OBJECTIVE -To evaluate urinary 8-hydroxydeoxyguanosine (8-OHdG) as a marker for the progression of diabetic macroangiopathic complications. RESEARCH DESIGN AND METHODS -The content of urinary 8-OHdG, common carotid intima-media thickness (IMT), the coronary heart disease (CHD) risk score, the severity of diabetic retinopathy, and urinary albumin excretion were examined in 96 patients with type 2 diabetes, including 32 patients who had been nominated for the Kumamoto Study [Shichiri M, et al. Diabetes Care 23 (Suppl 2):B21-B29, 2000]. In addition, the patients from the Kumamoto Study were further evaluated regarding the effect of intensive insulin therapy on urinary 8-OHdG excretion.RESULTS -The urinary 8-OHdG:creatinine ratio (U8-OHdG) was 2.5-fold higher in patients with increased HbA 1c than in those with normal HbA 1c (P Ͻ 0.05). In addition, U8-OHdG was 2.3-fold higher in patients with increased IMT (P Ͻ 0.005). A similar result was observed between U8-OHdG and CHD risk score (P Ͻ 0.01). U8-OHdG was significantly higher in patients with simple retinopathy (P Ͻ 0.05) and those with advanced retinopathy (P Ͻ 0.01) than in patients without retinopathy. Similarly, U8-OHdG was significantly higher in patients with albuminuria (P Ͻ 0.01). Furthermore, in the Kumamoto Study, U8-OHdG was significantly lower in the multiple insulin injection therapy group compared with the conventional insulin injection therapy group (P Ͻ 0.01).CONCLUSIONS -Hyperglycemia independently increases 8-OHdG in patients with type 2 diabetes. 8-OHdG is a useful biomarker of not only microvascular but also macrovascular complications in patients with type 2 diabetes. Diabetes Care 26:1507-1512, 2003V ascular complications are the leading cause of morbidity and mortality in patients with diabetes. In adult patients with diabetes, the risk of cardiovascular disease is three-to fivefold greater than in nondiabetic subjects despite controlling for other known risk factors for cardiovascular disease (1). In addition, diabetic microangiopathy still represents one of the main causes of blindness (2), terminal renal failure (3), and amputation (4).The outcomes of the Diabetes Control and Complication Trial (5), the Kumamoto Study (6 -8), and the U.K. Prospective Diabetes Study (9) seem to have effectively resolved the long debate over whether chronic hyperglycemia is an important cause of diabetic vascular complications. Furthermore, the Diabetes Insulin-Glucose in Acute Myocardial Infarction Study showed that intensive insulin treatment was associated with a lower mortality rate than conventional insulin treatment in subjects with acute myocardial infarction (10). It was also reported that early atherosclerosis could be retarded by improved glycemic control in patients with type 1 diabetes (11). Therefore, hyperglycemia represents a major contributing factor to not only microvascular complications in diabetes but also macrovascular complications. Next to this, the longest-running controversy yet to be resolved concerns the identification of the me...

Abstract. This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 µg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 µg/ dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.Key words: Adrenal insufficiency, Adrenal crisis, Cortisol, Hydrocortisone, Congenital adrenal hyperplasia Summary of Recommendations I. Chronic adrenal insufficiency (AI) I-1.0 SymptomsWe recommend suspecting AI in patients who have the following symptoms.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder and an unusual cause of Cushing s syndrome, of which familial transmission has rarely been reported. In this study, a mother and her son, the former affected with definite AIMAH and the latter with possible AIMAH, are described. Although the mother manifested overt Cushing s syndrome, her son remained with no stigmata of Cushing s syndrome except for bilateral adrenal tumor and mild hypertension, and a full suppression of plasma cortisol by lowdose dexamethasone was observed in him. Recently, aberrant expression of adrenal receptors for various ligands has been noted in AIMAH patients. In our cases, provocation tests in vivo suggested that AVP and catecholamines promoted cortisol production through V1a and/or V1b receptors and via beta-adrenergic receptor, respectively. Reverse transcriptional-PCR analysis of the operated adrenal tissues of mother revealed the abnormal expression of mRNA of receptors for V1b, V2, and LH/hCG, none of which was observed in a normal control. Inherited AIMAH is very rare, and the son might be at the earliest developmental stage of AIMAH among the cases reported so far. An intervention could be tried to prevent the development of overt Cushing s syndrome by suppression of the possible endogenous ligands or by blockade of the receptors that may be aberrantly expressed in his adrenal glands.

SummaryThe present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol. kg-1) or orally (5.0 mmolkg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol. kg -1) and oral administration of either delapril or enalapril (5.0 mmol.kg -1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-a-adamantaneacetyl-DArg-[Hyp3,ThiJ.8,D-Phe 7]-bradykinin) (0.5 nmol. kg-1. min -1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol. kg-1. min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol. kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group. Bradykinin may also possibly be involved in the mechanism underlying the improvement in insulin sensitivity associated with ACE-inhibition. [Diabetologia (1994) 37: 300-307]

It has been suggested that bradykinin stimulates glucose uptake in experiments in vivo and in cultured cells. However, its mechanism has not yet been fully elucidated. In this study, the effects of bradykinin on the insulin signalling pathway were evaluated in isolated dog adipocytes. The bradykinin receptor binding study revealed that dog adipocytes possessed significant numbers of bradykinin receptors (Kd = 83 pmol/l, binding sites = 1.7 x 10(4) site/ cell). Reverse transcription-polymerase chain reaction amplification showed the mRNA specific for bradykinin B2 receptor in the adipocytes. Bradykinin alone did not increase 2-deoxyglucose uptake in adipocytes; however, in the presence of insulin (10(-7) mol/l) it significantly increased 2-deoxyglucose uptake in a dose-dependent manner. Bradykinin also enhanced insulin stimulated GLUT4 translocation from the intracellular fraction to the cell membrane, and insulin induced phosphorylation of the insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in dog adipocytes. The time-course of insulin stimulated phosphorylation of the insulin receptor beta subunit revealed that phosphorylation reached significantly higher levels at 10 min, and stayed at the higher levels until 120 min in the presence of bradykinin, suggesting that bradykinin delayed the dephosphorylation of the insulin receptor. It is concluded that bradykinin could potentiate insulin induced glucose uptake through GLUT4 translocation. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by GLUT4 translocation.