Assessment of Safety and Effectiveness of Glaritus^®(Wockhardt’s Insulin Glargine) in a Prospective, Multi-Centric Post Marketing Observational Study in Nepalese Having Type 2 Diabetes Mellitus

Background: Nepal is one of the fastest urbanizing countries in South Asia and is facing the consequences of urban lifestyle leading to obesity and metabolic syndrome. Type 2 diabetes mellitus (T2DM) is currently a high-burden disease in Nepal with a prevalence of 8.4%. Of these 8% - 18% patients are on insulin and 42% patients were reported to have uncontrolled diabetes in the past year. This suggests a need for better therapy options in terms of efficacy and safety. The current study was designed to investigate the effects of Insulin glargine-based therapy in Nepalese with T2DM who could not achieve adequate glycemic control with oral and non-glargine-insulin therapy. Methods: This is a prospective, multi-centric, single arm and post marketing observational study to assess the safety and effectiveness of Glaritus®(Wockhardt’s Insulin Glargine) in 52 T2DM patients from 3 (three) different study sites in Nepal (Bharatpur, Kathmandu and Pokhra) from September 2015 to December 2016. The primary objective of the study was to evaluate the safety of Glaritus®, mainly in terms of hypoglycemia, renal function tests and liver function tests. The secondary objectives were to evaluate the effectiveness of Glaritus®in terms of percentage of patients achieving HbA1c goal of less than 7%, mean changes in HbA1c & fasting plasma glucose (FPG) levels from baseline till the end of study. Results: 3.85% of subjects experienced hypoglycemia during first 3 months of therapy whereas 1.92% had similar experience in next 3 months of therapy. The mean HbA1c values reduced from 9.16% to 7.15% at the end of study. 21.05% of the enrolled subjects achieved the goal of HbA1c ®was well tolerated by the study patients. Conclusion: In patients with type 2 diabetes mellitus inadequately controlled on oral hypoglycemic agents and/or insulin, initiation with Glaritus®significantly improved glycemic control with good tolerability and acceptability. This analysis in T2DM Nepalese patients shows that by significantly improving glycemic control while not increasing risk of hypoglycemia, Glaritus®provides safer basal insulin and may be suited to aggressive treatment regimens. From a societal perspective, it will help more patients reach the glycemic control target as recommended by the current treatment guidelines.

Compared with insulin glargine, insulin degludec narrows the day-to-day variability in the glucose-lowering effect rather than lowering blood glucose levels

Background: Changes in the day-to-day variability in the glucose-lowering effect of insulin [fluctuations of blood glucose levels (BG) seen during the same time period] that occur when insulin glargine (glargine) is replaced with insulin degludec (degludec) have not been sufficiently evaluated. Subjects: Five diabetics with unstable BG undergoing basal-bolus treatment using insulin glargine as basal insulin. Methods: Basal insulin was changed from glargine to same-dose degludec. The subjects’ HbA1c, glycoalbumin, and 1.5-anhydro-D-glucitol were measured before and after the switchover. Fasting blood glucose concentration (FBG) and predinner blood glucose concentration (PDBG) were measured continuously for 28 days immediately before the switchover, and 28 days immediately thereafter, to compare and evaluate 1) the changes in their mean values and standard deviations (SDs) before and after the switchover, and 2) the frequency of appearance of BG of over 180 mg/dL (BG ≥ 180) and under 70 mg/dL (BG Results: The levels of HbA1c, glycoalbumin, FBG’s mean value, SDs, BG ≥ 180 and BG Conclusion: The possibility was shown that degludec, to a greater extent than glargine, suppressed daily fluctuations of FBG and PDBG, suppressed the occurrence frequency of hyperglycemia and hypoglycemia, and exerted more steady hypoglycemic actions.

Effect of Initiation of Basal Insulin Glargine on Glycemic Control in Patients with Diabetes: Real Life Experience from Hong Kong

Introduction: To assess the changes in glycemic control after initiating or switching to a basal insulin analogue in patients with diabetes mellitus. Methods: A retrospective, observational analysis was conducted using electronic data from a Hong Kong regional hospital. Data from adult patients with type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively) who had been prescribed with basal insulin glargine in 2008-2010, with recorded HbA1c levels at the time of initiation, at 6 and 12 months thereafter, were analysed. Results: Data from 106 eligible patients were analysed. Substantial reduction in HbA1c and fasting sugar levels were reported in both T1DM (Δ HbA1c = 1.5%, Δ FBG = 1.3 mmol/L p < 0.05) and T2DM (Δ HbA1c = 1.2%, Δ FBG = 2.9 mmol/L p < 0.05) patients after 12 months of therapy. A total of 42% of T1DM and 26% of T2DM patients achieved HbA1c levels < 7.0%. After adjustment, T2DM patients who were insulin naive achieved a statistically greater HbA1c reduction (Δ = 1.7%) than those who previous treated with premixed or basal bolus insulin (Δ = 0.3%) (p < 0.05). Percentage of patients experiencing hypoglycaemia reduced from 69% to 62% in T1DM but increased from 26% to 36% in T2DM patients. All hypoglycaemic episodes recorded were either asymptomatic or mild and self-limiting. Only 4% of the patients discontinued treatment at the end of 12 months. Conclusions: In real life clinical practice, a single daily basal insulin analogue therapy provided effective glycemic control with an acceptable risk of mild hypoglycaemia.

Marked Improvement in Glycemic Control with Exenatide on Addition to Metformin, Sulfonylurea and Insulin Glargine in Type 2 Diabetes Mellitus, a Real World Experience

Background: The major effect of Exenatide is attributed to lowering of post-prandial glycemia, whereas insulin glargine mainly improves fasting glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide administration at 6 months and for at 1 year on glycemic control, lipids, body weight [BW], daily insulin dose and hypoglycemic events. Methods: Records of 164 subjects, 126 men and 38 women administered Exenatide between January 2011 and December 2013 are included in this report. Exenatide was initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI > 30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glargine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver enzymes > 2.5 times upper limit of normal. Indices of glycemic control include fasting plasma glucose levels and HbA1c. Lipids include serum concentrations of total, LDL and HDL cholesterol. Other endpoints are body weight, daily insulin dose and number of hypoglycemic events per patient during 4 weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Results: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks;29 due to onset of nausea and vomiting. Seven of these also complained of abdominal pain and in these, serum amylase and lipase were elevated indicating presence of acute pancreatitis. One subject discontinued because of chest pain. Fasting plasma Glucose remained unchanged following Exenatide administration. However, HbA1c declined significantly denoting improvement in overall glycemic control without significant changes in body weight, daily insulin dose and hypoglycemic events. Lipid panel improved as well. Conclusion: Exenatide may be an appropriate adjuvant option in obese subjects with Type 2 diabetes mellitus with lack of desirable glycemic control while receiving therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, improvement in glycemic control is likely to be secondary to lowering of post prandial hyperglycemia induced by Exenatide.

Safety and Efficacy of Combination Therapy with Insulin Glargine and Oral Hypoglycaemic Agents Including DPP-4 Inhibitors in Japanese T2DM Patients: ALOHA 2 Study, a Post-Marketing Surveillance for Lantus^&reg;

Aims: In the Add-on Lantus&reg;?to Oral Hypoglycaemic Agents 2 (ALOHA 2) Study in Japanese adults with type 2 diabetes mellitus (T2DM), data on the safety and efficacy of combination therapy with insulin glargine (Lantus&reg;) and oral anti-hyperglycaemic drugs (OADs) including dipeptidyl peptidase-4 (DPP-4) inhibitors in a real-life setting were collected and analyzed. Methods: This postmarketing surveillance was a prospective, observational, 24-week study that complied with the pharmaceutical affairs law and the ministerial ordinance of “Good Post-Marketing Study Practice (GPSP)” in Japan. Safety, efficacy and patient-reported outcomes (PROs);patients’ satisfaction with treatment (DTSQs and DTSQc) and patients’ self-reported health (EQ-5D and EQ-VAS) of combination therapy of insulin glargine and OADs were evaluated. Results: A total of 2,630 patients were enrolled. Of the 2,602 patients in the safety analysis population, 161 patients experienced 175 cases of adverse drug reactions, and the major adverse drug reaction was hypoglycaemia (140 patients, 5.38%). Out of those with hypoglycaemia, 11 patients (0.42%) had severe hypoglycaemia and the incidence rate (episodes per patient-year) was 0.019. Basal supported oral therapy (BOT) with insulin glargine substantially reduced the HbA1c, FPG and 2 hour-PPG levels for 24 weeks by -1.61%, -54.4 mg/dL and -74.5 mg/dL respectively. The mean weight was increased, however the change was +0.50 kg. In addition, the treatment satisfaction scores of DTSQs (mean treatment satisfaction score increased 3.6 from baseline to last observation) and DTSQc, EQ-5D index scores and EQ-VAS scores were significantly improved. Conclusion: Insulin glargine and OADs combination therapy was suggested to be effective and well tolerated. Patients’ satisfaction with treatment and their self-reported health improved in spite of the addition of injections to oral agents. The combination therapy of insulin glargine and OADs including DPP-4 inhibitors is likely to be considered an important therapeutic option in the diabetic patients.

Treatment Satisfaction with Insulin Glargine in Insulin-Naïve Type 2 Diabetes Patients—A Hong Kong Based Registry

Objective: To evaluate patient satisfaction with insulin glargine. Design: Multicentre observational registry. Data were collected at baseline/inclusion visit, and 12 and 24 weeks. Setting: Physicians in Hong Kong, who managed type 2 diabetes patients and had >5 years’ experience in using insulin glargine. Patients: People with type 2 diabetes, new to insulin, aged 18 - 75 years, who were previously being treated with ≤3 oral antidiabetes drugs (OAD) and had HbA1c > 7%, and in whom the?physicians had chosen to prescribe glargine for the first time. Main outcome measures: Treatment satisfaction assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQs), glycaemic control (fasting blood glucose and HbA1c) and adverse events. Results: Between April 2010-October 2011, 41 patients completed the study. Average duration of diabetes and OAD therapy was 7.8 ± 8.0 years and 6.7 ± 7.4 years, respectively. The global DTSQs treatment satisfaction scores improved from 20.9 at baseline to 28.4 (p < 0.05) at the end of 24 weeks insulin glargine treatment. Analysis of DTSQs scores showed a decrease in perceived frequency of hyperglycaemia (4.1 to 1.9, p < 0.001) and hypoglycemia (2.2 to 1.5, p = 0.079). Perceived convenience (0.60, p < 0.025) and flexibility (0.9, p < 0.009) were also improved from baseline. Reduction in mean HbA1c (10.2% ± 2.2% to 7.0% ± 1.0%) and fasting blood glucose (10.9 ± 4.0 mmol/L to 6.4 ± 1.8 mmol/L) from baseline to study termination was significant (p < 0.05). Almost half (48.7%) of patients achieved HbA1c ≤ 7.0%, while 26.0% patients had FBG < 5.6 mmol/L. In total, 9 (22.0%) patients experienced at least one hypoglycemia event;there were no reports of severe hypoglycaemia. Conclusions: Despite a small number of subjects completed in this study, the study demonstrated clearly that the addition of insulin glargine to OAD therapy in diabetes management improved treatment satisfaction and perceived frequency of hyper-and hypoglycaemia together with glycaemic control close to recommended target without severe side-effects in this cohort of patients in Hong Kong.

Iowa medicaid 2: lapse of glycemic control on abrupt transition from insulin glargine to insulin detemir in type 2 diabetes mellitus

Background: Iowa Care (Iowa Medicaid in State of Iowa, USA), switched insulin glargine to detemir in subjects with Diabetes Mellitus (DM) without the knowledge or approval of healthcare providers beginning 8/2006.Impact of this transition in subjects with Type 1 DM is recently reported. Objective: To examine the impact of this transition on various parameters of diabetes management in Type 2 DM. Subjects and Methods: A retrospective review of the records of subjects with Type 2 DM was conducted until 8/2007 in whom the transition had occurred. Only those subjects with adequate glycemic control while receiving insulin glargine [GI] and completing at least 3 months of therapy with insulin detemir [DI] are included in this report. Ten subjects with Type 2 DM, duration 7 ± 2 years with age, 55 ± 3 years who were switched from GI to DI (Group 1) fulfilled the criteria for inclusion. Subjects were switched from GI in Q AM to DI Q HS in the same daily dose. Glycemic control (HbA1c), body weight, daily insulin dose (Units) and severe hypoglycemic events during the last 2 weeks of the period, pre switch and again at the end of 3 months post switch were assessed. Records of 8 subjects matched for age, duration of DM, glycemic control while receiving GI for additional 3 months (Group 2) during the same period were examined for comparison. All subjects were followed in the outpatient clinic at intervals of 3 months. Results Glycemic control remained stable on continuing GI AM;HbA1c;7.1 ± 0.3 to 7.1 ± 0.3%, while it worsened on switching to DI Q HS;HbA1c, 7.1 ± 0.3 to 8.1 ± 0.5 [P < 0.01]. A mild weight loss was noted in subjects on transition. No severe hypoglycemic events were reported in any subject in either group. Conclusion Abrupt transition from insulin glargine to insulin detemir in subjects with Type 2 DM is likely to result in lapse of glycemic control which may cause decreased quality of life. Furthermore, use of insulin detemir may result in increased costs due to need of the higher daily dose as well as additional equipment required for probable twice daily administration to achieve adequate glycemic control. Therefore, insulin glargine and detemir appear to be far from being bioequivalent.

Hepatitis C virus infection and insulin resistance

Approximately 170 million people worldwide are chronically infected with hepatitis C virus(HCV).Chronic HCV infection is the leading cause for the development of liver fibrosis,cirrhosis,hepatocellular carcinoma(HCC)and is the primary cause for liver transplantation in the western world.Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of typeⅡdiabetes.Insulin resistance plays an important role in the development of various complications associated with HCV infection.Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis,steatosis,HCC and resistance to anti-viral treatment.Thus,HCV associated insulin resistance is a therapeutic target at any stage of HCV infection.HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway.Various mechanisms have been proposed in regard to HCV mediated insulin resistance,involving up regulation of inflammatory cytokines,like tumor necrosis factor-α,phosphorylation of insulin-receptor substrate-1,Akt,up-regulation of gluconeogenic genes like glucose 6 phosphatase,phosphoenolpyruvate carboxykinase 2,and accumulation of lipid droplets.In this review,we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

Assessing insulin effectiveness at the end of the day: Once-daily versus twice-daily insulin glargine injection

Objective: Evidence supporting the twice-daily administration of insulin glargine as an approach to address its waning effectiveness at the end of a 24 hour period is sparse. We hypothesized that insulin concentrations determined during the last four hours of a 24 hour period would be greater when identical doses of insulin glargine were administered twice-daily as compared to once-daily among type 1 diabetes patients. Research Methods: Ten subjects with insulin deficient type 1 diabetes were admitted for two 38-hour studies at least one week apart. Patients received full-dose insulin glargine once daily at 0800 and half-dose insulin glargine twice-daily at 0800 and 2000 for at least one week in random order prior to overnight studies. Overnight glucose was stabilized with intravenous insulin on the evening prior to study, and subjects fasted and did not receive short acting insulin during the study period. Insulin concentrations were assessed every 30 minutes with an ultrasensitive assay between study hours 20 and 24. Results: Insulin concentrations for the final four hours of study period did not differ between once-daily and twice-daily insulin glargine administration (p = 0.38). Home glucose testing results and overnight plasma glucose concentrations did not differ between study conditions. Conclusions: These results demonstrate that insulin concentrations are equivalent during the last four hours of a 24-hour period when insulin glargine is administered once- or twice-daily. These findings do not support a role for twice-daily insulin glargine in the management of patients with type 1 diabetes.

Insulin Glargine 300 Units/mL Effectiveness in Patients with T2DM Uncontrolled by Basal Insulin in Real-Life Settings in the Czech Republic

Introduction: To evaluate the clinical effectiveness of Gla-300 units/mL (Gla-300) in the treatment of patients with type 2 diabetes (T2DM) uncontrolled by basal insulin in real-life clinical settings in the Czech Republic (TOPAZ study). Methods: TOPAZ was a prospective, multi-center, non-interventional, 6-month study. Of the 312 patients screened, 289 were evaluated at month 6. The primary objective was the change of HbA1c after 6 months. The proportion of patients with HbA1c < 7.0% DCCT (< 53 mmol/mol), and those with a decrease of at least 0.5% of HbA1c at month 6, change in FPG, body weight and insulin dose at month 3 and 6 were analysed as secondary objectives. Incidence of hypoglycemia, adverse events and patient treatment satisfaction were also assessed. Results: HbA1c decreased significantly after 6 months (mean change 0.9% ± 1.1% DCCT [−9.9 ± 11.6 mmol/mol], p < 0.0001). HbA1c target < 7.0% DCCT was achieved in 17.6% of patients, 66.1% of patients showed mean HbA1c decrease of 0.5% ± 0.8%. At month 6, FPG decreased (mean change from baseline −1.8 ± 3.1 mmol/L) as well as the incidence of hypoglycemia decreased by 49% (p < 0.0001) while no weight gain was observed. No significant safety signals were identified. Conclusion: In a real-life setting, switching to Gla-300 in T2DM patients uncontrolled with other basal insulin was associated with improved glycemic control and reduced risk of hypoglycemia without weight gain, while patients’ satisfaction with treatment increased.

Effect of Insulin Glargine on Cardiovascular Risk Analysed by Mean HRV

Type 2 diabetes mellitus is an insidious disease that is increasingly present in geriatric population [1]. The greatest difficulty is represented by glycaemic control in geriatric patients often not very compliant with diet therapy and drug therapy. A new insulin glargine 300 units/ml formulation seems improve patient compliance due to the lower volume of insulin to be injected and improved glycaemic control over 24 hours. The HRV signal, derived from digital electrocardiographic recording, is the simplest and most immediate analysis that consists in calculating some temporal parameters [2]. HRV is a simple statistics derived from beat-beat intervals of sinus origin expressed as units of time in milliseconds. Data in the literature indicate that a decrease in HRV, measured with time domain analysis, denotes a worse prognosis and/or an increased risk of mortality in patients with heart disease, especially in the elderly ones.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Immunogenicity, Safety and Efficacy Comparison of Wockhardt’s Biosimilar Insulin Glargine—Glaritus®with Reference Product— Lantus®: Study Protocol &Early Data Trends

Objective: Present Phase IV Trial is aimed at evaluating the immunogenicity, safety, and efficacy of Wockhardt’s insulin glargine, Glaritus&reg;in comparison with reference insulin glargine, Lantus&reg;in subjects with type 2 diabetes mellitus (T2DM), inadequately controlled on oral hypoglycaemics. Setting: A head-to-head, prospective, open-label, parallel group, randomized, Phase IV, non-inferiority study over 6 months treatment conducted in 10 centres in India. Participants: Considering 20% drop-out rate, 180 subjects of either sex, age 18 - 55 years, diagnosed with T2DM with body mass index (BMI) 18 - 38 kg/m2 and HbA1c levels 8.0% - 10.0% inadequately controlled by 1 or more oral hypoglycaemics and according to investigator needed glargine treatment were enrolled in the study. Interventions: Subjects self-administered insulin glargine (Glaritus&reg;or Lantus&reg;) subcutaneously once daily for 6 months. Treatment in Glaritus&reg;arm was continued till 12 months. Percentage change in anti-insulin antibody (AIA) titre and HbA1C was ascertained at every 3 months interval. The tests were performed at accredited central laboratory. Treat-to-target dose titration: Starting doses of Glaritus&reg;and Lantus&reg;was 10 units (or 0.2 units/kg) once daily. The target fasting blood glucose was 70 to 130 mg/dL. Daily glargine dose was titrated by ±10% based on average of last 3 FBG values being out of target range and presence of nocturnal hypoglycemia. Early data trends: First interim analysis was planned once 100 subjects complete visit 8 (6 months treatment). By then, 119 subjects (78 males and 41 females) with mean age 46.3 years were enrolled, of which 90 (75.6%) subjects had evaluable data. The results of analysis indicated trend of comparability between Glaritus&reg;and Lantus&reg;at the end of 6 months in terms of immunogenicity (% change in AIA titre from baseline, &minus;10.52 ± 23.06 vs. 0.48 ± 63.95), glycemic control (change in HbA1c from baseline, &minus;1.09% ± 1.29% vs. 0.63% ± 1.19%) and hypoglycemic events (reported by 1 vs. 2 patients), respectively. Conclusion: The present study represents a robust design in line with international guidelines on biosimilar insulin development and the early data trends presents expected similarity of Glaritus&reg;in immunogenicity, efficacy and safety to that of Lantus&reg;in treatment of T2DM.

Hepatocellular Carcinoma: Known and Emerging Risk Factors

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a high mortality rate. While chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent the leading risk factors worldwide, the spreading of metabolic disorders, such as diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) justifies the increasing attention on their oncogenic mechanisms. This review discusses about the main pathogenic mechanisms implicated in occurrence of HCC in presence of viral and metabolic diseases. Additionally, it points to the importance of clinical surveillance for those patients considered at risk of HCC and highlights the strategical role of serum markers, such as alfa-fetoprotein (αFP) and Protein Induced by Vitamin K Absence or Antagonist II (PIVKA-II), which, in association to a strictly instrumental follow-up, contribute to the early detection of hepatic nodules with a better prognosis for affected patients.

An overview on antidiabetic medicinal plants having insulin mimetic property

Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8%of the world's population and is anticipated to cross 5.4%by the year 2025.Since long back herbal medicines have been the highly esteemed source of medicine therefore,they have become a growing part of modern,high-tech medicine.In view of the above aspects the present review provides profiles of plants(65 species) with hypoglycaemic properties,available through literature source from various database with proper categorization according to the parts used,mode of reduction in blood glucose(insulinomimetic or insulin secretagugues activity) and active phyloconsliluents having insulin mimetics activity.From the review it was suggested that,plant showing hypoglycemic potential mainly belongs to the family Leguminoseae,Lamiaceae,Liliaceae,Cucurbitaceae, Asteraceae,Moraceae,Rosaceae and Araliaceae.The most active plants are Allium sativum. Gymnema sylvestre,Citrullus colocynthis,Trigonella foenum greacum,Momordica charantia and Ficuts bengalensis.The review describes some new bioactive drugs and isolated compounds from plants such as roseoside,epigallocatechin gallate,beta-pyrazol-1-ylalanine,cinchonain Ib,leucocyandin 3-O-beta-d-galactosyl cellobioside,leucopelargonidin-3- O-alpha-L rhamuoside,glycyrrhetinic acid,dehydrotrametenolic acid,strictinin,isostrictinin,pedunculagin, epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity with more efficacy than conventional hypoglycaemic agents.Thus,from the review majorly,the antidiabetic activity of medicinal plants is attributed to the presence of polyphenols,flavonoida, terpenoids,coumarins and other constituents which show reduction in blood glucose levels.The review also discusses the management aspect of diabetes mellitus using these plants and their active principles.

Molecular mechanisms of insulin resistance in type 2 diabetes mellitus

Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.

Elevated alanine aminotransferase activity is not associated with dyslipidemias,but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

Objective:To explore demographic and metabolic factors associated with increased alanine aminotransferase(ALT)activity in non-diabetic non-alcoholic fatty liver disease(NAFLD)patients.Methods:Overall 372 patients who consecutively attended to Gastroenterology Clinic of Baqiyatallah University of Medical Sciences,Tehran,Iran awere diagnosed as NAFLD entered into analysis.Exclusion criteria were having diabetes mellitus and fasting blood glucose over126 mg/dL,active hepatitis B virus infection,having hepatitis C virus positive serology,and to be under corticosteroid therapy.ALT levels were considered pathologically high when it was over30 IU/L for men and over 19 IU/L for women.Results:Bivariate analyses using t test and chisquare test showed that patients with pathologically augmented ALT levels had significantly higher NAFLD grades in their ultrasonographic evaluations(P=0.003).Moreover,these patients represented significantly higher homeostatic model assessment levels(P=0.003),levels of serum insulin(P=0.002),fasting blood glucose(P<0.001),and uric acid(P=0.02).The prevalence of insulin resistance was also higher in patients with increased serum ALT concentrations.Multifactorial logistic regression models showed that ultrasonographic grading of NAFLD(P=0.027)and insulin resistance(P=0.013)were the only variables significantly associated with abnormal ALT levels.Conclusions:This study shows that the associations of increased ALT serum levels in NAFLD patients are different from what are supposed before.By excluding diabetic patients from our population,we find that increased ALT levels are not associated with dyslipidemias but are independently associated with insulin resistance and NAFLD grading on ultrasonographic evaluations.Further studies are needed to confirm our results.

Efficacy and Safety of Patient-Led Dosage Adjustments of Insulin Glargine: A Preliminary Report of Basal-Supported Oral Therapy for Japanese Type 2 Diabetes Patients

To evaluate the clinical utility for simple patient administered dose adjustment methods of insulin glargine during outpatient visits compared with a physician managed titration, changes in HbA1c and total daily dose of insulin were evaluated in 23 patients by dividing patients into physician-led (PL) group and self-titration (ST) group who were newly administered glargine basal-supported oral therapy (BOT) while continuing oral antidiabetic drugs at the discretion of their attending physician during regular outpatient visits. In the PL group, one month after initiation of glargine, HbA1c followed a declining trend, although this was not significant (P = 0.07), and decreased significantly after two and three months (P < 0.05, respectively). However, after 12 months, the significant difference had disappeared. By contrast, in the ST group, HbA1c did not significantly decrease one month after initiation of glargine, but did drop markedly after two and three months, with this trend continuing up to 12 months (P < 0.005). On examining the differences between both groups, we found that the initial dose was significantly larger in the PL group (P < 0.05), whereas the dose increased significantly more in the ST group after three months. While the insulin dose after 12 months was large in the ST group, no statistically significant difference was noted between the two groups (P = 0.14) whereas HbA1c was significantly low in the ST group. In conclusion, we believe that patient-led basal insulin dosage adjustment is an effective and useful therapeutic option when they can master self-monitoring of blood glucose.

Insulin like growth factor-1 increases fatty liver preservation in IGL-1 solution

AIM: To investigate the benefits of insulin like growth factor-1 (IGF-1) supplementation to serum-free institut georges lopez-1 (IGL-1) solution to protect fatty liver against cold ischemia reperfusion injury. METHODS: Steatotic livers were preserved for 24 h in IGL-1  solution supplemented with or without IGF-1 and then perfused "ex vivo " for 2 h at 37℃. We examined the effects of IGF-1 on hepatic damage and function (transaminases, percentage of sulfobromophthalein clearance in bile and vascular resistance). We also studied other factors associated with the poor tolerance of fatty livers to cold ischemia reperfusion injury such as mitochondrial damage, oxidative stress, nitric oxide, tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinases.RESULTS: Steatotic livers preserved in IGL-1 solutionsupplemented with IGF-1 showed lower transaminase levels, increased bile clearance and a reduction in vascular resistance when compared to those preserved in IGL-1solution alone. These benefits are mediated by activation of AKT and constitutive endothelial nitric oxide synthase (eNOS), as well as the inhibition of inflammatory cytokines such as TNF-α. Mitochondrial damage and oxidative stress were also prevented.CONCLUSION: IGL-1  enrichment with IGF-1 increasedfatty liver graft preservation through AKT and eNOS activation, and prevented TNF-α release during normothermic reperfusion.

Hypothesis:Intensive insulin therapy-induced mortality is due to excessive serotonin autoinhibition and autonomic dysregulation

Action to Control Cardiovascular Risk in Diabetes(ACCORD),The Action in Diabetes and Vascular Disease:Preterax and Diamicron Modified Release Controlled Evaluation and the Veterans Affairs Diabetes Trial were designed to study whether older patients with type 2 diabetes mellitus could reduce the risk of heart attacks and stroke and thereby prolong their lives by maintaining their blood glucose levels at near-healthy levels but failed to demonstrate the hoped-for benef it.Why the trials failed,though,and why ACCORD saw significantly more deaths due to increased rates of cardiovascular events in the intensive therapy arm of the study are not clear.These data have now been confirmed by the results of the recently concluded NICE-SUGAR Study which again revealed that intensive gluc ose control increased mortality among adults in intensive care units.I propose that the negative results noted in these trials are due to altered brain serot o nin concentrations and autonomic dysregulation in addition to the low-grade systemic inflammation,decreased endothelial nitric oxide and enhanced free radical generation,diminished anti-oxidant defenses and altered metabol ism of essential fatty acids present in patients with type 2 diabetes.