Oral Hypoglycemic Agents

This prospective, randomized study investigated the effect of exercise on leptin, insulin, cortisol and lipid profiles in obese children. A total of 40 obese boys aged 10-12 years with a body mass index (BMI) ≥ 30 kg/m 2 were randomly separated into an exercise group (n = 20) that underwent a 12-week aerobic exercise programme and a non-exercise (control) group (n = 20). The BMI, low-density lipoprotein, cortisol, leptin and insulin levels were significantly lower in the exercise group after 12 weeks compared with baseline values, whereas highdensity lipoprotein levels were significantly higher. In contrast, in the control group, low-density lipoprotein, cortisol and leptin levels were significantly higher after 12 weeks compared with baseline values while high-density lipoprotein levels were significantly lower. These findings indicate the importance of regular exercise in the regulation of body weight and protection against cardiovascular risk factors in obese children.

Aims/hypothesis We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. Materials and methods The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-d-[3H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. Results At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC50] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC50 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC50 1 μmol/l); at higher glucose concentrations, EC50s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. Conclusions/interpretation PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.

Diabetes" and related "Health Beliefs Concerning Diabetes" (Bradley's questionnaires, 1984), a fully randomized short-of structured outpatient education for Functional Insulin Treatment (FIT: selective insulin dosages for eating, fasting or term controlled Study 1 (four weeks, 32 patients), and longterm uncontrolled pilot Study 2 (three years, 68 patients) were correcting hyperglycaemia) on perceived control over diabetes and related health beliefs. FIT was thought to influence the performed. Results: The short-term study revealed that FIT induced the feeling of independence from situational control perception of self-efficacy in diabetes, in contrast to conventional treatment, based on scheduled, rigid food intake and while self-managing diabetes. In the long-term study, the patients were increasingly freed from the feeling of being under insulin delivery-it allows flexible eating, provided independent control of glycemia. Methods: Structured, comprehen-the control of physician and treatment-related restrictions, which-together with higher perceived self-efficacy-con-sive, outpatient group training in FIT for selective use of insulin either for eating, fasting or correction included practi-tributed to the feeling of "empowerment." This was associated with high treatment satisfaction and significant improvement cal "insulin games." The FIT program focused on everyday criteria for choices of insulin dosages and thus on the patient's of glycemic control. Conclusion: Structured out-patient group training for FIT results in measurable improvement of pa-ability to execute his/her newly gained flexible treatment to his/her everyday life while preventing acute and late complica-tients' perceived control over diabetes and self-efficacy.

Objective: Depression and insomnia are closely linked, yet our understanding of their prospective relationships remains limited. The aim of the current study was to investigate the directionality of association between depression and insomnia. Methods: Data were collected from a prospective population-based study comprising the most recent waves of the Nord-TrLndelag Health Study (HUNT) (the HUNT2 in 1995Y1997 and the HUNT3 in 2006Y2008). A total of 24,715 persons provided valid responses on the relevant questionnaires from both surveys. Study outcomes were onset of depression or insomnia at HUNT3 in persons not reporting the other disorder in HUNT2. Results: Both insomnia and depression significantly predicted the onset of the other disorder. Participants who did not have depression in HUNT2 but who had insomnia in both HUNT2 and HUNT3 had an odds ratio (OR) of 6.2 of developing depression at HUNT3. Participants who did not have insomnia in HUNT2 but who had depression in both HUNT2 and HUNT3 had an OR of 6.7 of developing insomnia at HUNT3. ORs were only slightly attenuated when adjusting for potential confounding factors. Conclusions: The results support a bidirectional relationship between insomnia and depression. This finding stands in contrast to the previous studies, which have mainly focused on insomnia as a risk factor for the onset of depression.

Brain-pancreas relative protein (BPRP) is a novel protein that mainly expresses in brain and pancreas. In our previous study, we found that various stressors significantly decreased the expression of BPRP in pancreas in vivo, accompanied by changes in insulin and glucose levels, and that expression of BPRP in pancreas also decreased significantly in diabetic rats induced by Streptozocin (STZ). All these findings suggest that BPRP may be a glucose or insulinsensitive protein. However, how the changes in insulin or glucose levels influence the expression of BPRP in hippocampus requires further study. Here, we investigated the effects of insulin or glucose on the expression of BPRP in primary cultured hippocampal neurons. We supplied hippocampal neurons with glucose, insulin, or supernatant from pancreatic b-cells, which secrete insulin into the supernatant. Our data showed that insulin had beneficial effect on the viability while no significant effect on the expression of BPRP in hippocampal neurons. On the contrary, 40 mM glucose or free glucose culture significantly decreased the expression of BPRP, while had no significant effect on the viability and apoptosis of hippocampal neurons. Further study showed that levels of insulin in the supernatant collected from pancreatic b-cells medium changed over days, and that supernatant increased the viability of hippocampal neurons, while it had no obvious effect on the expression of BPRP in hippocampal neurons. These results suggest that BPRP may be a glucose-sensitive protein.

Organovanadium compounds have been shown to be insulin sensitizers in vitro and in vivo. One potential biochemical mechanism for insulin sensitization by these compounds is that they inhibit protein tyrosine phosphatases (PTPs) that negatively regulate insulin receptor activation and signaling. In this study, bismaltolato oxovanadium (BMOV), a potent insulin sensitizer, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cells and enhanced insulin receptor activation in vivo. NMR and X-ray crystallographic studies of the interaction of BMOV with two different phosphatases, HCPTPA (human low molecular weight cytoplasmic protein tyrosine phosphatase) and PTP1B (protein tyrosine phosphatase 1B), demonstrated uncomplexed vanadium (VO ) in the active site. Taken together, these findings support phosphatase inhibition as a mechanism for insulin sensitization by BMOV 4 and other organovanadium compounds and strongly suggest that uncomplexed vanadium is the active component of these compounds. 

In the search for potent and selective human b b3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human b b3-, b b2-, and b b1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the b b3-AR with functional selectivity over the b b1and b b2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.

Ethnopharmacological relevance: Nervilia plicata (Orchidaceae) has long been used in the antidiabetic medicinal preparations of traditional healers of Wayanad (Kerala), but recuperative potential of the plant was remained undefined. We demonstrated the regenerative potential of the plant extract on kidney affected by type 2 diabetes besides lowering blood glucose. Aim of the study: The aim of the current study was to investigate the recuperative and regenerative potential of alcoholic stem extract of Nervilia plicata on streptozotocin-nicotinamide induced type 2 diabetic models. Materials and methods: Non insulin dependent diabetes mellitus (NIDDM) was induced in overnight fasted rats by intramuscular injection (IMI) of 60 mg/kg STZ and 120 mg/kg of nicotinamide after 5 min interval. Blood glucose was assessed by a glucometer, serum urea and creatinine levels were determined by diacetylmonooxime method and Jaffe reaction respectively. Kidney sections were taken and stained with Masson's tri-dye and Periodic Acid Schiff (PAS) and examined for structural changes. Also lipid peroxidation product (LPP) levels were determined as thio barbituric acid reactive substance levels (TBARS) method. Results: On administration of 5 mg/kg of plant extract, blood glucose levels of the NIDDM rats showed 62.00 and 76.29% decrease in the blood glucose levels on day 0 and day 30 respectively. Damages caused to the kidney tissue were negligible or not seen. Serum urea and creatinine levels showed 61.49 and 70.96% decrease on day 30. LPP levels of kidney and pancreas showed 70.58 and 77.41% decrease respectively. Conclusion: These results demonstrate significant antidiabetic and regenerative potential of the Nervilia plicata, justifying the use of plant in the indigenous system of medicine. Isolation and characterisation of the compound(s) playing pivotal role in the cure would open new vistas in the therapy of type 2 diabetes.

Phyllanthus sellowianus Müller Arg. (Euphorbiaceae) is a plant used in folk medicine as a hypoglycemic and diuretic agent. The present study describes the hypoglycemic effect of fractions obtained from the stem barks of P. sellowianus using a bioassay-guided fractionation protocol and streptozotocin-induced hyperglycemic mice. The aqueous extract was partitioned between dichloromethane and butanol to yield the dichloromethane (D), butanol (B) and the remaining aqueous (A) fractions. Fractions B and A, administered at the dose of 200 mg/kg p.o., caused a significant reduction in blood glucose concentration at 6 and 9 h, while the same dose of fraction D was ineffective. The reduction in blood glucose levels obtained with the B and A fractions was similar to that observed with glibenclamide (10 mg/kg) which was used as a reference for the hypoglycemic activity. Phytochemical analysis of fractions B and A revealed the presence of flavonoid compounds, of wich rutin and isoquercitrin were the major constituents, respectively. The possible involvement of these flavonoids in the hypoglycemic effect of the active fractions is discussed.

In this study, the total phenolic and flavonoid contents, the 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging ability and the ferric reducing power (FRAP) of Aloe vera were measured to determine the antioxidant activity of this species. The in vivo antidiabetic effects of the plant were also investigated using streptozotocin-induced type 2 diabetic model rats that were divided into five groups based on the treatment received:

Background Examining variation in diabetes care across regions/organizations provides insight into underlying factors related to quality of care. The aims of this study were to assess quality of diabetes care and its variation among Aboriginal community health centres in Australia, and to estimate partitioning of variation attributable to health centre and individual patient characteristics.

Aims To de®ne the number of people in Tayside, Scotland (population 349 303) with Type 2 diabetes who use metformin, the incidence of contraindications to its continued use in these people and the proportion that discontinued metformin treatment following the development of a contraindication.

In vivo modulation of levels of fasting blood glucose by O. canum extract was evaluated in type-II diabetes mellitus using the C57BL/KsJ db/db genetically diabetic animal model, and its effects on glucose-stimulated insulin release in vitro were monitored using isolated rat pancreatic β-islet cells. The results showed that fasting blood glucose levels and body weight decreased significantly (p < 0.05) in diabetic and non-diabetic C57BL/KsJ mice, which were administered aqueous extract of O. canum. In vitro, the O. canum extract significantly enhanced insulin release from isolated rat pancreatic β-islet cells. Insulin release was found to be dependent on glucose concentration and increased with increasing O. canum concentration in the incubation medium up to an optimum extract concentration of 0.03 mg/ml. Release of the hormone decreased beyond this concentration of extract in the medium. Addition to the medium of Desmodium adscendens, a plant preparation used to manage inflammatory disorders, did not increase but rather inhibited insulin secretion by the pancreatic β-islet cells. These results could explain the use of O. canum in Ghanaian folk medicine to manage diabetes mellitus.

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes.

Background: Little is known about the consequences of excessive alcohol ingestion in patients with type 1 diabetes. Aim: To examine the metabolic effects of acute ingestion of liberal amounts of alcohol in patients with type 1 diabetes. Design: A pilot study using a randomized, placebo controlled, double blind design in Hospital Clinical Research Unit. Methods: The study included 10 patients with type 1 diabetes (seven male, age 43.9 AE 9.0 years, duration of diabetes 17.3 AE 13.8 years, HbA 1c 8.0 AE 1.5%) who had a standard 600-calorie lunch on two separate occasions, together with either white wine (men eight units, women six units), or an equivalent volume of alcohol-free wine. Bloods were collected before lunch and hourly for 4 h for glucose, intermediary metabolites, counterregulatory hormones and inflammatory markers. Results: There were no significant differences between alcohol and alcohol-free days in levels of glucose, triglycerides, free fatty acids, glycerol, cortisol and growth hormone. In contrast, lactate levels rose in response to the meal but with alcohol the overall response was augmented (P = 0.014). b-Hydroxybutyrate levels were suppressed post prandially on the alcohol-free day but were significantly elevated with alcohol (P < 0.001). Conclusions: A rise in ketones following alcohol ingestion occurred despite subjects being in a strictly controlled environment with no interruption in insulin administration. Such individuals might be at risk of significant ketosis in less-controlled circumstances where insulin administration might be more erratic. Patient education material should contain information to highlight these potential problems.

To investigate the relationship between changes in glycated haemoglobin (HbA 1c ) and postprandial glucose excursions on 1,5-anhydroglucitol (1,5-AG) in patients with Type 2 diabetes, utilizing the differential effects between biphasic insulin aspart 30 (BIAsp 30) or insulin glargine (IGlar) on postprandial glucose (PPG) levels.

Fenugreek has a long history of medical uses in Ayurvedic and Chinese medicine, and has been used for numerous indications, including labor induction, aiding digestion, and as a general tonic to improve metabolism and health. Preliminary animal and human trials suggest possible hypoglycemic and antihyperlipidemic properties of oral fenugreek seed powder.

Elevated glucose concentration increases oxidation and Advanced Glycation End product (AGE) formation. The binding of circulatory AGEs or AGEs included in erythrocyte membrane to the receptor for AGEs (RAGE) generates in endothelial cells an oxidative stress and enhances the expression of inflammatory molecules. Engagement of RAGE by AGEs and subsequent signaling plays an important role in the development of diabetic complications. Soluble RAGE isoforms (sRAGE) neutralize the ligand-mediated damage by acting as a decoy. If the expression of RAGE is upregulated during the pathogenesis of inflammatory diseases, sRAGE mostly found decreased when complications ensue. By modulating RAGE isoform expression, it could be possible to reduce the incidence of complications. This review focused on the capability of Angiotensin Receptor Blockers (ARBs), which are used to treat patients with hypertension and/or diabetes, to modulate RAGE isoform expression because some data reported the interfere...

Aim: This systematic review and meta-analysis was to evaluate the body weight increase and its clinical correlates, through direct weighted regressions, as well as the effect of different insulin regimens and insulin analogues, through meta-analysis.

We sought to compare the effects of the thiazolidinedione ciglitazone with the endogenous fatty acid PPARg agonists 9-and 13hydroxyoctadecadienoic acid (9-and 13-HODE), in U937 monocytic cells. Ciglitazone and 9-HODE inhibited cell proliferation and all three agonists increased cellular content of C18:0 fatty acids. Ciglitazone and 13-HODE resulted in an increased percentage of cells in S phase and ciglitazone reduced the percentage of cells in G 2 /M phase of cell cycle, whilst 9-HODE increased the percentage of cells in G 0/1 and reduced the fraction in S and G 2 /M phases. 9-HODE selectively induced apoptosis in U937 cells, and increased PPARg2 gene expression. Induction of apoptosis by 9-HODE was not abrogated by the presence of the PPARg antagonist GW9662. Synthetic (TZD) and endogenous fatty acid ligands for PPARg, ciglitazone and 9-and 13-HODE, possess differential, ligand specific actions in monocytic cells to regulate cell cycle progression, apoptosis and PPARg2 gene expression. r

Aim and methods. -The present study compared the clinical and metabolic characteristics of latent autoimmune diabetes in adults (LADA) with type 2 diabetes, as well as the residual beta-cell function and progression to insulin treatment, over a 2-year follow-up period, of antibody (Ab)-positive and Ab-negative patients who achieved tight glycaemic control (HbA 1c 7.0 ± 0.8% and 6.5 ± 0.9%, respectively, at the time of entry into the study).

While evidenced-based guidelines promote glycated hemoglobin (HbA(1c)) targets &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;7.0% in order to reduce the long-term risk of diabetic complications, many individuals with type 2 diabetes do not achieve these targets. Fear of hypoglycemia provides a major barrier to improving blood glucose control as a result of delayed insulin initiation and failure to appropriately titrate insulin following initiation. Modern insulin analogs were designed to achieve improved blood glucose control with similar hypoglycemic risk compared with non-analog insulins (or similar blood glucose control with reduced hypoglycemic risk). While this has been demonstrated in randomized controlled trials, there is a need to confirm these findings in an everyday clinical setting. The A(1)chieve study will evaluate adverse events and effectiveness of premix (biphasic insulin aspart 30 [NovoMix 30]), basal (insulin detemir [Levemir]), and meal-time (insulin aspart [NovoRapid]) insulin analogs in people with type 2 diabetes in near-routine clinical practice. A(1)chieve is an international, prospective, multi-center, open-label, non-interventional, 24-week study of people with type 2 diabetes using an insulin analog. The study will recruit 60 000 people from 30 countries across four continents (Asia, Africa, South America, and Europe). The primary aim of the study is to assess the adverse event profile of the study insulins in routine clinical practice, including rates of hypoglycemia. In addition, effectiveness (HbA(1c), fasting plasma glucose, and postprandial plasma glucose) and patient quality of life outcomes will be measured. Comprehensive epidemiological data will be collected at baseline, including recent plasma glucose results and hypoglycemic episodes, prevalence of diabetes-related complications, and measures of current standards of care. Thus, A(1)chieve should provide important information about how insulin analogs perform in daily clinical practice.

The purpose of this study was to compare the pharmacokinetics and pharmacodynamics of the premixed insulin analogue biphasic insulin aspart (BIAsp 30) with the equivalent premixed biphasic human insulin (BHI 30), administered twice daily, in patients with type 2 diabetes mellitus. In this randomized, double-blind, crossover trial, 13 patients (mean age, 64 years; baseline mean glycosylated hemoglobin, 7.7%; mean body mass index, 28.1 kg/m2) received 2 weeks of treatment with BIAsp 30 and 2 weeks of BHI 30 administered immediately before dinner and breakfast. At the end of each 2-week treatment period, 24-hour serum insulin and glucose profiles were determined using specific 2-sided enzyme-linked immunosorbent assays. All pharmacodynamic and pharmacokinetic end points were analyzed using analysis of variance. Total daily insulin exposure was similar between treatment periods. Mean area under the total insulin concentration-time profile during the 2 hours following administration of BIAsp 30 was 17% greater than that of BHI 30 after dinner and 44% greater after breakfast; both differences were statistically significant. The maximum serum insulin aspart concentrations following BIAsp 30 were significantly higher after dinner (18%) and breakfast (35%). Peak serum insulin concentration was reached 1 hour earlier after breakfast and 45 minutes earlier after dinner in the BIAsp 30 group; differences were significant only after breakfast. The mean daily prandial glucose excursion was significantly lower for BIAsp 30 (16.2 mmol x h x L(-1)) than BHI 30 (17.9 mmol x h x L(-1)). Postprandial 4-hour glucose excursions were significantly lower with BIAsp 30 than with BHI 30 after dinner and breakfast, but were significantly greater after lunch. Mean 24-hour and nocturnal serum glucose concentrations were similar, and both insulins were associated with &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 7 minor and no major hypoglycemic events. Premeal injection of BIAsp 30 in a twice-daily regimen significantly reduced overall postprandial glucose excursions. This effect may be of importance when improvement in postprandial glucose control is desired.

The effects of short- versus long-term alpha tocopherol administration on oxidative stress and survival of dorsal random flaps were studied in diabetic rats. Seven groups, with 20 rats in each, were constructed: (1) control, (2) noncontrolled diabetes, (3) noncontrolled diabetes+short-term alpha tocopherol, (4) noncontrolled diabetes+long-term alpha tocopherol, (5) insulin treatment, (6) insulin+short-term alpha tocopherol, and (7) insulin+long-term alpha tocopherol. After 3 months of diabetes, dorsal McFarlane flaps were raised. Flap viability and free-radical measurements with histopathological examination were investigated. Mean flap survival in Groups I to VII were 84.0+/-2.2%, 55.0+/-2.4%, 57.0+/-2.5%, 57.8+/-3.7%, 64.1+/-4.1%, 70.0+/-4.9%, and 77.0+/-6.6%, respectively. Free-radical concentration, as assessed with luminol- and lucigenin-enhanced chemiluminiscence, was inversely correlated with flap survival. The results for viability and free-radical concentrations were significant between Groups 1, 2, 5, 6, and 7. Random flaps in diabetic animals showed significantly greater necrosis compared with controls. Among the diabetic animals, group receiving combination of insulin and long-term alpha tocopherol treatment had the greatest flap viability and least tissue free-radical concentration. Histopathological studies showed a hyalinization of arterioles in diabetics with long-term alpha tocopherol treatment protecting the vessel wall. In conclusion, random flaps in experimental diabetes mellitus show greater tissue oxidative stress and necrosis, which is only partially corrected with insulin treatment. Long-term antioxidant supplementation as an adjunct to insulin further lowers the oxidative stress, protects vessel structure and function, and therefore increases flap survival.

A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N&#39;-(adamantan-1-yl)-morpholine-4-carbothioimidates 7a-e and 4-arylmethyl (Z)-N&#39;-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidates 8a-e were prepared via the reaction of N-(adamantan-1-yl)morpholine-4-carbothioamide 5 and N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide 6 with benzyl or substituted benzyl bromides, in acetone, in the presence of anhydrous potassium carbonate. The structures of the synthesized compounds were confirmed by ¹H-NMR, (13)C-NMR, electrospray ionization mass spectral (ESI-MS) data, and X-ray crystallographic data. The in vitro antimicrobial activity of the new compounds was determined against certain standard strains of pathogenic bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7b, 7d and 7e displayed potent broad-spectrum antibacterial activity, while compounds 7a, 7c, 8b, 8d and 8e were active against the tested Gram-positive bac...

Background: Treatment of diabetes mellitus (DM) is complex, requiring multifaceted lifestyle change or regulation and, for many, self-regulation of insulin levels in the blood. Historically, daily insulin treatment has been viewed as burdensome to patients, prompting newer formulations and improved delivery methods. Objective: This multicenter, clinical study was designed to develop a conceptually sound, clinically meaningful, and psychometrically valid measure of insulin treatment satisfaction, applicable to a wide range of insulin therapies. Methods: A 3-phase iterative process was employed to develop and validate the Insulin Treatment Satisfaction Questionnaire (ITSQ): (1) conceptual development of items, (2) preliminary validation among patients with DM, and (3) confirmatory validation among patients with DM. Results: The ITSQ was validated with 170 patients in phase 2 and 402 patients in phase 3. Confirmatory factor analysis produced a 5-factor, 22-item instrument assessing regimen inconvenience, lifestyle flexibility, glycemic control, hypoglycemic control, and satisfaction with the insulin delivery device. Results for reliability and construct validity of the final version were consistent in both samples of patients treated with insulin, with different data collection methods. Internal consistency (using Cronbach α coefficient) of the subscales ranged from 0.79 to 0.91. Test-retest reliability (using Spearman rank correlation coefficients) ranged from 0.63 to 0.94. ITSQ scores showed moderate to high correlation with related measures of treatment burden. The ITSQ differentiated among insulin delivery methods, glycosylated hemoglobin values, the number of times the patient required assistance administering insulin, and insulin adherence. Conclusion: In our study samples, the ITSQ appeared to be conceptually and psychometrically sound and applicable to a wide range of insulin therapies.

The inappropriate overproduction of glucose by the liver is one of the key contributors to the hyperglycaemia of the diabetic state, and thus is a logical site of intervention for novel anti-diabetic approaches. Metformin is the only currently marketed anti-hyperglycaemic drug whose action is attributed largely to its having inhibitory effects on hepatic glucose production, but its molecular site and mechanism(s) of action remain unknown, whereas the liver acting PPARα agonists have their effects primarily on lipid metabolism. This review therefore rather focuses on candidate molecular targets within the liver for anti-hyperglycaemic therapy, and describes potential rate-controlling receptors and enzymes within the glucose producing pathways (glycogenolysis and gluconeogenesis). Most focus is directed towards inhibitors of the enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and towards glucagon receptor antagonists, as these appear to be the most advanced in preclinical and clinical development, although progress with other potential targets is also described. Evidence of the anti-diabetic potential of such agents from animal studies is presented, and the relative merits of each approach are reviewed and compared. It is likely that such agents will become important additions to the therapeutic approaches to combat diabetes.

In previous studies, we identified a truxillic acid derivative as selective activator of the peroxisome proliferator-activated receptor c, which is a member of the nuclear receptor family and acts as ligand-activated transcription factor of genes involved in glucose metabolism. Herein we present the structureactivity relationships of 16 truxillic acid derivatives, investigated by a cell-based reporter gene assay guided by molecular docking analysis.

Bariatric surgery improves glycaemia in obese people with type 2 diabetes, but its effects are uncertain in overweight people with this disease. We aimed to identify whether laparoscopic adjustable gastric band surgery can improve glucose control in people with type 2 diabetes who were overweight but not obese. We did an open-label, parallel-group, randomised controlled trial between Nov 1, 2009, and June 30, 2013, at one centre in Melbourne, Australia. Patients aged 18-65 years with type 2 diabetes and a BMI between 25 and 30 kg/m2 were randomly assigned (1:1), by computer-generated random sequence, to receive either multidisciplinary diabetes care plus laparoscopic adjustable gastric band surgery or multidisciplinary diabetes care alone. The primary outcome was diabetes remission 2 years after randomisation, defined as glucose concentrations of less than 7.0 mmol/L when fasting and less than 11.1 mmol/L 2 h after 75 g oral glucose, at least two days after stopping glucose-lowering...

Purpose: The purpose of this article was to examine how aldose reductase (AR) inhibitors are used in the prevention and treatment of peripheral neuropathy in diabetes, specifically focusing on efficacy. Methods: Medline searches were used to identify clinical trials investigating AR inhibitors and their proposed mechanism of action, efficacy, and adverse effects. Additionally, the references of the articles returned by the Medline search were examined for pertinent publications. Results: Three AR inhibitors were selected for review. Modest improvements in the preservation and restoration of nerve conduction velocities were reported in the studies. Additionally, patients reported improvements in the subjective symptoms associated with diabetic peripheral neuropathy. Adverse effects for the studied agents were minimal or not reported. Conclusions: Given the mechanism by which diabetic peripheral neuropathy can result, targeting the polyol pathway as a method of treatment appears promising, yet the efficacy of newer AR inhibitors is still to be proven. Currently, these agents are not marketed in the United States. As newer studies emerge, diabetes educators will learn more about their efficacy and safety in preventing and treating diabetic peripheral neuropathy.

The objective was to compare the impact on treatment satisfaction (TS) and quality of life (QoL) of early insulinization with glargine versus adjusting oral antidiabetic drug (OAD) therapy in people with Type 2 diabetes with uncontrolled glycemia. TS and QoL were assessed at baseline, weeks 12 and 24 within the Canadian INSIGHT, a randomized 24-week trial of Type 2 patients. A total of 366 patients randomized to either the insulin glargine arm (n=182) or the adjusted OAD therapy arm (n=184) completed both questionnaires. At baseline, TS and QoL were similar in both groups. A1c reduction was greater in the insulin glargine arm. TS improved from baseline in both treatment arms; however, there was greater increase with insulin glargine+OAD. Perceived frequency of hypoglycemia and hypoglycemia were lower at week 24, with no differences between the two groups. Perceived frequency of hyperglycemia improved with glargine at week 12, and no difference was found at 24 weeks. Finally, QoL imp...

We retrospectively evaluated a possible difference in periods until start of insulin treatment between type 2 diabetic patients treated with gliclazide (GCZ) and glibenclamide (GBC), because GCZ might be protective for beta cells than GBC. Subjects were Japanese patients. GCZ group consisted of patients treated with GCZ alone or with GCZ and GBC in the separate treatment periods in combination with or without other oral hypoglycemic agents (OHAs), while GBC group consisted of patients with GBC alone or in combination with other OHAs except GCZ. The periods until the treatment of insulin commenced were calculated using the Kaplan-Meier method. Proportional hazards models were used to adjust the differing variables between GCZ and GBC groups. The periods until the start of insulin treatment from diabetes onset, diabetes treatment, or GCZ or GBC treatment were significantly longer in the GCZ group than those in GBC group (P < 0.001 in each group). Independent variables affecting the period were average HbA1c levels during GCZ or GBC treatment (hazard ratio = 2.5 per %), other OHAs combined (hazard ratio = 1.9 on combination), and difference between GCZ and GBC groups (hazard ratio = 0.5 on GCZ). These results imply that GCZ may be more protective against secondary beta cell failure than GBC. #

Background.Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine-QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c ≤7.0%).Methods.1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c ≤7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier:NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for ang...

Effects of principal saponins, chakasaponins I-III, from the flower buds of Camellia sinensis cultivated in Fujian province, China on plasma triglyceride (TG) and glucose levels in olive oil or sucrose-loaded mice were examined. Chakasaponins I-III at 50 and 100 mg/kg significantly inhibited increases in plasma TG and glucose levels. Furthermore, they prevented gastric emptying, suggesting that the former inhibitory effect is partly dependent on the inhibition of gastric emptying. In addition, the chemical structure of a new acylated oleanane-type triterpene oligoglycoside, chakasaponin IV, was elucidated on the basis of chemical and physicochemical evidence.

The objective of this study was to quantify 1-year weight gain associated with the initiation of sulphonylurea (SU), metformin, insulin and thiazolidinedione (TZD) therapy in a representative real world population of type 2 diabetic patients. Research Design and Methods: The study population was 9546 members of Kaiser Permanente Northwest (KPNW) who initiated an anti-hyperglycaemic drug between 1996 and 2002 and continued use of that drug for at least 12 months without adding other therapies. Change in weight was calculated as the annualized difference between baseline and follow-up weight and was adjusted for demographic and clinical characteristics. We then compared the weight changes observed in patients newly initiating SU, metformin, insulin and TZD therapies. Results: After adjustment for demographic and clinical characteristics that might affect weight change, metformin initiators lost an average of 2.4 kg while all other groups gained weight. SU initiators gained the least (1.8 kg), followed by insulin initiators (3.3 kg) and TZD subjects (5.0 kg). All comparisons were highly statistically significant. Conclusions: In an observational study of 1-year weight changes following the initiation of SUs, metformin, insulin or TZDs, we found similar but somewhat smaller weight changes than those previously reported in clinical trials. Our observed weight changes could not be explained by the many other factors we tested and seemed to apply across the full spectrum of diabetes patients. Our report provides valuable information that will allow the patient and clinician to anticipate, and perhaps address, expected weight changes that accompany the initiation of anti-hyperglycaemic drugs.

Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARα agonists, such as the already available fibrates, improve dyslipidemia, while PPARγ agonists, such as thiazolidinediones, improve