The Role of Adiponectin as a Compensatory Mediator for the Primary Secretory Defect in Latent Autoimmune Diabetes in Adults

Background

Increased adiposity in patients with newly diagnosed type 2 diabetes mellitus (DM), as well as in patients who do not have DM, affects the regulation of insulin sensitivity and the metabolic effects of adiponectin.

Objective

The goal of this study was to investigate the relationship between plasma adiponectin levels and obesity in patients developing DM mainly due to an early decline in β-cell function.

Methods

We studied 29 patients with latent autoimmune diabetes in adults (LADA), 38 patients with type 1 DM, and 55 healthy volunteers.

Results

Plasma adiponectin levels, adjusted for body mass index (BMI), were higher in patients with type 1 DM than in controls (P < 0.001) and similar to those in patients with LADA (P = 0.464). Plasma adiponectin levels were higher in LADA patients compared with controls (P < 0.001). In LADA patients, plasma adiponectin levels, adjusted for BMI, correlated significantly with insulin resistance (β coefficient, –6.453 [2.772]; P = 0.028). Interestingly, this relationship in LADA patients was significant in more overweight patients (β coefficient, –7.142 [3.249]; P = 0.048) but not in leaner patients (P = 0.571), a finding that was not confirmed through the results in the controls (P = 0.520 and P = 0.992, respectively).

Conclusions

In patients with LADA, increases in plasma adiponectin levels, after adjustment for BMI, could act as a mediator for improvement in insulin sensitivity and thus compensate for the primary secretory defect. This effect seems more profound in more overweight subjects than in leaner subjects.     

Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.     

Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC)

The single-nucleotide polymorphisms (SNPs) rs402710 (5p15.33), rs16969968 and rs8034191 (15q25.1) have been consistently identified by genome-wide association studies (GWAS) as significant predictors of lung cancer risk, while rs4324798 (6p22.1) was previously found to influence survival time in small-cell lung cancer (SCLC) patients. Using the same population of one of the original GWAS, we investigated whether the selected SNPs and 31 others (also identified in GWAS) influence survival time, assuming an additive model. The effect of each polymorphism on all cause survival was estimated in 1094 lung cancer patients, and lung cancer-specific survival in 763 patients, using Cox regression adjusted for a priori confounders and competing causes of death where appropriate. Overall, after 1558 person-years of post-diagnostic follow-up, 874 deaths occurred from all causes, including 690 from lung cancer. In the lung cancer-specific survival analysis (1102 person-years), only rs7452888 (6q27) and rs2710994 (7p15.3) modified survival, with adjusted hazard ratios of 1.19 (P = 0.009) and 1.32 (P = 0.011) respectively, taking competing risks into account. Some weak associations were identified in subgroup analysis for rs16969968 and rs8034191 (15q25.1) and rs4324798 (6p22.1) and survival in never-smokers, as well as for rs402710 in current smokers and SCLC patients. In conclusion, rs402710 (5p15.33), rs16969968 and rs8034191 (both 15q25.1) and rs4324798 (6p22.1) were found to be unrelated to survival times in this large cohort of lung cancer patients, regardless of whether the cause of death was from lung cancer or not. However, rs7452888 (6q27) was identified as a possible candidate SNP to influence lung cancer survival, while stratified analysis hinted at a possible role for rs8034191, rs16969968 (15q25.1) and rs4324798 (6p22.1) in influencing survival time in lung cancer patients who were never-smokers, based on a small sample.     

Infliximab for Diabetic Macular Edema Refractory to Laser Photocoagulation: A randomized, double-blind, placebo-controlled, crossover, 32-week study

OBJECTIVE

Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti–tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition.

RESEARCH DESIGN AND METHODS

This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis.

RESULTS

Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 ± 5.1 (mean ± SD) letters read at baseline to 28.8 ± 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 ± 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 ± 10.3 at baseline to 30.4 ± 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 ± 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8–43.7; P = 0.017). Infliximab treatment was well tolerated.

CONCLUSIONS

The positive results of this small phase III study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME.Diabetic macular edema (DME) is a serious complication of diabetes and a leading cause of vision loss in the working-age population of most developed countries (1,2). Data from the Wisconsin Epidemiological Study of Diabetic Retinopathy estimate that after 15 years of known duration of diabetes, the prevalence of DME is 20% in patients with type 1 diabetes, 25% in patients with type 2 diabetes who are treated with insulin, and 14% in the patients with type 2 diabetes who are not treated with insulin (3). A previous study has shown that 53% of the eyes with DME involving the center of the macula lost two or three lines of visual acuity over a 2-year period (4). Focal/grid laser photocoagulation (two sessions for optimal results) has been the standard for treatment for DME over the past two decades. However, this treatment effectively reduces the risk of vision loss in <50% of patients. Even among those patients who achieve an initial response, recurrences requiring ongoing treatment are common (1,5). Currently, there are no approved treatment options for eyes with DME refractory to laser photocoagulation (2,6).Tumor necrosis factor (TNF) is a pleiotropic cytokine, central to the development and homeostasis of the immune system and a regulator of cell activation, differentiation, and death. In the past few decades, there has been an enormous scientific and clinical interest in understanding the function of TNF in physiology and disease, and a vast amount of data has accumulated at the biochemical, molecular, and cellular levels, establishing TNF as a prototype for in-depth understanding of physiological and pathogenic functions of a cytokine (7). This knowledge primed the successful development of anti-TNF therapies in the 1990s. Infliximab (Remicade) is a chimeric monoclonal antibody specific for human TNF that has shown efficacy in treatment of chronic inflammatory diseases affecting the joints, skin, and gut. Since its first launch in 1998, >1,100,000 patients worldwide have been treated with this drug for approved indications, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and Crohn disease, including pediatric patients (8). Infliximab is given intravenously every 4–8 weeks at a dose ranging from 3 to 10 mg/kg and has an acceptable safety profile.Several lines of evidence suggest an inflammatory basis for DME (9). Along this line, treatment modalities have been tried with variable success. Such treatments include pharmacological therapy with oral protein kinase C inhibitors (10), antibodies targeted to vascular endothelial growth factor (VEGF) (11), intravitreal injections of corticosteroids (12,13), and high doses of nonsteroidal anti-inflammatory drugs that lower retinal expression of TNF (14). According to our previously published preliminary results, a clinically meaningful recovery of useful vision was achieved after two infliximab infusions in four of six eyes with severe diffuse DME (15). Comparable beneficial results have been obtained in patients with severe, chronic cystoid macular edema complicating intermediate uveitis, Adamantiades-Behçet disease, or adult-type vascular pseudotumor (16). Repeated treatment in one diabetic patient produced a further significant improvement of DME (15), suggesting that the clinical response to anti-TNF dosing regimens is individualized, as observed in patients with arthritis (8) or in patients with uveitic macular edema (16).Based on the evidence for anti-TNF treatment in DME and the limitations of current treatments, we undertook this phase III study to prospectively investigate the efficacy and safety of infliximab in the treatment of patients who were in danger of vision loss due to DME refractory to laser photocoagulation.     

Genetic variation in the lactase gene,dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition

High dairy protein intake has been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). To further examine this possible relationship, we investigated the hypothesis that a genetic polymorphism in the lactase (LCT) gene might be associated with elevated dairy product intake and increased prostate cancer risk in a case–control study nested in EPIC. The C/T‐13910 lactase variant (rs4988235) was genotyped in 630 men with prostate cancer and 873 matched control participants. Dairy product consumption was assessed by diet questionnaire. Odds ratios (ORs) for prostate cancer in relation to lactase genotype were estimated by conditional logistic regression. Lactase genotype frequency varied significantly between countries, with frequencies of the T (lactase persistence) allele ranging from 7% in Greece to 79% in Denmark. Intake of milk and total dairy products varied significantly by lactase genotype after adjustment for recruitment center; adjusted mean intakes of milk were 44.4, 69.8 and 82.3 g/day among men with CC, CT and TT genotypes, respectively. The lactase variant was not significantly associated with prostate cancer risk, both in our data (adjusted OR for TT vs. CC homozygotes: 1.10, 95% CI: 0.76–1.59) and in a meta‐analysis of all the published data (combined OR for T allele carriers vs. CC homozygotes: 1.12, 0.96–1.32). These findings show that while variation in the lactase gene is associated with milk intake in men, the lactase polymorphism does not have a large effect on prostate cancer risk.     

Mast cells squeeze the heart and stretch the gird: their role in atherosclerosis and obesity

Mast cells are crucial for the development of allergic and anaphylactic reactions, but they are also involved in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases through activation by non-allergic triggers such as neuropeptides and cytokines. This review discusses how mast cells contribute to the inflammatory processes associated with coronary artery disease and obesity. Animal models indicate that mast cells, through the secretion of various vasoactive mediators, cytokines and proteinases, contribute to coronary plaque progression and destabilization, as well as to diet-induced obesity and diabetes. Understanding how mast cells participate in these inflammatory processes could help in the development of unique inhibitors with novel therapeutic applications for these diseases, which constitute the greatest current threat to global human health and welfare.