man. 2. 2. When related to the EFA content of the tested tissue sample, the lipolytic activity of adipose tissue is different, within the same genus or species, even if tissue slices are taken from the same region. 3. 3. The lipolytic activity of the individual fat cells is similar in young, normal-weight men, in young metabolically intact mice and in those mice that later on will develop diabetes and obesity, depending on their genetic code. 4. 4. Differences in re-esterification are rather a consequence of the nutritional state than species-specific.

The metabolic differences between rat and human adipose tissue have been briefly reviewed. In addition, newer studies have been discussed on hormonal control of glucose metabolism by human adipose tissue in vitro. Contrary to earlier reports, human adipose tissue does appear to be quite sensitive to physiologic doses of insulin, particularly in children under 15 years of age. With advancing age, a gradual insulin insensitivity develops, most pronounced over the age of 50. At present, one can only speculate how this may correlate with the increased incidence of obesity and/or diabetes in the older population. Failure to observe an insulin effect on human adipose tissue in vitro had previously led to the assumption that in man the liver may play a major role in lipid synthesis from glucose; however, the more recent data would place emphasis back in adipose tissue.