Abstract. Osteopontin (OPN) is thought to play multiple roles in the progression of atherosclerotic plaque including diabetic vascular complications. However, it still remains unclear whether the level of OPN in vivo is indeed clinically associated with the progression of diabetic complications. This study evaluated whether the levels of OPN in plasma and urine are correlated with the progression of diabetic complications, such as retinopathy, neuropathy, and nephropathy in patients with type 2 diabetes. In 229 patients with type 2 diabetes, OPN level in plasma and urine was evaluated by both the severity of diabetic complications, such as retinopathy, neuropathy, and nephropathy, and the clinical characteristics and the substantial laboratory findings. Plasma OPN level increased significantly with aging and the progression of diabetic nephropathy, especially at the stage of renal failure (p<0.05). However, the level was not related to the progression of retinopathy or neuropathy, or to laboratory findings, such as HbA1c or serum lipids. In contrast, urinary OPN level was not associated with diabetic complications in any of the subjects. There was no correlation between the plasma and urinary values of OPN. The results established that the plasma OPN was elevated in proportion to the progression of diabetic nephropathy, indicating that the plasma concentration may be a potential diagnostic predictor of diabetic end-stage renal disease.

Objective-We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs). Methods and Results-VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF ␤-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB-induced p38 phosphorylation in diabetic cells was more enhanced via MAPK kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-␤II and PKC-␦ were activated by diabetes, PDGF-BB could further enhance the level of PKC-␦ alone. PDGF-BB-induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-␦. PDGF-BB-induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580. Conclusions-Our study established that PDGF-BB phosphorylated p38 via PKC-␦ and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs. Key Words: p38 Ⅲ PDGF-BB Ⅲ VSMC Ⅲ PKC Ⅲ migration D iabetes mellitus is a most crucial risk factor for atherosclerosis. 1,2 Several hypotheses, such as hyperosmolarity, 3 advanced glycation end products, 4 oxidant formation, 5 abnormality of sorbitol and myoinositol metabolism, 6 and diacylglycerol protein kinase C (PKC) activation, 7 have been proposed to explain the various pathological changes induced by hyperglycemia in vasculature. Glucose and its metabolites possibly mediate their adverse effects by altering the various signal transduction pathways used by vascular cells to perform their functions and maintain cellular integrity. Some changes in vascular cells include increases in contractility, cellular proliferation, migration, and extracellular matrix production, which are abnormal in diabetes. 7 We and other investigators recently identified that the activation of p38 mitogen-activated protein kinase (MAPK) could be responsible for some vascular dysfunctions observed in the diabetic state. 8 -11 However, it has not been determined whether hyperglycemia and its metabolites can affect other signal transduction systems and/or the cellular targets of p38 activation.In contrast, the platelet-derived growth factor (PDGF) is recognized as a major mitogen in serum and one of the most important growth factors that promote atherogenesis, including the proliferation of vascular smooth muscle cells (VSMCs). 12-15 PDGF-BB can bind all types of receptors and activate the GTPase-activating protein of Ras (Ras-GTP) and, subsequently, extracellular-regulated protein kinase (extracellular signal regulated kinase [ERK]) 1/2, leading to cellul...

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Abstract. This study investigates whether the plasma brain natriuretic peptide (BNP) level is increased by the clinical traits of diabetes, including its complications, and whether these levels are affected by the presence of other combined diseases such as hypertension, hyperlipidemia, and coronary heart disease (CHD) in patients with diabetes. In 223 patients with Type 2 diabetes, the mean value of plasma BNP reached 32.3 ± 4.1 pg/mL. The levels significantly increased with age, hypertension, and CHD but not with the duration of diabetes, HbA1c level, or hyperlipidemia. With regard to the type of therapy, the BNP levels were significantly lower in the combinations of both sulfonylurea and metformin and sulfonylurea and pioglitazone than those in insulin alone. In addition, the BNP levels in the group with diabetic complications, including retinopathy and nephropathy, and macroalbuminuria were significantly elevated in comparison with those without these complications and macroalbuminuria. Interestingly, however, no difference was observed between these groups after removal of the values in patients with CHD. These results have clarified that the plasma BNP levels in diabetic patients could increase only by the progression of macrovascular diseases, such as CHD, but not by the current diabetic control or diabetic microvascular complications.