The impact of the chromium supplementation on insulin signalling pathway in different tissues and milk yield in dairy cows.

Thirty days before expected time of parturition, 20 Holstein cows were divided into -Cr and +Cr groups. From day 25 before parturition (BP) up to day 30 after parturition (AP), +Cr cows received 10 mg of Cr (chromium-enriched yeast) daily. Muscle and adipose tissue samples were taken at days -30, -10, +7 and +10 related to parturition, when body condition score (BCS) was also determined. Hepatic tissue samples were taken at days -10 and +7. Tissue samples were used for determination of the insulin signalling pathway protein expressions. Intravenous glucose tolerance test (IVGTT) was performed at days -28, -7, +10 and +30. Milk yield was recorded during first 14 weeks AP. Milk composition was obtained at days 7 and 28 AP. At day 10 BP, protein content of ß-subunit of insulin receptor (IRß) was significantly higher (p Ë‚ 0.05) in muscle, and phosphorylation of insulin receptor substrate 1 at serine 307 (pIRS-1 Ser307 ) was significantly lower (p Ë‚ 0.05) in hepatic tissue of +Cr group. After parturition, pIRS-1 Ser307 was significantly lower in muscle tissue at days 7 and 28 (p Ë‚ 0.05 and p Ë‚ 0.001, respectively), while phosphorylation of Akt at serine 473 (pAkt Ser473 ) was significantly higher (p Ë‚ 0.01) in hepatic tissue at day 7 AP in +Cr group. Chromium had opposite effect on insulin kinetics during IVGTTs obtained BP and AP. Insulin secretion was significantly reduced at day 7 BP and significantly enhanced at day 10 AP, when NEFA concentration was also significantly increased. Milk yield and ECM value were depressed in +Cr group. DMI and BCS were significantly enhanced in +Cr group at day 7 BP. In conclusion, chromium modulates insulin signalling pathway in dairy cows, but targeted signalling molecules are different in antepartal then post-partal period, probably due to duration of exposure to chromium and different energy status between those periods.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

KLF4 expression and apoptosis-related markers in gastric cancer.

PURPOSE: To correlate the expression of Kruppel-like factor 4 (KLF4) with clinicopathological properties of gastric cancer (GC) and to evaluate any possible correlation between KLF4 expression and the expression of apoptosis-related markers p53, Fas, Bcl-2, survivin and FLICE inhibitory protein (Flip-l). METHODS: Formalin-fixed, paraffin-embedded tissue specimens obtained from 96 patients with GC who had undergone gastric surgery were analyzed for pathological parameters, while KLF4, p53, Fas, Bcl-2, survivin and Flip-l expression was assessed by immunohistochemistry. RESULTS: TKLF4 immunohistochemical staining was noted in 78.1% of the cases. Strong positivity was found in 15.6% and weak in 62.5% of the samples. Positive expression of p53, Fas, Bcl-2, survivin, Flip-l was found in 56.2%, 44.8%, 15.6%, 41.7% and 38.5% of the samples, respectively. KLF4 expression was significantly associated with p53 nuclear staining and Fas immunoreactivity. p53-positive tumors demonstrated more often high KLF4 staining compared to p53-negative tumors. Fas-positive tumors were associated with decreased KLF4 expression. Logistic regression analysis of apoptosis-related markers to KLF4 expression revealed that Fas positivity significantly decreased the probability of strong KLF4 expression, and inversely, Bcl-2 expression improved the prediction of KLF4 staining. When all 5 predictive variables were considered together (p53, Fas, survivin, Bcl-2, Flip-l) they significantly predicted the type of KLF4 expression in GC cells (p=0.019). CONCLUSION: Our results suggest that the decrease or loss of KLF4 expression correlates with diffuse-type GC and immunoreactivity to Fas, and are inversely linked with p53 nuclear accumulation. The significance of KLF4 in GC requires further studies and should be more thoroughly investigated for potential use in the evaluation and better stratification of GC patients.

Development of a multi-parametric model predictive control algorithm for insulin delivery in type 1 diabetes mellitus using clinical parameters.

A multi-parametric model predictive control (mpMPC) algorithm for subcutaneous insulin delivery for individuals with type 1 diabetes mellitus (T1DM) that is computationally efficient, robust to variations in insulin sensitivity, and involves minimal burden for the user is proposed. System identification was achieved through impulse response tests feasible for ambulatory conditions on the UVa/Padova simulator adult subjects with T1DM. An alternative means of system identification using readily available clinical parameters was also investigated. A safety constraint was included explicitly in the algorithm formulation using clinical parameters typical of those available to an attending physician. Closed-loop simulations were carried out with daily consumption of 200 g carbohydrate. Controller robustness was assessed by subject/model mismatch scenarios addressing daily, simultaneous variation in insulin sensitivity and meal size with the addition of Gaussian white noise with a standard deviation of 10%. A second-order-plus-time-delay transfer function model fit the validation data with a mean (coefficient of variation) root-mean-square-error (RMSE) of 26 mg/dL (19%) for a 3 h prediction horizon. The resulting control law maintained a low risk Low Blood Glucose Index without any information about carbohydrate consumption for 90% of the subjects. Low-order linear models with clinically meaningful parameters thus provided sufficient information for a model predictive control algorithm to control glycemia. The use of clinical knowledge as a safety constraint can reduce hypoglycemic events, and this same knowledge can further improve glycemic control when used explicitly as the controller model. The resulting mpMPC algorithm was sufficiently compact to be implemented on a simple electronic device.

Technology and pregnancy.

The World Health Organisation projects that the number of diabetes-related deaths will double between the years 2005 and 2030. An important method for reducing the number of new cases of diabetes is by screening for and controlling glucose in women with gestational diabetes, the form of diabetes that afflicts up to 10% of the pregnant population. Uncontrolled gestational diabetes mellitus results in an increased risk of complications due to maternal hyperglycaemia and the resultant fetal hyperinsulinaemia. These complications include macrosomia and an increased risk of metabolic disorders including diabetes later in the child's life. Advances in the treatment of gestational diabetes have shown promising results in minimising fetal complications; they have also helped to slow the vicious cycle of women who contract gestational diabetes mellitus producing children with a high risk of developing diabetes later in life. A comprehensive literature review with an emphasis on technology has resulted in the following collection of papers relating to pregnancy and diabetes. Last year there were several technological advances in glucose monitoring. This year the applications of telemedicine in the treatment of gestational diabetes and the use of ultrasound for early detection of the disease have been at the forefront. The authors aimed to include articles that were not only relevant to the field of diabetes technology in pregnancy, but that also improved treatment and advanced understanding. The study design and results were also carefully examined in considering the articles. The selected articles contain findings that provide new techniques for diagnosing gestational diabetes mellitus as well as provide additional treatment methods for those affected by the disease.

Temporal trends in incidence of Type 1 diabetes between 1986 and 2006 in Brazil.

BACKGROUND: Scarce information is available about the variation in the incidence of Type 1 diabetes in the Brazilian population in the last decades. AIM: The objective of this study was to assess the long-term trends (1986-2006) in the incidence of Type 1 diabetes in Bauru, São Paulo State, Brazil. SUBJECTS AND METHODS: The annual incidence of Type 1 diabetes (per 100,000 per yr) from 1986 to 2006 was determined in children or=20/100,000 per yr) in 71.43% of the study-years. Incidence was slightly higher among females, Caucasians, children in the 5-9 yr of age range and belonging to lower socio-economic classes. Most diagnoses were established during the colder months and/or with higher pluviometric indexes. CONCLUSIONS: The incidence of Type 1 diabetes in children is increasing in Bauru, São Paulo State, Brazil, and the global pattern of incidence was classified as high or very high, mainly in the last 10 yr. All Brazilian regions should be involved in the study.

Technology and pregnancy.

In the USA, depending upon the diagnosis criteria used, 135,000-200,000 women annually develop gestational diabetes mellitus, adding to the number of pregnant women already suffering from either type 1 or type 2 diabetes. Maternal hyperglycaemia and the resultant fetal hyperinsulinaemia are central to the pathophysiology of diabetic complications of pregnancy. These complications include congenital malformations and an increase in neonatal intensive care unit admission and birth trauma. In addition, there is an increased rate of accelerated fetal growth, neonatal metabolic complications and risk for stillbirth. Importantly, during the last century there were two breakthroughs in diabetes management and monitoring that changed the course of treatment: the discovery of insulin and the progress in the understanding of glucose monitoring. As technology has evolved, both glucose monitoring and insulin administration can now be achieved in a continuous fashion. In this review of the literature we focus on the utility of new technologies in the management and monitoring of diabetes in pregnancy.

Screening for twin pregnancy.

A group of 590 women who, 4 to 5 weeks after their last menstrual period, were confirmed to be pregnant, as measured by the human chorionic gonadotropin (hCG) by radioreceptor assay. Nine of these women had serum hCG levels approximately twofold higher than the others and were suspected of having twin pregnancy. When these women were tested at 12 weeks of gestation, pelvic sonography confirmed twin pregnancies in all the nine cases. Serum hCG levels thus provide a simple, rapid, and easy method to detect twin pregnancy.

A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer.

MicroRNA-375 (miR-375) is frequently elevated in prostate tumors and cell-free fractions of patient blood, but its role in genesis and progression of prostate cancer is poorly understood. In this study, we demonstrated that miR-375 is inversely correlated with epithelial-mesenchymal transition signatures (EMT) in clinical samples and can drive mesenchymal-epithelial transition (MET) in model systems. Indeed, miR-375 potently inhibited invasion and migration of multiple prostate cancer lines. The transcription factor YAP1 was found to be a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression, and overexpression of YAP1 rescued anti-invasive effects mediated by miR-375. Furthermore, transcription of the miR-375 gene was shown to be directly repressed by the EMT transcription factor, ZEB1. Analysis of multiple patient cohorts provided evidence for this ZEB1-miR-375-YAP1 regulatory circuit in clinical samples. Despite its anti-invasive and anti-EMT capacities, plasma miR-375 was found to be correlated with circulating tumor cells in men with metastatic disease. Collectively, this study provides new insight into the function of miR-375 in prostate cancer, and more broadly identifies a novel pathway controlling epithelial plasticity and tumor cell invasion in this disease.

Screening for gestational diabetes. Optimum timing and criteria for retesting.

Because of the morbidity associated with undiagnosed gestational diabetes (GDM), screening programs are advocated in all pregnancy clinics. The purpose of this study was to elucidate the optimum time to test for diabetes during gestation, the indication for retesting, and the predictive value of a positive screening test for a large (greater than 4000 g) infant. Women (N = 300) were screened at three time points: 9-20 wk, 27-31 wk, and 33-36 wk. An additional group of 300 women were screened at two time points: 27-31 wk and 33-36 wk. The prevalence of GDM in this group was 3.2%. The optimum timing for screening for highest yield was 27-31 wk. Retesting at 33-36 wk appeared cost effective if (1) maternal age was greater than or equal to 33 yr, (2) a positive screen was present at 27-31 wk, and (3) the mother was obese (greater than 120% ideal body wt).

Systemic lupus erythematosus in men. Genetic and endocrine features.

Sixteen men with systemic lupus erythematosus (SLE) were examined to assess their genetic and hormonal status. The results of buccal smears in 13 patients examined were normal. Hormonal profiling was done in eight patients receiving no steroid therapy. Four patients had elevated plasma estradiol levels (30, 35, 55, and 103 pg/mL; normal, 12 to 23 pg/mL) and elevated plasma estrone levels (115, 150, 155, and 160 pg/mL; normal, 48 to 100 pg/mL). One patient had a decreased serum testosterone level (134 ng/dL; normal, 300 to 1,000 ng/dL), with an elevated luteinizing hormone (LH) level (4.2 ng/mL; normal, 1.6 to 4.0 ng/mL). One patient had an elevation in both levels of serum follicle-stimulating hormone (17.6 ng/mL; normal, 1 to 5 ng/mL) and LH (10.0 ng/mL). Two patients given infusions of 3H-androstenedione and 14C-testosterone had normal findings from kinetic studies of these hormones. Hyperestrogenemia and hypoandrogenemia observed in some men with SLE suggest that female sex hormones may create an immunologic milieu that facilitates the autoimmune phenomena.

Spontaneous hypoglycemic seizures in pregnancy. A manifestation of panhypopituitarism.

A 32-year-old woman had seizures and coma due to severe hypoglycemia (26 mg/dL) in the 32nd week of an otherwise uncomplicated pregnancy. She responded dramatically to the administration of cortisol. Initial endocrine evaluation disclosed prolactin (PRL), corticotropin, and thyrotropin (TSH) deficiencies. The patient recovered completely with cortisol and thyroid hormone therapy and was delivered of a healthy male child at term. Endocrine reevaluations one week and six months postpartum disclosed luteinizing hormone, follicle-stimulating hormone, growth hormone, PRL, corticotropin, and probable TSH deficiencies. The cause of this panhypopituitarism has not been determined. This case suggests that the appropriate initial treatment for spontaneous symptomatic hypoglycemia in pregnancy, while awaiting further endocrine evaluation, is the administration of cortisol.

American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions.

This review summarizes Session IV: Therapeutic Interventions of the Fourth International Gestational Diabetes Workshop and suggests intervention protocols based on the presentations at this meeting and the literature. The opinions of the six presenters and their interpretation of the review of the literature in their specific areas, the synthesis of the 30 abstracts presented at this symposium on therapeutic interventions, and my interpretations of the literature to date on these strategies are discussed. Also, the suggested intervention protocols are outlined as to medical nutritional therapy, weight gain, insulin prescriptions, and the utility of an exercise program for gestational diabetes mellitus. The goals of an intervention protocol for the gestational diabetic women are to achieve and maintain normoglycemia and thus to minimize the risk of maternal or fetal morbidity.

Management of the pregnant, insulin-dependent diabetic woman.

An intensive care program was offered to all insulin-dependent, pregnant diabetic women who presented to The New York Hospital Obstetrical Clinic in their eighth week or less of gestation. The patients were hospitalized for 1 wk to normalize their blood glucose and to teach the technique of self-monitored glucose determination, diet and exchange lists, and the method to titrate insulin according to the blood glucose determination. The mean blood glucose for the first 10 patients accepted to the program was 169 mg/dl at the start of the program with a mean hemoglobin A1c of 9.4% for the group (normal < 5.5%) and glucosuria up to 50 g/24 h. After discharge, mean glucose was 91 mg/dl, and urinary glucose excretion was 1.4 g/24 h. HbA1c fell into the normal range 5 wk after normoglycemia was achieved (3.4%) (nl < 5.5%). Normoglycemia was maintained as outpatients until 3 wk before delivery when the patients were readmitted for tests of fetal well-being. Mean weight gain for the mothers was 12.2 kg. Mean glucose at delivery was 87 mg/dl and HbA1c was 3%. Hormonal profiles (hCG, hPRL, estrogens, progesterone, hPL) normalized after normoglycemia was achieved and remained normal until delivery. Mean gestational age at time of delivery was 38.8 wk with a mean infant birth weight of 2988 g. No infant manifested hypoglycemia, hypocalcemia, erythremia, or respiratory disease. The use of self-monitored blood glucose allows for optimal care of the insulin-dependent, pregnant diabetic woman while she remains at home with her family.

Optimal insulin delivery for the pregnant diabetic patient.

It is now possible to virtually normalize ambient blood glucose levels in insulin-dependent diabetic women during pregnancy. Successful programs have been developed that utilize home blood glucose monitoring, physiologic delivery of insulin, and quantitation of caloric intake carefully matched to insulin dosage. The results of establishing normoglycemia throughout gestation appear to be a normalization of mortality and morbidity for both infant and mother. Pregnancy provides a need for continuous upward adjustment of insulin dose concomitant with the ongoing fetal and hormonal changes associated with gestation.

The evaluation of a pocket computer as an aid to insulin dose determination by patients.

A small and inexpensive computer was programmed to assist patients in making decisions regarding insulin delivery using constant subcutaneous infusion systems. Insulin dosage was based on gender, pre- and postprandial blood glucose, between-meal blood glucose, patient weight, time of day, and when appropriate, the carbohydrate content of food ingested. The system was self-adjusting based on postprandial and fasting blood glucose levels. A developmental phase in which the computer program was refined was undertaken with five highly trained type I patients using an insulin infusion pump. Then, based on the suggestions made by these patients, a final program was used by these same five patients for 1 mo. Computer-assisted insulin delivery resulted in lower mean blood glucose (162 versus 130 mg/dl) and hemoglobin A1c (7.2% versus 5.8%) values when compared with precomputer values. In addition, there was a significant increase in the frequency of blood glucose testing during the computer-assisted periods in that patients monitored their blood glucose 4.9 times per day during the physician-alone period whereas a mean of 7.5 glucose tests were performed during the computer-assisted periods. Patient response to the concept was overwhelmingly favorable. These studies demonstrate that computer-assisted insulin-delivery decision making is feasible, acceptable to patients already accustomed to pump use, safe, effective, and may provide a savings in terms of professional time.

Effect of normoglycemia before conception on early pregnancy hormone profiles.

Insulin-dependent diabetic women have been shown to have subnormal hormone levels in the first trimester of pregnancy. To determine whether these abnormalities were the result of poor diabetes control, testosterone, androstenedione, human chorionic gonadotropin (HCG), and prolactin were studied longitudinally in diabetic women made normoglycemic before conception (N = 11) and normal (N = 6) control subjects beginning at the fifth week of gestation. HCG levels rose normally in all 11 diabetic and six control subjects and then declined as expected, with peak levels between 8 and 12 wk of gestation. Prolactin levels similarly rose significantly (P less than 0.00001) during the period studied. Plasma androstenedione did not increase during the course of this study, but testosterone levels increased significantly (P = 0.0001). Androgen levels were consistently higher in diabetic subjects despite the normoglycemic state, although the differences reached statistical significance at only one point. This study demonstrates that when normoglycemia is achieved before conception, HCG and prolactin are normal at 5 wk after the last menstrual period. The possibility that androgen levels may be higher in insulin-requiring diabetic women, perhaps due to peripheral hyperinsulinemia, should be explored.

Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes.

OBJECTIVE: To compare long-term glycemic control and safety of using insulin aspart (IAsp) with that of regular human insulin (HI). RESEARCH DESIGN AND METHODS: This was a multicenter randomized open-label 6-month study (882 subjects) with a 6-month extension period (714 subjects) that enrolled subjects with type 1 diabetes. Subjects administered IAsp immediately before meals or regular HI 30 min before meals; basal NPH insulin was taken as a single bedtime dose in the majority of subjects. Glycemic control was assessed with HbA1c values and 8-point blood glucose profiles at 3-month intervals. RESULTS: Mean postprandial blood glucose levels (mg/dl +/- SEM) were significantly lower for subjects in the IAsp group compared with subjects in the HI group after breakfast (156 +/- 3.4 vs. 185 +/- 4.7), lunch (137 +/- 3.1 vs. 162 +/- 4.1), and dinner (153 +/- 3.1 vs. 168 +/- 4.1), when assessed after 6 months of treatment. Mean HbA1c values (% +/- SEM) were slightly, but significantly, lower for the IAsp group (7.78% +/- 0.03) than for the regular HI group (7.93% +/- 0.05, P = 0.005) at 6 months. Similar postprandial blood glucose and HbA1c values were observed at 12 months. Adverse events and overall hypoglycemic episodes were similar for both treatment groups. CONCLUSIONS: Postprandial glycemic control was significantly better with IAsp compared with HI after 6 and 12 months of treatment. The improvement was not obtained at an increased risk of hypoglycemia. HbA1c was slightly, but significantly, lower for IAsp compared with HI at 6 and 12 months.

Anti-insulin antibody titers do not influence control or insulin requirements in early pregnancy.

IgG antibodies (AB) to insulin have been reported to influence insulin requirements and control in patients who have taken insulin for prolonged periods of time. Nineteen pregnant type I diabetic patients (C-peptide less than 0.03 pmol/ml) were studied in their fifth week of gestation after the establishment of normoglycemia. Mean age was 27.5 yr and duration of diabetes, 14.2 yr (range: 1-23 yr). IgG AB to beef and pork insulin were measured. IgG AB to insulin were encountered in all diabetic patients (range: 103-6736 microU/ml). None of the nondiabetic pregnant controls in their fifth week of gestation (N = 17) had detectable (greater than 50 microU/ml) AB levels. The antibody titer did not affect the insulin requirement (P greater than 0.2, NS) or ability to achieve normoglycemia. AB levels were correlated with years of treatment with conventional insulin preparations (r = 0.73; P less than 0.001). At 5 wk postmenstruation the mean AB level in the patients with less than 10 yr duration of diabetes (N = 7) was 727 microU/ml and mean insulin requirement was 0.7 U/kg/24 h. In the group of patients with greater than 10 yr duration of diabetes (N = 12) the mean antibody titer was 3716 microU/ml and the insulin requirement was also 0.7 U/kg/24 h. IgG AB to insulin increase with increasing duration of treatment with beef/pork insulin. IgG AB do not affect the insulin requirement or the ability to achieve normoglycemia during early pregnancy.

Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes.

OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.