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Hyperglycemia is detrimental to β-cell viability, playing a major role in the progression of β-cell loss in diabetes mellitus. The permeability transition pore (PTP) is a mitochondrial channel involved in cell death. Recent evidence suggests that PTP inhibitors prevent hyperglycemia-induced cell death in human endothelial cells. In this work, we have examined the involvement of PTP opening in INS-1 cell death induced by high levels of glucose or fructose. PTP regulation was studied by measuring the calcium retention capacity in permeabilized INS-1 cells and by confocal microscopy in intact INS-1 cells. Cell death was analyzed by flow cytometry. We first reported that metformin and cyclosporin A (CsA) prevented Ca²+-induced PTP opening in permeabilized and intact INS-1 cells. We then showed that incubation of INS-1 cells in the presence of 30 mM glucose or 2.5 mM fructose induced PTP opening and led to cell death. As both metformin and CsA prevented glucose- and fructose- induced PTP opening, and hampered glucose- and fructose- induced cell death, we conclude that PTP opening is involved in high glucose- and high fructose- induced INS-1 cell death. We therefore suggest that preventing PTP opening might be a new approach to preserve β-cell viability.

Free radical production is increased during diabetes. Serum albumin is a major antioxidant agent, and structural modification of albumin induced by glucose or free radicals impairs its antioxidant properties. Therefore the aim of the present study was to compare the antioxidant capacities and structural changes in albumin in patients with T2DM (Type 2 diabetes mellitus) treated with MET (metformin) or SU (sulfonylureas) and in healthy control subjects. Structural changes in albumin were studied by fluorescence quenching in the presence of acrylamide. Albumin thiols and fructosamines, reflecting oxidized and glycation-induced changes in serum albumin respectively, were assessed. Structural changes in albumin were demonstrated by a significant decrease in fluorescence quenching in patients with T2DM, with patients treated with MET exhibiting a significant difference in the conformation of albumin compared with patients treated with SU. Oxidation, resulting in a significant decrease in thiol groups and plasma total antioxidant capacity, and glycation, associated with a significant increase in fructosamines, were both found when comparing healthy control subjects with patients with T2DM. When patients treated with MET were compared with those treated with SU, oxidative stress and glycation were found to be significantly lower in MET-treated patients. In conclusion, patients with T2DM have a decrease in the antioxidant properties of serum albumin which may aggravate oxidative stress and, thus, contribute to vascular and metabolic morbidities. Moreover, a significant protection of albumin was found in patients with T2DM treated with MET.

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.

A major aim of glucose-lowering therapy in people with diabetes is to delay or prevent the late-developing complications of diabetes that threaten the quality and duration of life. While intensive interventions to control hyperglycaemia may impair well-being to some extent, the balance of quality of life is usually highly positive. Diet and exercise therapy remains the cornerstone of management, and should usually be given a trial alone first. However, the magnitude and duration of benefit from this intervention is insufficient for most people. More frequent, early, use of metformin is an evidence-based strategy for reducing the risk of adverse outcomes of diabetes in people with type 2 diabetes with sub-optimal glucose control on lifestyle measures alone. This has been recognised in recent evidenced-based guidelines from the UK National Institute for Clinical Excellence and from Diabetes UK, which now support the use of metformin as initial pharmacological therapy for all people without contraindications to the drug. Other national and local guideline committees should consider updating their recommendations on diabetes management in line with these findings.

Aim: To compare the effect of glimepiride in combination with metformin with monotherapy of each drug on glycaemic control in Type 2 diabetic patients., Design and Methods: Randomized, double-blind, double-dummy, parallel-group multicentre study conducted in France. Type 2 diabetic patients aged 35-70 years inadequately controlled by metformin monotherapy 2550 mg daily for at least 4 weeks were randomized to either metformin, glimepiride or metformin and glimepiride., Results: Three hundred and seventy-two patients aged 56 +/- 8 years were treated for 5 months. Combination treatment was significantly more efficient in controlling HbA1c (% change + 0.07 +/- 1.20 for metformin, + 0.27 +/- 1.10 for glimepiride, -0.74 +/- 0.96 for combination treatment, P < 0.001), fasting blood glucose (FBG) (mmol/l change + 0.8 +/- 0.4 for metformin, + 0.7 +/- 3.1 for glimepiride and -1.8 +/- 2.2 for combination treatment, P < 0.001) and post-prandial blood glucose (PPBG) (mmol/l change + 1.1 +/- 5.9 for metformin, + 0.1 +/- 5.1 for glimepiride and -2.6 +/- 3.9 for combination treatment, P < 0.001) than either glimepiride or metformin alone. There was no significant difference between metformin or glimepiride monotherapy with respect to the change in HbA1c or FBG; however, glimepiride was significantly more effective than metformin in reducing PPBG. The incidence of symptomatic hypoglycaemia was higher in the combination group than in either monotherapy group (P = 0.039)., Conclusions: Addition of glimepiride to metformin in Type 2 diabetic patients inadequately controlled by metformin alone resulted in superior glycaemic control compared with glimepiride or metformin monotherapy.

This 6-month, double-blind, placebo-controlled, randomised, parallel-group study investigated the potential of acarbose add-on therapy for improving the glycaemic control of overweight patients with Type 2 diabetes and was inadequately controlled with metformin monotherapy. Patients were randomised to receive acarbose titrated up to 100 mg three times daily (n=74) or placebo (n=78). All patients were receiving metformin 850 mg twice or thrice daily before the study and continued to receive this dose throughout the study. The mean difference in glycated haemoglobin (HbA(1c)) (+/-S.D.) from baseline to endpoint was -0.7+/-1.2% U in the acarbose intention-to-treat (ITT) group, compared with +0.2+/-1.3% in the placebo ITT group (P=0.0001). Significantly, more patients in the acarbose group were classified as 'responders', with an HbA(1c) at the end of treatment of less than 7.0% or a decrease by at least 15% relative to baseline (acarbose vs. placebo; 42 vs. 17%; P=0.002). The difference in fasting blood glucose level from baseline to endpoint was -1.0+/-2.8 (S.D.) mmol/l in the acarbose ITT group, compared with +1.3+/-2.8 mmol/l in the placebo ITT group (P=0.0001), and for 2-h postprandial blood glucose level -1.4+/-3.8 vs. +1.1+/-3.5 mmol/l (P=0.0001). In all, 60% of patients in the acarbose group and 33% in the placebo group had an adverse event considered to be possibly or probably related to drug therapy, leading to withdrawal by 15 and 3%, respectively. The results indicate that acarbose has potential clinical utility for improving glycaemic control in overweight patients with Type 2 diabetes inadequately controlled with metformin.

Recently there has been growing interest in the effects of antioxidants on insulin activity. In the present study, we investigated the effect of metformin on free radical activity and insulin sensitivity in high fructose-fed rats, a diet that leads to insulin resistance. The animals were divided into four groups (n = 16 per group; experiment duration = 6 weeks): the control (C) group received a standard diet; the control metformin (CM) group was fed a control diet and received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control (FT) group was fed a diet in which fructose composed 56.8% of the total carbohydrates; and the fructose metformin (FM) group received high-fructose diet and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique was used to determine insulin sensitivity in eight animals per group. Metabolic and oxidative stress parameters were measured in the remaining rats. In the FT rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and lower blood reduced glutathione were observed. Metformin treatment improved both the insulin activity and the antioxidant defense system. In the CM group, metformin had no effect on metabolic parameters, but improved red cell antioxidant enzyme activities and the blood GSH level, which suggests that it has an antioxidant activity independent of its effect on insulin activity.

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims: This study assessed the efficacy of add-on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. Methods: This multicentre, double-blind, parallel-group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA1c) ≤6.5%] or titrated up to 45 mg (if HbA1c >6.5%), or placebo for a further 4 months. The primary efficacy end-point was improvement in HbA1c (per cent change). Secondary end-points included changes in fasting plasma glucose (FPG), insulin, C-peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-B) were calculated. Results: Pioglitazone add-on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between-group difference after 7 months of triple therapy was 1.18% in HbA1c and −2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA1c level of <8.5% achieved the HbA1c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA1c level was ≥ 8.5%, 13% achieved the HbA1c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA-IR, insulin, proinsulin and C-peptide decreased and HOMA-B increased in the pioglitazone group relative to the placebo group. Conclusions: In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA1c, FPG and surrogate measures of β-cell function. Patients were more likely to reach target HbA1c levels (< 7.0%) with pioglitazone treatment if their baseline HbA1c levels were < 8.5%, highlighting the importance of early triple therapy. [ABSTRACT FROM AUTHOR]

Abstract: Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves β-cell mass by reducing apoptosis and stimulates of β-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5–1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8–1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment. [Copyright &y& Elsevier]

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectif: Décrire en vie réelle une population DT2 en bithérapie orale, jeûnant durant le Ramadan, typologie et nature de la prise en charge : ajustements thérapeutiques (doses, horaires, ASG), conseils, alimentation. Patients et méthodes: 201 DT2 décidés à jeûner, en bithérapie orale>2 mois avec HbA1c ≤ 8,0 %, inclus par 52 généralistes et 6 endocrinologues (parmi 1649 médecins sollicités, tirés au sort dans zones géographiques ciblées, 112 ayant accepté de participer) entre mai-juillet 2012 : 87 patients recevaient metformine+sulfamide/glinide (MET/IS) et 114 metformine+vildagliptine (MET/VILDA). Données d’inclusion rapportées ; patients suivis ensuite pour estimer incidence et circonstances des hypoglycémies durant le Ramadan Résultats: 2 groupes sont similaires : ~96 % ont déjà pratiqué le Ramadan depuis le diagnostic du diabète ; 59 % d’hommes, âge 59±11 ans, 91 % originaires du Maghreb, ancienneté diabète 7,5±5,4 ans (38 % ≥ 10 ans), HbA1c 7,14±0,62 % et IMC hommes 26,9kg/m2 (22 % obèses) et femmes 29,6kg/m2 (40 % obèses). 24 % ont une complication du DT2 (17 % atteinte macrovasculaire) et 84 % d’autres FDR CV associés (dont 20 % ≥ 3 FDR). Concernant la bithérapie : en 3 prises/J chez 66 % sous MET/IS vs 29 % sous MET/VILDA (p<0,001) avec même dose de MET (2,2g/j). Ancienneté bithérapie : 3,5±3,8 ans pour MET/IS et 1,1±0,8 an pour MET/VILDA (p<0,001). Conseils alimentaires en vue du Ramadan donnés de façon similaire (~89 %) mais adaptation du traitement (modification des doses et/ou fréquence des prises) pour 68 % des patients MET/IS (concernant IS pour 3/4;) vs 18 % des MET/VILDA (p<0,001), 85 % des MET/IS ont un lecteur glycémique vs 63 % des MET/VILDA (p=0,001). Conclusion: Disponibles dans des pays musulmans ou en Grande Bretagne, ces données sont les premières en France décrivant des DT2 pratiquant le Ramadan. Fait important : 96 % pratiquaient déjà le jeûne quels que soient leurs traitements à risque hypoglycémique et leur risque CV. [ABSTRACT FROM AUTHOR]

Objectif: Le statement ADA/EASD insiste sur l’individualisation. ENVISAGE étudie en vie réelle une vaste cohorte de DT2 en France lors de l’intensification thérapeutique après monothérapie metformine, raisons du choix du 2èmeADO, rôle de l’âge du patient, particulièrement ≥ 75 ans. Patients et méthodes: Observationnelle transversale : 4665 patients inclus de novembre 2011 à mai 2012 (4120 par MG, 545 par diabétologues) ajout du 2nd ADO : 87 % iDPP-4 et 13 % autre, 11,4 % SU/glinide et 1,6 % IAG Résultats: 58 % d’hommes, âge moyen 62±10 ans (12 % ≥ 75 ans), ancienneté diabète 6,0±3,9 années (22 % ≥ 10 ans) metformine depuis 3,9±3,0 ans à 2,3±0,6 g/j (37 % à 3 g/j), IMC à 29,3±3,6kg/m2. HbA1c à l’intensification 7,8±0,8 %, 9,3 % des patients < 7 % et 36,3 % ≥ 8 %; 88 % ont d’autres FDR CV et 30,6 % une complication. Motif renforcement : ű recherche d’efficacité Ƈ principalement (80 %), associé à ű éviter les hypoglycémies Ƈ (61,2 %) et ű minimiser la prise de poids Ƈ (61,8 %). Age participe à décision (31 %), raison principale pour 111 patients (âge moyen 73 ans). Item ű Éviter les hypoglycémies Ƈ plus cité chez les plus âgés, DT2 ancien et compliqué. En analyse multivariée : l’âge élevé est l’unique facteur significatif associé à cet item (OR 3,66 si ≥ 75 vs < 65 ans). Les patients ≥ 75 vs < 65 ans (n = 545 vs 2756) ont un DT2 plus ancien (47 % ≥ 10 ans vs 13 %, moyenne 9,5 vs 3,6 ans), 7,5 vs 3,9 années sous metformine à dose plus faible (24 % à 3 g/j vs 41 %), compliqué pour 56 % vs 21 %, avec plus de FDR CV, sont moins obèses, mais le seuil d’intervention pour l’intensification reste identique (moyenne 7,9 % ; 8,7 % < 7 %). Conclusion: ENVISAGE analyse une vaste population en France au moment de l’intensification thérapeutique après metformine et les déterminants du choix de bithérapie chez les MG et spécialistes. L’inertie thérapeutique est confirmée malgré la disponibilité d’ADOs sans risque hypoglycémique. De très nombreuses autres données riches d’enseignements sont disponibles. [ABSTRACT FROM AUTHOR]

Introduction: Vildagliptine (vilda), inhibiteur de la DPP-4, permet une réduction de l’HbA1c de 1,1 % versus placebo en addition à la metformine (met) chez des patients présentant un diabète de type 2 (DT2) insuffisamment contrôlé (RCP, étude pivot 2303). L’objectif de cette étude comparative directe (analyse intérimaire prévue à 1 an) était de démontrer la non-infériorité de vilda versus glimépiride (glim), en ajout à la met, sur la réduction de l’HbA1c après 52 semaines de traitement. Patients et méthodes: Étude multicentrique, en double-aveugle, randomisée, comparant vilda (50mg 2 f/j ; n=1 396 patients) au glim (titré jusque 6mg/j, dose moyenne 4,5mg/j ; n=1 393) chez des patients DT2 non contrôlés (HbA1c : 6,5-8,5 %) par met seule (reçue depuis 36 mois en moyenne) à dose stable (moyenne 1,9g/j à l’inclusion). Résultats: Les 2 groupes étaient comparables à l’inclusion : âge 57,5 ans, HbA1c 7,3 %, IMC 31,8kg/m2, ancienneté du diabète 5,7 ans. La non-infériorité a été démontrée (limite sup IC à 97,5 % ≤ 0,3, IC : 0,02 %-0,16 %) avec une réduction d’HbA1c de 0,44 % avec vilda et 0,53 % avec glim. Alors qu’une proportion similaire de patients atteignait une HbA1c < 7 % avec vilda (54,1 %) et glim (55,5 %), plus de patients atteignaient cette cible sans hypoglycémie dans le groupe vilda (50,9 % versus 44,3 % ; P<0,01). Vilda offre un avantage pondéral significatif (Δpoids versus glim -1,79kg, P <0,001). L’incidence des hypoglycémies confirmées était 10 fois plus faible sous vilda (1,7 % des patients versus 16,2 % ayant au moins une hypoglycémie, soit 39 épisodes hypoglycémiques versus 554, P<0,01) sans hypoglycémie sévère (versus 10 sous glim, P<0,01). L’incidence des EI et EIG était respectivement de 74,5 % et 7,1 % pour vilda et de 81,1 % et 9,5 % pour glim. Conclusion: Après échec de met, l’ajout de vilda permet une efficacité glycémique comparable à celle du glim à 52 sem, avec un bénéfice significatif sur le poids et une réduction considérable des hypoglycémies confirmées et sévères. [Copyright &y& Elsevier]

Introduction: Il est dorénavant recommandé un renforcement du traitement pour atteindre l’objectif glycémique HbA1c ≤ 7 %. Les glitazones ont montré leur capacité à réduire l’insulinorésistance périphérique et à améliorer le fonctionnement de la cellule β. Une trithérapie orale offre une meilleure acceptabilité par les patients que l’insulinothérapie. Reste donc à déterminer le moment optimal d’introduction de cette trithérapie. Le but de cette étude est d’évaluer l’efficacité de l’adjonction de PIO glitazone versus placebo chez des patients diabétiques déjà sous bithérapie (MET + SU, ou MET + GLINIDE) mais insuffisamment contrôlés. Matériels et méthodes: Émulticentrique randomisée en double aveugle, groupes parallèles où 299 patients diabétiques de type 2 recevaient pendant trois mois PIO30mg/jour ou du Placebo. Puis les 4 mois suivants, les patients continuaient soit avec PIO30mg/jour si HbA1C ≤ 6,5 % soit 45mg/jour si HbA1c > 6,5 % soit le placebo. Le critère primaire d’efficacité : amélioration de l’HbA1c. Les critères secondaires : changement de la glycémie à jeun, lipides, insuline, C-peptide, Pro-insuline/insuline, HOMA-IR et HOMA-B étaient calculés. Résultats: L’ajout de la Pioglitazone chez les patients en échec de bithérapie a montré une amélioration significative du contrôle glycémique par rapport au placebo. La différence entre les deux groupes après sept mois de trithérapie a été de 1,18 point d’HbA1c et de 2,56 mMol/L pour la glycémie à jeun (p<0,001). À la visite finale 44,4 % des patients du groupe PIO ayant une HbA1c initiale ≤ 8,5 % ont atteint l’objectif (HbA1c < 7 %) alors qu’ils n’étaient que 4,9 % dans le groupe placebo. Ces proportions chutaient si les patients avaient une HbA1c initiale > 8,5 % avec respectivement 13 % dans le groupe PIOet 0 % dans le groupe placebo. Enfin, dans le groupe Pio, HOMA-IR, Proinsuline, C-peptide étaient réduits et Homa-B augmenté par apport au groupe Placebo. Conclusion: Chez des patients mal équilibrés par bithérapie, l’ajout précoce de Pioglitazone, c’est à dire quand l’HbA1c est < 8,5 %, permet d’atteindre l’objectif d’une Hb1Ac < 7 %, sans avoir recours à l’insuline. [Copyright &y& Elsevier]