The role of CD8+ cells in the establishment and maintenance of a Trichuris muris infection

Chronic infection by the caecal-dwelling intestinal murine nematode Trichuris muris occurs if given as a high-dose infection to 'susceptible' AKR mice or as a low-dose infection to the normally 'resistant' C57BL/6 mouse strain. Both regimes result in a type 1 cytokine response, i.e. high levels of IFN-gamma and IL-12. Here we show this susceptible response is associated with a large population of CD8(+) IFN-gamma(+) cells within the mesenteric lymph nodes and numerous CD8(+) cells infiltrating the caecal mucosa. Despite this, the in vivo abolition of CD8(+) cells within AKR and C57BL/6 mice, either prior to infection or once infection has become established, failed to affect chronicity, implying that CD8(+) T cells are not essential for the initiation or maintenance of the susceptible response to T. muris. Interestingly, the percentage of IFN-gamma(+) CD4(+) cells increased in treated groups, perhaps in a compensatory role. The majority of antigen-specific cytokine responses were comparable in both treated and control groups, although IL-5 was fivefold higher in animals receiving anti-CD8 mAbs and IFN-gamma was also raised in treated mice. Mastocytosis was unaltered by CD8 depletion, however, paradoxically, eosinophilia within the caecum was reduced in treated mice. Together these data clearly demonstrate that CD8(+) T cells are associated with chronic T. muris infection; however, these cells are dispensable for both the early and late phases of this response, but do appear to play a role in the regulation of certain cytokines and caecal eosinophilia.     

Trichuris muris: antigen recognition and transfer of immunity in mice by IgA monoclonal antibodies

Mesenteric node lymphocytes from mice that had been infected with the nematode Trichuris muris, and then boosted with adult worm excretory-secretory antigens were fused with myeloma cells to produce a panel of 9 monoclonal antibodies (MoAbs). Five of the MoAbs were of the IgA isotype. The antigen recognition profiles of these MoAbs were studied using SDS-PAGE and immunoblotting; three major profile patterns were identified. Five MoAbs recognized a major band in the MW range 43-48 kD; all recognized a range of antigens. Three MoAbs were used to localize antigens in the bodies of adult worms. Granules within the anterior stichocytes were recognized strongly, as was material within the eggs and pseudocoelom. Two MoAbs stained the cuticle. Although the phosphorylcholine (PC) determinant was widely distributed within worm tissues none of the MoAbs tested recognized PC. Passive transfer of immunity was achieved using two of the IgA monoclonals; no immunity was transferred by the IgM and IgG MoAbs used. The limited recognition profiles of these IgA MoAbs, and the ability to stain stichocyte granules, suggest that their protective activity results from an interaction with ES antigens.     

Nutrition, immunity and helminth infection: effect of dietary protein on the dynamics of the primary antibody response to Trichuris muris (Nematoda) in CBA/Ca mice

The effect of dietary protein on the specific antibody responses (total immunoglobulins, IgG1 and IgA) to the intestinal nematode Trichuris muris was studied in CBA/Ca mice fed isocaloric diets containing 16% or 4% protein. Mice fed the 16% diet and given a high infection dose of 650 eggs expelled almost their entire primary infection by day 21 post infection. In similarly infected animals fed the 4% protein diet, there was prolonged survival of adult worms. At a low infection dose of 10 eggs, there was no evidence of an expulsion response in either dietary group. The primary antibody response to parasite excretory/secretory (E/S) antigen was time-dependent, regardless of dietary protein or infection dose, and was predominantly an IgG1 response. Within each dietary group, antibody production and antigen recognition occurred earlier and the antibody responses were more intense in mice given the higher infection dose. The principal finding was that the specific antibody response was more vigorous, both quantitatively (serum titres) and qualitatively (antigen recognition by IgG1), in mice on a low protein diet, even though worm expulsion did not occur in these hosts. This result suggests that serum antibody level or antigen recognition is not related simply to protective immunity against T. muris in CBA/Ca mice.     

The role of TNF-alpha receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning

The specific role of TNF-α receptors I (TNFR-I, p55) and II (TNFR-II, p75) in myocardial ischemic injury remains unclear. Using genetically engineered mice, we examined the relative effects of TNF-α signaling via p55 and p75 in acute myocardial ischemia/reperfusion injury under basal conditions and in late preconditioning (PC). Wild-type (WT) (C57BL/6 and B6,129) mice and mice lacking TNF-α (TNF-α^−/−), p55 (p55^−/−), p75 (p75^−/−), or both receptors (p55^−/−/p75^−/−) underwent 30 min of coronary occlusion and 24 h of reperfusion with or without six cycles of 4-min coronary occlusion/4-min reperfusion (O/R) 24 h earlier (ischemic PC). Six cycles of O/R reduced infarct size 24 h later in WT mice, indicating a late PC effect. This late PC-induced infarct-sparing effect was abolished not only in TNF-α^−/− and p55^−/−/p75^−/− mice, but also in p55^−/− and p75^−/− mice, indicating that TNF-α signaling via both p55 and p75 is necessary for the development of protection. In nonpreconditioned TNF-α^−/−, p55^−/−/p75^−/−, and p75^−/− mice, infarct size was similar to strain-matched WT mice. In contrast, infarct size in nonpreconditioned p55^−/− mice was reduced compared with nonpreconditioned WT mice. We conclude that (i) unopposed p75 signaling (in the absence of p55) reduces infarct size following acute ischemia/reperfusion injury in naive myocardium, whereas unopposed p55 signaling (in the absence of p75) has no effect; and (ii) the development of the infarct-sparing effects of the late phase of PC requires nonredundant signaling via both p55 and p75 receptors. These findings reveal a fundamental, heretofore unrecognized, difference between the two TNF-α receptors in the setting of myocardial ischemia/reperfusion injury: that is, both p55 and p75 are necessary for the development of protection during late PC, but only signaling via p75 is protective in nonpreconditioned myocardium.     

Contrasting effects of Trichinella spiralis and Trichuris muris antigens on the infection by Leishmania infantum in BALB/c mice

The interaction of Trichinella spiralis and Trichuris muris derived antigens with the infection by Leishmania infantum was investigated in BALB/c mice. Infection with 10(6) promastigotes of L. infantum did not induce relevant serum antibody (IgG subclasses), nor cytokine (IFN-gamma, IL-4) responses despite that mice could partially control the infection. Immunization with T. spiralis activated a moderate IgG1 and secondarily an IgG2a anti-leishmanial response whereas immunization with T. muris elicited only a weak and late activation of IgG1 anti-leishmanial response. Immunization with T. muris caused an elevation of serum IFN-gamma levels which was drastically reinforced by the L. infantum infection, and that was accompanied by almost complete parasitological cure of infected mice. Immunization with T. spiralis induced an elevation of serum IL-4 levels but this response was greatly (about 60%) neutralized by the infection with L. infantum, and this was associated to exacerbation of the infection.     

The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection

Summary. Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver injury and viral control. Forty-seven liver biopsies from patients with chronic HBV with varying degrees of inflammation (ALT values) were selected. Acute hepatitis and normal liver specimens served as controls. Immune effector cells, cytotoxic effector molecules and cytokine producing cells were quantified after immunohistochemical staining in lobular and portal areas of the biopsies. The intralobular number of CD8+ T-lymphocytes was significantly decreased in biopsies of patients with high ALT ( r  = −0.54; P  < 0.001). Higher ALT-values were correlated with increased numbers of granzyme+ cells in portal areas ( r  = 0.65; P  < 0.001) and higher numbers of intralobular Fas-L+ cells ( r  = 0.32; P  = 0.05). Fas-L was expressed on Kupffer and lymphoid cells. More intralobular CD8+ T-lymphocytes were found in HBeAg− than in HBeAg+ patients ( P  = 0.002). But IFN- γ and TNF- α producing cells were observed sporadically in chronic HBV patients. Hence, in chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T-lymphocytes. Persistence of the virus may be caused by the absence of cells producing anti-viral cytokines in the liver. Inflammatory liver injury during chronic HBV infection is probably not the result of increased numbers of infiltrating CD8+ T-lymphocytes, but of Fas-L expression by Kupffer cells and increased cytolytic activity of cells in portal areas.     

The role of CD4+ and CD8+ T cells in protective immunity to the murine nematode parasite Trichuris muris

The role ofCD4⁺ and CD8⁺ T cells in protective immunity to Trichuris muris was studied in CD4⁺ or CD8⁺ or both CD4⁺ and CD8⁺ T cell-depleted BALB/c mice. To assess in vivo depletion of T-cell subsets, CD4⁺ and CD8⁺ T cells in the Peyer's patches, the mesenteric lymph nodes (MLN), and the spleens of mice treated with T cell-specific monoclonal antibodies (MoAbs) were analysed by FACS. CD4⁺ T cells were selectively depleted in mice injected with anti-CD4 MoAb i.p. and injection of anti-CD8 MoAb resulted in selective depletion ofCD8⁺ T cells. The expulsion ofl. muris was inhibited in CD4⁺ T cell-depleted mice and numerous worms were detected in the large intestine on days 14 and 21 after infection, although no suppression of protective immunity to T. muris was observed in CD8⁺ T cell-depleted mice. Moreover, there was no difference in suppression of protective immunity to T. muris between CD4⁺ T cell-depleted and both CD4⁺ and CD8⁺ T cell-depleted mice. These results indicate that CD4⁺ T cells play a central role in protective immunity to T. muris infection.     

The role of IL-4, IL-13 and IL-4Ralpha in the development of protective and pathological responses to Trichinella spiralis

T helper type 2 (Th2) responses have been shown to be important in protective responses to gastrointestinal (GI) helminth infections and in the development of the intestinal pathology accompanying expulsion of the parasite. Different inbred mouse strains have been shown to develop different cytokine profiles following infection with GI helminths with increased resistance observed in those strains where Th2 cytokines predominate. The aim of this study was to determine the role of IL-4, IL-13 and IL-4Ralpha and the impact of host background on the development of the protective and pathological responses induced by infection with the gastrointestinal helminth Trichinella spiralis. IL-4, IL-13 and IL-4Ralpha were required for the generation of Th2 responses to T. spiralis; however, the role these responses play in the development of protection and enteropathy was less clear. IL-4Ralpha-deficiency mice resulted in substantially reduced parasite expulsion, intestinal pathology and Th2 responses. Similarly, lack of IL-13 resulted in inhibited expulsion and the development of enteropathy. Although Th2 responses were reduced in BALB/c IL-4-/- mice, neither expulsion nor enteropathy were different from wild-type mice. In contrast, C57BL/6 IL-4-/- exhibited delayed expulsion and reduced pathology, suggesting that host genetics are important in the function of individual cytokines. Thus, differences in background genotype may be an important component in the development host protection and the development of intestinal pathology accompanying the loss of GI helminths.     

The role of the p75 neurotrophin receptor in the morphology of dorsal root ganglion cells in streptozotocin diabetic mice: effects of sciatic nerve crush

Aims/hypothesis Neuronal dorsal root ganglion (DRG) cells seem to be vulnerable in diabetes. The aim of this study was to determine whether the p75 neurotrophin receptor stimulates perikaryal shrinkage and neuronal death, and further accelerates neuronal DRG cell loss after axotomy in a mouse model of diabetes.Methods Nine non-diabetic BALB/c p75^+/+ mice, seven diabetic BALB/c p75^+/+ mice, nine non-diabetic p75^–/– mice and nine diabetic p75^–/– mice received a unilateral sciatic nerve crush 1 to 2 days after streptozotocin treatment. Tissues were fixed 28 days later by vascular perfusion, and the volume and number of the fifth lumbar DRG neurons were obtained using assumption-free stereological techniques.Results In diabetic p75^+/+ mice there was a 9% reduction in the perikaryal volume of the DRG A cells (p<0.05) and a 10% reduction in the perikaryal volume of the DRG B cells (p<0.05) on the non-crushed side compared with in non-diabetic p75^+/+ mice. However, neuronal cell number was not reduced. Conversely, no perikaryal shrinkage of A cells or B cells occurred on the non-crushed side in diabetic p75^–/– mice, and no neuronal cell loss was observed. Following nerve crush, there was a loss of B cells in non-diabetic p75^+/+ mice (37±6%) and in diabetic p75^+/+ mice (36±4%). In non-diabetic p75^–/– mice, no neuronal cell loss occurred after crush, whereas in diabetic p75^–/– mice the loss of B cells (14±4%) was small but significant (p<0.02).Conclusions/interpretation In experimental diabetes the p75 neurotrophin receptor is involved in neuronal DRG cell body shrinkage without loss of neuronal DRG cells. Following sciatic nerve crush, DRG cell loss is not accelerated in diabetic p75^+/+ mice.     

Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes

Aims/hypothesis: First-degree relatives of patients with Type I (insulin-dependent) diabetes mellitus diagnosed at 20 years of age or under were screened for islet cell antibodies (ICA) in the course of recruitment to an international diabetes prevention trial. Our aim was to evaluate the influence of age, gender, proband characteristics and nationality on the prevalence of ICA and co-existence of autoantibodies to GAD, IA-2 and insulin. Methods: A central laboratory screened samples from 10 326 non-diabetic relatives who were aged less than 40 years, from eight European countries for ICA. Antibodies to GAD and IA-2 were measured in all samples with ICA of 10 JDF units or more. Results: Overall, 8.9 % of relatives had ICA of 10 JDF units or more, 3.8 % with ICA of 20 JDF units or more. Of 921 relatives with ICA of 10 JDF units or more, 29 % had co-existing antibodies to GAD or IA-2 or both. ICA of 10 JDF units or more were more prevalent in males (10.8 %) than females (7.3 %). ICA with GAD or IA-2 antibodies or both were also more common in males (3.4 %) than females (1.9 %) and in relatives under 20 years of age (3.5 % vs 1.5 %). Multiple regression analysis showed nationality to be a determinant of ICA of 10 JDF units or more but not of ICA of 20 JDF units or more or of ICA with co-existing islet antibodies, and confirmed the importance of age and gender as determinants of islet autoimmunity. Conclusions/interpretation: Relatives from different European countries have similar rates of islet autoimmunity despite wide variation in the background incidence of childhood diabetes, and male excess is equally evident in all populations. The male excess of ICA and islet autoimmunity over 10 years of age reflects the higher male incidence of Type I diabetes in this age group, and suggests that boys may be more likely than girls to develop islet autoimmunity during adolescence. [Diabetologia (2002) 45: 217–223] Received: 9 August 2001 and in revised form: 16 October 2001     

Roles of gender, obesity, and lifestyle-related diseases in alcoholic liver disease: Obesity does not influence the severity of alcoholic liver disease

Aim: To elucidate gender differences and the influence of obesity and/or metabolic syndrome‐related fatty liver on alcoholic liver disease (ALD), we analyzed characteristic features of ALD. Methods: We investigated 266 ALD patients (224 males and 42 females) without hepatocellular carcinoma stratified by gender and the presence of cirrhosis. Male and female patients matched for age and total ethanol intake were also analyzed. A diagnosis of ALD was based on alcohol intake (>70 g daily for more than 5 years), clinical features, and exclusion of other liver diseases. The prevalence of obesity, lifestyle‐related diseases, and psychological disorders were assessed. Results: The prevalence of psychological disorders showed a significant gender difference among all ALD patients (12% in males versus 43% in females, P < 0.001), as well as in patients matched for age and total ethanol intake. There were 156 cirrhotic patients. Absence of dyslipidemia, presence of diabetes, and high total ethanol intake were selected as independent predictors of cirrhosis in males by multivariate analysis after excluding laboratory data of liver function tests. The prevalence of obesity was significantly lower in cirrhotic male patients than in non‐cirrhotic male patients (34% vs. 20%, P = 0.023). Among females, there were no significant predictors of cirrhosis on multivariate analysis after eliminating liver function tests. The prevalence of obesity and diabetes was similar in non‐cirrhotic and cirrhotic female patients. The prevalence of psychological disorders was 47% in cirrhotic females with ALD. Conclusions: Obesity was not common in cirrhotic ALD. Psychological disorders seem to be important for female ALD.     

Local release of human neutrophil lipocalin (HNL), IL-8, and TNF-alpha is decreased as response to topical prednisolone treatment in distal ulcerative colitis and proctitis

The local release of human neutrophil lipocalin, considered to be highly specific for neutrophil granulocyte activation, and interleukin-8 and tumor necrosis factor- were studied in 11 patients with distal ulcerative colitis and proctitis before and during treatment with steroid enemas. A rectal perfusion technique for sampling and specific immunoassays for analysis were used. In responders (N = 8) the concentrations of all proteins decreased during the study. There was a close correlation between human neutrophil lipocalin concentrations and treatment response. Tumor necrosis factor- showed an initial decline in concentrations irrespective of treatment outcome and preceded the decline of human neutrophil lipocalin and interleukin-8. We conclude that decreased neutrophil degranulation is correlated with treatment outcome. Furthermore, an important role of tumor necrosis factor- in the process of stimulating neutrophil activation and degranulation in ulcerative colitis is suggested.     

The role of XPB in cell apoptosis and viability and its relationship with p53, p21 and c-myc in hepatoma cells

BACKGROUND: Accumulation of DNA damage has been implicated in hepatocarcinogenesis. XPB plays a pivotal part in repairing damaged DNA. However, up to now, the biological effect of XPB on hepatoma cells remains elusive. MATERIALS AND METHODS: Here, we investigated the role of XPB in the apoptosis and the viability of hepatoma cells by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labelling and cell viability assay; we also investigated their relationship with p53, p21(waf1/cip1) and c-myc by using the RT-PCR and Western blot. RESULTS: Compared with the control cells HepG2/pcDNA3.1 or HepG2, XPB-transfected HepG2 cells (HepG2/pcDNA3.1-XPB) displayed lower viability, weaker activity and higher apoptosis index. At the same time, an increased expression of p21(waf1/cip1) mRNA, protein and p53 protein in addition to a decreased expression of c-myc mRNA and protein were detected in HepG2/pcDNA3.1-XPB cells. CONCLUSIONS: Our results indicated that XPB could inhibit the proliferation of hepatoma cells and had a positive effect on the expression of p53 and p21(waf1/cip1) but a negative effect on c-myc.     

The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors

Insulin-like growth factor I (IGF-I) exerts pleiotropic effects on mammalian cells via stimulation of its receptor (IGF-IR), a receptor tyrosine kinase. In vivo, IGF-I acts both as a local tissue growth factor and as a circulating hormone. In oncological research, IGF-I has received increased attention as the activated IGF-I/IGF-IR system displays mitogeneic, transforming, and anti-apoptotic properties in various cell types by stimulating distinct intracellular signaling pathways. Recent data suggest that the anti-apoptotic effect of IGF-I may mediate decreased sensitivity to chemotherapeutic drugs in vitro and in vivo. Thus, targeting the IGF-I/IGF-IR system could serve as an approach to overcome clinical drug resistance in certain tumors. Received: 15 December 1998 / Accepted: 4 January 1999     

Recruitment of HIV/AIDS treatment‐naïve patients to clinical trials in the highly active antiretroviral therapy era: influence of gender,sexual orientation and race

Background

In the USA, women, racial/ethnic minorities and persons who acquire HIV infection through heterosexual intercourse represent an increasing proportion of HIV‐infected persons, and yet are frequently underrepresented in clinical trials. We assessed the demographic predictors of trial participation in antiretroviral‐naïve patients.

Methods

Patients were characterized as trial participants if highly active antiretroviral therapy (HAART) was initiated within a clinical trial. Prevalence ratios (PRs) were obtained using binomial regression.

Results

Between 1996 and 2006, 30% of 738 treatment‐naïve patients initiated HAART in a clinical trial. Trial participation rates for men who have sex with men (MSM), heterosexual men, and women were respectively 36.5, 29.6 and 24.3%. After adjustment for other factors, heterosexual men appeared less likely to participate in trials compared with MSM [PR 0.79, 95% confidence interval (CI) 0.57, 1.11], while women were as likely to participate as MSM (PR 0.97, 95% CI 0.68, 1.39). The participation rate in Black patients (25.9%) was lower compared with non‐Black patients (37.5%) (adjusted PR 0.80, 95% CI 0.60, 1.06).

Conclusions

In our clinical setting, gender did not appear to impact participation in HIV treatment trials, but Black patients were slightly less likely to participate in these trials. Considering the substantial proportion of HIV‐infected patients who are Black, future trials need to consider strategies to incorporate such underrepresented populations.     

Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1)

Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF and interleukin (IL)-6. Mouse MSCs from male wild type (WT), female WT, male TNFR1 knockouts (TNFR1KO) and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 h hypoxia. MSC activation was determined by measuring VEGF, TNF and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6 and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6 and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF and IL-6 expression. TNFR1 may autoregulate VEGF, TNF and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.     

The DURABLE Trial Study Design: Comparing the Safety, Efficacy, and Durability of Insulin Glargine to Insulin Lispro Mix 75/25 Added to Oral Antihyperglycemic Agents in Patients with Type 2 Diabetes

Background

While studies have compared the safety and efficacy of starter insulin regimens in type 2 diabetes, none have evaluated regimen durability (length of time a patient can maintain glycemic control) or the safety and efficacy of subsequent intensification regimens in a large, multinational cohort.

Methods

The DURABLE (Assessing the DURAbility of Basal vs Lispro Mix 75/25 Insulin Efficacy) trial will compare the ability of glargine once daily vs lispro mix 75/25 (75% insulin lispro protamine suspension, 25% lispro) twice daily added to oral antihyperglycemic agents to achieve and maintain hemoglobin A1c (HbA1c) goals. This randomized, open label, parallel study will enroll over 2000 insulin-naïve patients with type 2 diabetes from 11 countries, ages 30 to 80, with HbA1c >7.0% on at least two oral antihyperglycemic agents. At the completion of the 6-month initiation phase, safety and efficacy of the two regimens will be compared. Patients who achieve an HbA1c ≤7.0% at 6 months will continue into the 24-month maintenance phase to evaluate durability.In a substudy, patients not achieving HbA1c ≤7.0% at 6 months may be randomized to one of two intensification comparisons: patients previously on glargine will receive lispro mix 75/25 twice daily or basal/bolus therapy (glargine + thrice-daily mealtime lispro) and patients previously on lispro mix 75/25 will receive lispro mix 50/50 (50% insulin lispro protamine suspension, 50% lispro) thrice daily or basal/bolus therapy.

Results

Upon completion, this trial will provide new information about starter insulin durability, defined as the length of time patients can maintain HbA1c control (HbA1c ≤7.0%, or >7.0% but with an increase of <0.4% from the most recent HbA1c ≤7.0%). Additionally, the study will provide comparative data on HbA1c, blood glucose profiles, 1,5-anhydroglucitol, hypoglycemic episodes, weight change, and insulin dose for starter insulin regimens following 6 and 24 months of treatment, as well as intensified insulin via the 6-month substudy.

Conclusion

This trial aims to broaden clinicians'' understanding of the ability of starter insulin and insulin intensification regimens to achieve and maintain glycemic control in patients with type 2 diabetes.