Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a liver disease that complicates insulin-resistant states. This trial tested the efficacy and safety of rosiglitazone, an insulin-sensitizing agent, in patients with NASH. METHODS: Sixty-three patients with histologically proven NASH were randomly assigned to receive rosiglitazone (4 mg/day for the first month and 8 mg/day thereafter; n = 32) or placebo (n = 31) for 1 year. Liver biopsy was performed at the end of treatment. End points were improvement in the histologic score of steatosis, normalization of serum transaminase levels, and improvement in necroinflammation and fibrosis. RESULTS: More patients treated with rosiglitazone than receiving placebo had improved steatosis (47% vs 16%; P = .014) and normalized transaminase levels (38% vs 7%; P = .005), although only half of patients responded. There was no improvement in other histologic lesions, including fibrosis, and a composite score of activity, the nonalcoholic fatty liver disease activity score. Improvement of steatosis correlated with reduction of transaminase levels (r = 0.36; P < .005), improvement in insulin sensitivity (r = 0.34; P = .008), and increase in adiponectin levels (r = -0.54; P < .01) but not with weight variations. Independent predictors of response were rosiglitazone treatment, the absence of diabetes, and massive steatosis. Weight gain was the main adverse effect (mean gain of 1.5 kg in the rosiglitazone group vs -1 kg in the placebo group; P < .01), and painful swollen legs was the main reason for dose reduction/discontinuation. Serum hemoglobin level was slightly but significantly reduced. There was no hepatic toxicity. CONCLUSIONS: In patients with NASH, rosiglitazone improves steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity. However, there is no improvement in other parameters of liver injury.

Screening for liver fibrosis by using a noninvasive biomarker in patients with diabetes.

BACKGROUND & AIMS: Patients with diabetes are at risk for nonalcoholic fatty liver disease leading to advanced fibrosis, cirrhosis, and liver cancer. We examined the efficacy of a screening strategy with a noninvasive fibrosis biomarker (FibroTest) in patients with diabetes. METHODS: We prospectively studied 1131 consecutive patients without a history of liver disease seen for diabetes. The biomarker data were obtained, and patients with presumed advanced fibrosis were reinvestigated by a hepatologist using elastography and, if necessary, ultrasonography, endoscopy, or liver biopsy. RESULTS: The biomarker predicted advanced fibrosis in 63 of 1131 (5.6%) patients. A total of 45 patients was reinvestigated, and advanced fibrosis was confirmed in 32 patients, a 2.8% (32/1131) prevalence of confirmed advanced fibrosis, 5 cases of cirrhosis, and 4 cases of hepatocellular carcinoma. In the population with type 2 diabetes who were 45 years or older, the prevalence of confirmed advanced fibrosis was 4.3% (30/696), and hepatocellular carcinoma was 5.7 of 1000 (4/696). CONCLUSIONS: The fibrosis biomarker might be used for the detection of advanced fibrosis in patients with type 2 diabetes.

[The diabetic foot]. / Le pied du diabétique.

Diabetic patients are concerned with foot complications when a peripheral neuropathy is present. Screening of predisposed patients may be annually assessed using monofilament testing. Peripheral arterial disease, when associated, increases amputation risk. Ideal treatment requires a multidisciplinary approach with a first-line medical treatment including an optimal off-loading of the diabetic ulcer, ulcer dertersion, glycemic control, and if necessary antibiotic therapy. In case of associated osteomyelitis, a limited surgical resection of the infected bone may be performed. In case of associated arterial disease, a revascularization procedure precede bone resection.

Effects of bed-time insulin versus pioglitazone on abdominal fat accumulation, inflammation and gene expression in adipose tissue in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Intra-abdominal fat (IAF) and inflammatory markers are correlated with cardio-vascular risk. We compared the impact of bed-time insulin versus pioglitazone treatment on these parameters in type 2 diabetic (T2D) patients. METHODS: Twenty-eight T2D patients poorly controlled with metformin and sulfonylurea were randomized to receive add-on therapy with pioglitazone or bed-time NPH insulin. IAF and subcutaneous fat (SCF) content, systemic low-grade inflammation level and expression of inflammation related genes in SCF, were measured before and after 24 weeks of treatment. RESULTS: Insulin and pioglitazone resulted in a significant decrease in HbA1c (-1.6% and -1.2%, respectively) and a significant increase in total body fat mass (1+/-2.3 and 3.3+/-2.7 kg, respectively). There was no change in IAF content after both treatments whereas significant increase in SCF content was only seen after pioglitazone treatment (p<0.05 versus insulin). hsCRP level decreased after pioglitazone and ferritin level decreased after insulin treatment. No change in mRNA expression of inflammation related genes was found after either treatment. CONCLUSION/INTERPRETATION: This suggests that a 24-week treatment with pioglitazone or bed-time insulin has a similar impact on intra-abdominal fat mass and systemic low-grade inflammation.

A longitudinal study of coping, anxiety and glycemic control in adults with type 1 diabetes.

Diabetes is a unique disorder in how much it requires a high degree of individual self management strategies. Anxiety and stress can affect glycemic control, and thus management of emotions may be key to good glycemic control. This study is the first to examine how anxiety and coping style, and their interaction, can affect long-term glycemic control. We measured anxiety, coping, and HbA1C, a measure for mean blood glucose levels in the previous 6-8 weeks, in 115 patients with Type 1 diabetes at baseline and roughly 5 years later. We found that coping predicted outcomes, especially for those high in trait anxiety. Trait anxiety predicted limited increases in HbA1C (mean increase = 0.02%). Lower levels of emotion-oriented coping predicted clinically significant increases in HbA1C, but only for those high on baseline trait anxiety (mean increase = 0.92%). Task-oriented coping predicted decreases in state anxiety. Use of task- and emotion-oriented coping appears especially important for highly anxious patients, both for emotional regulation and glycemic control. So, coping styles, basal anxiety and their interactions should be considered in designing follow-up and interventions with diabetic patients.

The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.

OBJECTIVE: The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS: We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS: Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03). CONCLUSIONS: These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.

An altered self-peptide with superagonist activity blocks a CD8-mediated mouse model of type 1 diabetes.

T cell tolerance can be experimentally induced through administration of self-peptides with single amino acid substitution (altered peptide ligands or APLs). However, little is known about the effects of APLs on already differentiated autoreactive CD8+ T cells that play a pivotal role in the pathogenesis of autoimmune diabetes. We generated a panel of APLs derived from an influenza virus hemagglutinin peptide exhibiting in vitro functions ranging from antagonism to superagonism on specific CD8+ T cells. A superagonist APL was further characterized for its therapeutic activity in a transgenic mouse model of type 1 diabetes. When injected i.v. 1 day after the transfer of diabetogenic hemagglutinin-specific CD8+ T cells into insulin promoter-hemagglutinin transgenic mice, the superagonist APL proved more effective than the native hemagglutinin peptide in blocking diabetes. This protective effect was associated with an inhibition of CD8+ T cell cytotoxicity in vivo and with a decreased accumulation of these cells in the pancreas, leading to a marked reduction of intrainsulitis. In conclusion, a superagonist "self-peptide" APL was more effective than the native peptide in treating a CD8+ T cell-mediated diabetes model.