Factors associated with discontinuing insulin therapy after diabetic ketoacidosis in adult diabetic patients.

AIMS: To assess the factors associated with successful discontinuation of insulin therapy after diabetic ketoacidosis (DKA) in adult patients. METHODS: Patients (>or= 18 years) attending the Endocrine and Metabolism Clinic at a major hospital in southern Taiwan were recruited. After recovery from the acute stage, those with no contraindications to oral antidiabetic agents, with adequate beta cell reserve, and with no antiglutamic acid decarboxylase (GAD) antibody were treated with oral agents. RESULTS: Sixty-six patients (38 males, 28 females, aged 18-76 years) were included, and 21 qualified for treatment with oral agents. These 21 patients were older at diagnosis of diabetes (45.5 +/- 14.0 vs. 40.0 +/- 13.8 years, P = 0.047), had shorter diabetes duration (median 0 vs. 5.5 months, P = 0.040), higher BMI (median 23.4 vs. 19.5 kg/m2, P < 0.001), higher serum osmolality during DKA (352.1 +/- 40.7 vs. 318.0 +/- 16.4 mmol/kg, P = 0.005), and lower insulin dose following recovery (median 0.49 vs. 0.83 unit/kg/d, P < 0.001) than those patients that had to continue insulin therapy. Thirteen patients (8 males, 5 females; 62%) successfully discontinued insulin for at least one year without recurrence of DKA. Multiple logistic regression analyses showed that BMI >or= 25 kg/m2 (adjusted relative risk (ARR) 8.85, 95% CI 1.05, 8.39), diabetes onset age >or= 40 years (ARR 8.08, 95% CI 1.16, 6.95), and undiagnosed diabetes before DKA (ARR 8.90, 95% CI 1.19, 7.51) were significant factors associated with successful discontinuation of insulin therapy. CONCLUSION: We identified three independent clinical factors associated with successful discontinuation of insulin therapy after DKA.     

Study of Once Daily Levemir (SOLVE™): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice

Aims: The aim of this analysis is to determine the timing of insulin initiation in routine clinical practice, especially in relation to glycaemic control and use of oral antidiabetic drugs (OADs). Methods: Study of Once Daily Levemir was a 24‐week international observational study involving 10 countries which evaluated the safety and effectiveness of initiating once‐daily insulin detemir in people with type 2 diabetes mellitus (T2DM) being treated with one or more OADs (clinical trial number NCT00825643 and NCT00740519). Results: A total of 17 374 participants were enrolled in the study: aged 62 ± 12 years, 53% male, T2DM duration 10 ± 7 years, body mass index 29.3 ± 5.4 kg/m². Pre‐insulin HbA1c was 8.9 ± 1.6%. The proportion of patients with HbA1c ≥9.0% ranged from 64% (UK) to 23% (Poland). Pre‐insulin OAD treatment included metformin (81%), sulphonylureas (59%), glinides (16%), thiazolidinediones (TZD) (12%), α‐glucosidase inhibitors (12%) and dipeptidyl peptidase (DPP)‐IV inhibitors (7%). The mean starting dose of insulin detemir for the total cohort was 0.16 ± 0.09 U/kg. Differences in OAD use and insulin doses at initiation were evident among participating countries. The largest proportional changes in OAD prescribing at insulin initiation were seen with glinides (+15%), sulphonylureas (?19%), TZD (?31%) and DPP‐IV inhibitors (?28%). Conclusions: Despite well‐documented benefits of timely glycaemic control and consensus guidelines encouraging earlier use of insulin, considerable clinical inertia exists with respect to initiating appropriate insulin therapy in people with T2DM. Considerable regional differences exist in the timing of insulin initiation and in the use of OADs.     

Controlled extension of oral antidiabetic therapy on former insulin dependent diabetics by means of the combined i.v. glibenclamide-glucose-response-test

Summary A new sulphonylurea response test is described for predicting the results of long-term treatment with a recently developed sulphonylurea compound, glibenclamide, particularly in insulin-dependent tolbutamide-non-responsive elderly diabetics. The test is based on the observation that the insulin-stimulating capacity of glucose and the determination of the insulin increases are strikingly potentiated following glibenclamide plus glucose i.v. (25 plus 0.33 g/kg body weight) in serum samples where insulin binding antibodies have been removed. 11 out of 40 diabetics demonstrating between 60 and 90 min following injection, a mean increase of insulin of more than 500 per cent above the initial values, correlated satisfactorily with successful long-term oral treatment with glibenclamide. A positive glibenclamide-glucose-response test contrasted with primary failure of glibenclamide therapy in only one patient suffering from haemochromatosis. Oral treatment with glibenclamide may have certain advantages over insulin therapy, especially in elderly diabetics suffering from visual impairment, who are unable to inject themselves with insulin.Support of this Study by Deutsche Forschungsge-meinschaft (Pf 38/28) is gratefully acknowledged.     

Pharmacological Effects of Glycyrrhiza spp. and Its Bioactive Constituents: Update and Review

The roots and rhizomes of various species of the perennial herb licorice (Glycyrrhiza) are used in traditional medicine for the treatment of several diseases. In experimental and clinical studies, licorice has been shown to have several pharmacological properties including antiinflammatory, antiviral, antimicrobial, antioxidative, antidiabetic, antiasthma, and anticancer activities as well as immunomodulatory, gastroprotective, hepatoprotective, neuroprotective, and cardioprotective effects. In recent years, several of the biochemical, molecular, and cellular mechanisms of licorice and its active components have also been demonstrated in experimental studies. In this review, we summarized the new phytochemical, pharmacological, and toxicological data from recent experimental and clinical studies of licorice and its bioactive constituents after our previous published review. Copyright © 2015 John Wiley & Sons, Ltd.     

Antidiabetic activity of gossypin, a pentahydroxyflavone glucoside, in streptozotocin-induced experimental diabetes in rats

Background: Most of the currently available oral hypoglycemic drugs for the treatment of diabetes mellitus elicit detrimental side effects. Hence, the search for plant‐derived products for the treatment of diabetes continues. Gossypin, a pentahydroxy flavone glucoside found in the flowers of Hibiscus vitifolius, has many biological properties, including as an antioxidant, anti‐inflammatory and anticancer agent. The aim of the present study was to evaluate the effect of gossypin in streptozotocin (STZ)‐induced experimental diabetes in rats. Methods: Diabetic rats were administered 20 mg/kg per day gossypin orally for 30 days. On the 28th day, rats were subjected to an oral glucose tolerance test. In addition, blood glucose, plasma insulin, hemoglobin, and HbA1c levels were determined, as was the glycogen content of the liver and muscles. Plasma protein and blood urea were also estimated. Results: Oral administration of gossypin to diabetic rats resulted in improved glucose tolerance. Increased blood glucose and HbA1c levels and the reduced plasma insulin and hemoglobin levels in diabetic rats were significantly reversed to near normal after oral administration of gossypin. Furthermore, the glycogen content of the liver and muscles was significantly improved after gossypin treatment of diabetic rats, and plasma protein and blood urea levels were almost normalized. The data obtained in gossypin‐treated rats were comparable with those obtained following gliclazide treatment of rats, a standard reference drug for diabetes. Conclusions: The results of the present study indicate that gossypin has potent antidiabetic activity in STZ‐induced experimental diabetes in rats.     

Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial

Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycaemic control, necessitating insulin therapy. Fear of hypoglycaemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS^®, glargine, Sanofi-aventis, Paris, France) therapy using two treatment algorithms. This subgroup analysis investigated the initiation of once-daily glargine therapy in patients suboptimally controlled on multiple OADs. Research Design and Methods: This study was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose ≤100 mg/dl (≤5.5 mmol/l). Algorithms were compared for incidence of severe hypoglycaemia [requiring assistance and blood glucose <50 mg/dl (<2.8 mmol/l)] and baseline to end-point change in haemoglobin A_1c (HbA_1c). Results: Of the 4961 patients enrolled in the study, 865 were included in this subgroup analysis: 340 received glargine plus 1 OAD and 525 received glargine plus >1 OAD. Incidence of severe hypoglycaemia was <1%. HbA_1c decreased significantly between baseline and end-point for patients receiving glargine plus 1 OAD (−1.4%, p < 0.001; algorithm 1 −1.3% vs. algorithm 2 −1.5%; p = 0.03) and glargine plus >1 OAD (−1.7%, p < 0.001; algorithm 1 −1.5% vs. algorithm 2 −1.8%; p = 0.001). Conclusions: This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA_1c with a low risk of hypoglycaemia. The greater reduction in HbA_1c was seen in patients randomized to the patient-driven algorithm (algorithm 2) on 1 or >1 OAD.     

Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation

Aim: The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. Methods: Normoglycaemic and non‐insulin‐dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high‐density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 μM) on 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. Results: Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin–nicotinamide–induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of α‐glucosidase activity in vitro. However, NG (10 μM) was shown to inhibit 11β‐HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD₅₀ > 5000 mg/kg and ranking at level five based on OECD protocols. Conclusion: Our findings suggest that NG may exert its antidiabetic effect by extra‐pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels.     

Pharmacological study of a new hypoglycaemic sulphonamide: Glisoxepid (RP 22410)

Summary Glisoxepid or RP 22410 is a new very active hypoglycaemic sulphonylurea. In the normal conscious dog, RP 22410 administered intravenously was 81 or 131 times more active than tolbutamide, depending on whether the dose is expressed in grams or in moles. The hypoglycaemic effect did not occur in the totally pancreatectomized dog. — RP 22410 stimulated insulin secretion.In vivo in the anaesthetized or conscious dog, the action of the drug (whether it be administered intravenously or orally) resulted in a rapid and considerable increase of the amount of insulin secreted by the pancreas. This action lasted several hours.In vitro the direct action of the product on the pancreas was demonstrated on the isolated and perfused rat pancreas, even at very low concentrations. — In the mouse, prolonged oral administration of RP 22410 stimulated neogenesis of the islets of Langerhans and of the beta cells. It therefore possesses betacytotrophic action.

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Pharmakologische Studie über das neue blutzuckersenkende Sulfonamid Glisoxepid RP 22410

Zusammenfassung Glisoxepid oder RP 22410 ist ein neuer, stark aktiver, blutzuckersenkender Sulfonylharnstoff. Je nachdem ob die Dosen in Gewichten oder Mol ausgedrückt werden, ist er am wachen Hund bei intravenöser Applikation 81 bzw. 131mal aktiver als Tolbutamid. Die blutzuckersenkende Wirkung zeigt sich nicht am vollständig pankreatektomierten Hund. -Diese Substanz stimuliert die Insulinsekretion.In vivo zeigt sich ihre Wirkung am anästhesierten oder wachen Hund in einer schnellen und beträchtlichen Erhöhung der vom Pankreas sezernierten Insulinmenge unabhängig davon ob sie intravenös oderper os verabreicht wird. Diese Wirkung bleibt über mehrere Stunden bestehen.In vitro wurde die direkte Wirkung der Substanz auf den isolierten und perfundierten Pankreas der Ratte auch in sehr geringen Konzentrationen nachgewiesen. -Bei der Maus stimuliert RP 22410 bei chronischer Verabreichungper os die Neubildung von Langerhansschen Inseln und B-Zellen. Sie besitzt daher eine betacytotrophe Wirkung.

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Etude pharmacologique d'un nouveau sulfamide hypoglycémiant: le glisoxepid (RP 22410)

Résumé Le glisoxepid ou RP 22410 est un nouveau sulfonylurée hypoglycémiant très actif. Chez le chien normal éveillé, administré par voie intraveineuse, il est 81 ou 131 fois plus actif que le tolbutamide, suivant que les doses sont exprimées en poids ou en moles. Cette action hypoglycémiante ne se manifeste pas chez le chien totalement dépancréaté. — Ce produit stimule la sécrétion d'insuline.In vivo chez le chien anesthésié ou éveillé, l'action du produit (que celui-ci soit administré par voie intraveineuse ou par voie digestive) se traduit par une augmentation rapide et considérable de la quantité d'insuline sécrétée par le pancréas. Cette action se prolonge pendant plusieurs heures.In vitro l'action directe du produit sur le pancréas a été démontrée sur le pancréas isolé et perfusé du rat, même à très faibles concentrations. — Chez la souris le RP 22410 administré chroniquementper os stimule la néogénèse des îlots de Langerhans et des cellules bêta. Il est donc doué de l'action bêtacytotrophe.

     

2型糖尿病中降糖药与心力衰竭风险

长期以来2型糖尿病作为心血管事件高危因素,显著增加各类心血管并发症风险,而心力衰竭(心衰)已成为2型糖尿病患者最常见死因,降糖治疗可显著降低心血管死亡风险和心衰住院率,但目前临床上对于各类降糖药尤其是传统降糖药的心衰风险研究资料有限,自从2008年美国FDA和欧洲医学会临床研究指南求新型降糖药须评估心血管结局风险,使得...