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Introduction: Recent studies indicate that cancer is a new complication of diabetes. In Japan, cancer is the most critical cause of death in patients with type 2 diabetes. Areas covered: Unlike diabetic angiopathies, diabetes does not accelerate the onset and progression of cancer, even though diabetes and cancer exhibit very similar pathophysiological features including obesity, insulin resistance, chronic inflammation, oxidative stress, and decreased adipokine imbalance. Agonists to glucagon-like peptide-1 (GLP-1) receptor are a newly identified therapy for type 2 diabetes. These drugs exert their effects by enhancing glucose-induced insulin secretion and inhibiting appetite. However, the relationship between GLP-1 receptor agonists and cancer is controversial. Expert commentary: GLP-1 receptor agonist may possess anti-cancer effect in several kind of cancers. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator-activated receptor (PPAR)α, a ligand-activated transcription factor with pleiotropic anti-inflammatory effects in macrophages, is the molecular target for fibrates, which are frequently used to treat dyslipidemia in patients with type 2 diabetes at high risk for cardiovascular disease. In the present study, we examined the regulation of OPN by PPAPα agonists in macrophages and determined the effect of fibrate treatment on OPN plasma levels in patients with type 2 diabetes. Treatment of human macrophages with the PPAPα ligands bezafibrate or WY14643 inhibited OPN expression. PPARα ligands suppressed OPN promoter activity, and an activator protein (AP)-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPARα ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPARα ligands inhibited c-Fos and phospho-c-Jun binding to the OPN promoter. Moreover, c-Fos and phospho-c-Jun protein expression was inhibited by PPARα agonists, indicating that PPARα ligands suppress OPN expression through negative cross talk with AP-1-dependent transactivation of the OPN promoter. This inhibitory effect of PPARα ligands on OPN expression was absent in PPARα-deficient macrophages, suggesting a receptor-mediated mechanism of OPN suppression. Finally, treatment of type 2 diabetic patients with bezafibrate significantly decreased OPN plasma levels. These results demonstrate a novel mechanism whereby PPARα ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease. Diabetes 56:1662-1670, 2007 [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The effects of antidiabetic agents on lipoprotein subclasses are assumed to be pivotal, but this assumption has not been studied. We evaluated lipoprotein subclasses in patients, randomly selected from REASON (Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes) Trial participants, with type-2 diabetes treated with either anagliptin or sitagliptin. We measured total cholesterol (TC) and triglycerides (TG) in 4 (chylomicron (CM), very low-density lipoprotein (VLDL), low density lipoprotein (LDL), and high-density lipoprotein (HDL)) lipoprotein classes and 20 (2 CM, 5 VLDL, 6 LDL, and 7 HDL) lipoprotein subclasses. Between 0 and 52 weeks, TC and TG in lipoprotein and the lipoprotein subclass were distributed differently in patients treated with anagliptin and sitagliptin. The preferable changes in TC and TG levels were observed dominantly in the anagliptin-treated group under standard statin therapy, but the benefits were observed in both the anagliptin- and sitagliptin-treated groups, at least partially under strong statin therapy. In future studies, the atherogenic properties of lipoprotein subclasses might be considered when employing antidiabetic dipeptidyl peptidase-4 (DPP-4) inhibitors, especially in patients with type-2 diabetes who are at risk of atherosclerotic cardiovascular disease (ASCVD) or are undergoing statin treatment. [ABSTRACT FROM AUTHOR]

Background: We previously reported that the carotid artery intima-media thickness (IMT) increased with age and that patients with type 2 diabetes mellitus (DM) had a significantly larger IMT than did age-matched nondiabetic subjects with normal glucose tolerance. Although the exact mechanism behind the increase in IMT in diabetic patients has not been determined, data obtained from in vivo and in vitro studies suggest that hyperglycemia-induced oxidative stress may lead to atherogenesis.Objective: The aim of this single-center study was to determine whether long-term oxidative stress and the carotid IMT are influenced by differences of the angiotensin-converting enzyme insertion/deletion (ACE I/D) and NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase p22phox C242T genotypes.Methods: Eligible subjects were Japanese patients with type 2 DM. Polymorphism of the ACE I/D and p22phox gene was investigated using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively. The rate of an acquired mutation of mitochondrial DNA—that is, A-to-G substitution at position 3243 (mtDNA A3243G)—was determined by real-time PCR. As a marker of early atherosclerosis, the carotid artery IMT was measured using high-resolution B-mode ultrasonography.Results: A total of 262 Japanese patients (173 men, 89 women; mean [SEM] age, 58 [0.6] years [range, 18–80 years]) were recruited and enrolled for study. An ACE D-positive (DD or DI) and p22phox 242T-negative genotype (CC) was associated with a significantly higher mtDNA A3243G mutation rate than the other 3 possible genotypes (0.0219% [0.0028%] vs 0.0097% [0.0012%]; P < 0.05). This genotype also had higher maximum and mean IMT values than the other genotypes (1.13 [0.048] mm vs 0.99 [0.03] mm and 1.01 [0.036] mm vs 0.92 [0.023] mm; P < 0.05). These parameters were similar among the other 3 genotypes.Conclusion: In this study, the ACE D-positive and p22phox 242T-negative genotype showed higher rates of somatic mtDNA mutation (mtDNA A3243G) and higher carotid mean and maximum IMT levels. [Copyright &y& Elsevier]

Small, dense LDL, as well as chylomicron- and VLDL-remnant lipoproteins, are known to be important risk factors for coronary heart disease in patients with type 2 diabetes mellitus. The aim of this study was to clarify the relationship between LDL particle size and postprandial remnant lipoprotein levels in Japanese type 2 diabetic patients Forty-six patients with type 2 diabetes mellitus were divided into tertiles according to LDL particle size. The peak LDL particle diameter was <26.30 nm in tertile 1, 26.30–26.85 nm in tertile 2, and >26.85 nm in tertile 3. After a test meal, tertile 1 had a significantly greater increment of triglycerides (TG), remnant-like particle (RLP)-TG, and RLP-cholesterol (RLP-C) than tertiles 2 and 3. There was a negative correlation between LDL particle size and the postprandial increases of TG, RLP-TG, and RLP-C.These results indicate that smaller sized LDL particles may be a marker of fasting state for an exaggerated postprandial increase of remnant lipoproteins as well as an increase of TG-rich lipoproteins. [Copyright &y& Elsevier]