Interleukin (IL)-

Abstract. It is known that glycation among various proteins is increased in diabetic patients compared with non-diabetic subjects. Currently, among these glycated proteins, glycated hemoglobin (HbA 1C ) is used as the gold standard index of glycemic control in clinical practice for diabetes treatment. However, HbA 1C does not accurately reflect the actual status of glycemic control in some conditions where plasma glucose changes during short term, and in patients who have diseases such as anemia and variant hemoglobin. In comparison, another index of glycemic control, glycated albumin (GA), more accurately reflects changes in plasma glucose during short term and also postprandial plasma glucose. Although GA is not influenced by disorders of hemoglobin metabolism, it is affected by disorders of albumin metabolism. This review summarizes diseases and pathological conditions where GA measurement is useful. These include the status of glycemic control changes during short term, diseases which cause postprandial hyperglycemia, iron deficiency anemia, pregnancy, chronic liver disease (liver cirrhosis), chronic renal failure (diabetic nephropathy), and variant hemoglobin.

Salt-inducible kinase (SIK), first cloned from the adrenal glands of rats fed a high salt diet, is a serine/threonine protein kinase belonging to an AMP-activated protein kinase family. Induced in Y1 cells at an early stage of ACTH stimulation, it regulated the initial steps of steroidogenesis. Here we report the identification of its isoform SIK2. When a green fluorescent protein-fused SIK2 was expressed in 3T3-L1 preadipocytes, it was mostly present in the cytoplasm. When coexpressed in cAMP-responsive element-reporter assay systems, SIK2 could repress the cAMP-responsive element-dependent transcription, although the degree of repression seemed weaker than that by SIK1. SIK2 was specifically expressed in adipose tissues. When 3T3-L1 cells were treated with the adipose differentiation mixture, SIK2 mRNA was induced within 1 h, the time of induction almost coinciding with that of c/EBP␤ mRNA. Coexpressed with human insulin receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser 794 of human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated the level of phosphorylation at Ser 789 , the mouse equivalent of human Ser 794 . Moreover, the activity and content of SIK2 were elevated in white adipose tissues of db/db diabetic mice. These results suggest that highly expressed SIK2 in insulin-stimulated adipocytes phosphorylates Ser 794 of IRS-1 and, as a result, might modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance in diabetic animals.The lipid metabolism in adipose tissues is under the control of two hormonal signaling pathways; insulin stimulates glucose uptake and lipogenesis, whereas cAMP, generated by exogenous stimuli like adrenalin and glucagon, stimulates lipolysis. If the balance between the two signaling systems becomes lost and the adipose tissues are exposed to hyperinsulinemia for a prolonged time, they gradually become resistant to insulin stimulation (1, 2). The insulin resistance occurring in tissues involved in biological fuel metabolism, such as adipose tissues, liver, and skeletal muscles, would finally cause disorders in energy metabolism of the whole body, such as obesity and type 2 diabetes (3, 4). Insulin receptor substrate (IRS) 1 proteins are key molecules of the insulin-signaling cascade (5); they are phosphorylated on tyrosine residues by the action of insulindependently activated insulin receptor kinase, and the tyrosine-phosphorylated IRS proteins trigger further intracellular cascades. Several investigators recently reported (6, 7) that IRS proteins, under certain non-physiological conditions, were phosphorylated on serine residues. The serine phosphorylation of IRS proteins would modulate the efficiency of the insulinsignaling cascade (8, 9) and eventually render the animals resistant to insulin stimulation (10, 11). Molecular identification of several protein kinases responsible for the serine phosphorylation of IRS proteins has been reported (12-24).Salt-inducible kinase (SIK) was first cloned from ...

We conclude that insulin sensitivity is reduced to a similar extent in acromegalic patients with normal glucose tolerance and those with impaired glucose tolerance or diabetes. Compensatory hyperfunction of beta-cells appears to counterbalance the reduced insulin sensitivity in the acromegalic patients with normal glucose tolerance but not in those with impaired glucose tolerance or diabetes.

Objective-There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor ␣ (PPAR␣) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR␣ activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. Methods and Results-Bovine aortic endothelial cells were treated with the PPAR␣ activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR␣ action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. Conclusions-PPAR␣ activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR␣-mediated cardiovascular protection. Key Words: atherosclerosis Ⅲ endothelium Ⅲ nitric oxide Ⅲ vascular biology Ⅲ vasodilatation H ypolipidemic fibrates are pharmacological compounds that activate peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the nuclear hormone receptor superfamily. 1 These fibrates have been widely used as effective drugs lowering serum triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol. 2 There has been accumulating evidence showing that fibrates have favorable effects of slowing the progression of atherosclerosis and reducing the number of events of coronary heart diseases in high-risk patients. 3-5 PPAR␣ is known to be expressed in the liver, which is mainly involved in lipid and lipoprotein metabolism exerted by fibrates. 1 In addition, recent studies have shown that PPAR␣ is also expressed in the cardiovascular system, including heart and vascular wall component cells such as vascular endothelial, vascular smooth muscle, and monocyte cells, and performs a direct antiatherogenic and antiinflammatory action. 6 Staels et al have shown that PPAR␣ ligands inhibit interleukin (IL)-1-induced expression of IL-6, prostaglandin, and cyclooxygenase 2 in aortic smooth muscle cells. 7 These authors further showed that patients receiving fenofibrate, a potent fibrate, had lower plasma C-reactive protein, fibrinogen, and IL-6 concentrations. 7 Furthermore, it has been demonstrated that PPAR␣ activators inhibit cytokine-induced vascular cell adhesion molecule-1 (VCAM-1), 8,9 and thrombin-induced endothelin-1 expression 10 in vascular en...