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Immunoglobulin light-chain (AL) amyloidosis is characterized by the deposition of insoluble fibrils composed of immunoglobulin light chains secreted by monoclonal plasma cells. Given the recent advances in the therapy of AL amyloidosis, it is important to diagnose this disease as early as possible. Herein, we describe the case of a 62-year-old man with hepatitis C virus (HCV)-related cirrhosis presenting with hematochezia. Colonoscopy showed multiple submucosal hematomas within the region ranging from the transverse colon to the sigmoid colon. Kappa immunoglobulin light-chain amyloid deposition was also detected. Bone marrow examination revealed a monoclonal abnormal plasma cell population. Thus, the patient was diagnosed with systemic immunoglobulin light-chain amyloidosis. The hematochezia was conservatively managed. However, because of liver failure caused by liver cirrhosis, the patient developed massive pleural effusion and died of respiratory failure. Postmortem examination revealed amyloid deposition in the esophagus, stomach, duodenum, ileum, descending colon, pancreas, heart, and lung. In these organs, amyloid deposition was limited to the vascular wall. We concluded that AL amyloidosis can present hematochezia arising from submucosal hematoma in the large colon before other systemic symptoms appear.

We investigated the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and their relation with clinical and metabolic parameters in non-obese type 2 diabetic patients. The plasma levels of TAFI and PAI-1 were evaluated in 47 non-obese type 2 diabetic patients and 31 normal subjects. The intra-abdominal visceral and subcutaneous fat areas were measured by computed tomography (CT). The degree of insulin resistance was evaluated by the euglycemic-hyperinsulinemic clamp technique using artificial pancreas. The plasma levels of TAFI (169.0+/-108.8% versus 103.7+/-52.3%; p

To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2α (PGF2α) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2α than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2α were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2α and glucose infusion rate in obese men (r = −0.552; P < 0.05) and all men (r = −0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2α were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2α are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 +/- 2.6 vs. 8.3 +/- 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 +/- 1.4 vs. 26.5 +/- 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 +/- 11.6 vs. 99.5 +/- 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 +/- 24.5 vs. 128.8 +/- 12.3%; P < 0.02) or normal subjects (194.1 +/- 24.5 vs. 99.5 +/- 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.

To clarify whether homeostasis model assessment (HOMA IR) and quantitative insulin sensitivity check index (QUICKI) may be indicators of insulin resistance in elderly patients with type 2 diabetes mellitus, their relationship with the glucose infusion rate during the euglycemic hyperinsulinemic clamp study (clamp IR) was assessed. This study comprised 56 Japanese patients with type 2 diabetes mellitus; of these, 28 were 70 yr of age or older (group 1) and 28 were less than 70 yr of age (group 2). Their blood sugars were in poor control (fasting plasma glucose levels: group 1, 9.0 2.6 mmol/liter; group 2, 8.9 2.3 mmol/liter; hemoglobin A1c: group 1, 9.5 2.0%; group 2, 9.2 1.7%). Log-transformed HOMA IR was significantly correlated with the clamp IR in group 2 patients (r 0.51, P < 0.01), but not in group 1 patients (r 0.28, P 0.15). There was a significant positive correlation between QUICKI and clamp IR in group 2 patients (r 0.50, P < 0.01). However, no significant correlation was observed between QUICKI and clamp IR in group 1 patients (r 0.31, P 0.12). There was a significant correlation between log-transformed HOMA IR (r 0.37, P < 0.01) or QUICKI (r 0.37, P < 0.01) and clamp IR when both groups were combined. In conclusion, neither HOMA IR nor QUICKI should be used as an index of insulin resistance in elderly patients with poorly controlled type 2 diabetes mellitus. The results of this study suggest the need for developing a new noninvasive method for evaluating insulin resistance in those patients. (J Clin Endocrinol Metab 87: 5332–5335, 2002)

Objective: To investigate the relationship between active ghrelin and oxidative stress in obese subjects. Design: We measured the plasma levels of free 8-epi-prostaglandin F2α (8-epi-PGF2α, a reliable and systemic marker of oxidative stress) and the active form of ghrelin in 17 obese and 17 normal subjects. The biologically active forms of ghrelin were measured using a commercially available radio-immunoassay kit and free 8-epi-PGF2α was measured using an enzyme immunoassay kit. Results: The circulating level of active ghrelin was significantly decreased (20.4 ± 2.6 vs 40.9 ± 3.9 fmol/ml, P < 0.01) while that of 8-epi-PGF2α was significantly increased (61.5 ± 9.6 vs 17.3 ± 3.4 pg/ml, P < 0.01) in obese subjects compared with normal subjects. The plasma levels of active ghrelin and 8-epi-PGF2α were significantly correlated in obese (r = −0.507, P < 0.05) and in all (r = −0.577, P < 0.01) subjects. Multivariate analysis showed that the plasma levels of active ghrelin and 8-epi-PGF2α were significantly and independently correlated in all subjects (F = 7.888, P < 0.01). Conclusions: There is an inverse correlation between circulating levels of active ghrelin and oxidative stress in obesity. Low circulating levels of active ghrelin may enhance oxidative stress and the process of atherosclerosis in obese subjects.

Metformin is thought to decrease blood glucose levels by reducing hepatic glucose output. To elucidate the pharmacological action of metformin on hepatic glucose production, we examined its effect on the gene expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in H4IIE rat hepatoma cell line by RT-PCR and quantitative real-time PCR. Metformin suppressed dexamethasone/cAMP-induced expression of G6Pase mRNA in a dose dependent manner, its maximum effect being observed at 2 mM (79.3% inhibition, P

OBJECTIVE: It is well known that nitric oxide synthase (NOS) is expressed and that it modulates glucose transport in skeletal muscles. Recent studies have shown that adipose tIssues also express inducible and endothelial nitric oxide synthase (eNOS). In the present study, we investigated whether nitric oxide (NO) induces glucose uptake in adipocytes, and the signaling pathway involved in the NO-stimulated glucose uptake in 3T3-L1 adipocytes. METHODS: First, we determined the expression of eNOS in 3T3-L1 adipocytes, and then these cells were treated with the NO donor sodium nitroprusside (SNP) and/or insulin, and glucose uptake and phosphorylation of insulin receptor substrate (IRS)-1 and Akt were evaluated. Moreover, we examined the effects of a NO scavenger, a guanylate cyclase inhibitor or dexamethasone on SNP-stimulated glucose uptake and GLUT4 translocation. RESULTS: SNP at a concentration of 50 mmol/l increased 2-deoxyglucose uptake (1.8-fold) without phosphorylation of IRS-1 and Akt. Treatment with the NO scavenger or guanylate cyclase inhibitor decreased SNP-stimulated glucose uptake to the basal level. Dexamethasone reduced both insulin- and SNP-stimulated glucose uptake with impairment of GLUT4 translocation. CONCLUSION: NO is capable of stimulating glucose transport through GLUT4 translocation in 3T3-L1 adipocytes, via a mechanism different from the insulin signaling pathway.

Previous studies have demonstrated that oxidative stress is associated not only with hyperglycemia and hypertension but also with the metabolic syndrome and cadiovascular disease (1–3). Adrenomedullin (AM) is a novel vasorelaxant peptide isolated from human pheochromocytoma (4,5). Oxidative stress enhances AM production from endothelium and vascular smooth muscle cells in vitro (6,7). However, whether oxidative stress is associated with circulating levels of AM in vivo is unknown. In the present study, we evaluated the relationship between the plasma levels of 8-epi-prostaglandinF2α (8-epi-PGF2α; currently regarded as the most reliable marker for the assessment of oxidative stress in humans) (8,9) and AM in normal subjects and hypertensive patients with type 2 diabetes. This study comprised 17 hypertensive patients with type 2 diabetes (15 men and 2 women, age 47.3 ± 3.0 years [mean ± SE], BMI 23.2 ± 0.8 kg/m2, fasting plasma glucose 8.2 ± 0.5 mmol/l, HbA1c 9.9 ± 0.5%, fasting serum insulin 30.6 ± 3.0 …

OBJECTIVE: To investigate the effect of acute hyperinsulinemia on the plasma levels of adrenomedullin (AM) in patients with type 2 diabetes mellitus. DESIGN: We measured the plasma levels of AM in 18 patients with type 2 diabetes mellitus and in 19 normal subjects before and during a euglycemic hyperinsulinemic clamp study (the goal was for blood sugar levels of 5.24 mmol/l and insulin levels of 1200 pmol/l). Both plasma AM and serum insulin were measured by immunoradiometric assays. RESULTS: Before the glucose clamp study there was no significant difference in the plasma levels of AM between patients with type 2 diabetes mellitus and normal subjects. During the glucose clamp study, the serum levels of insulin significantly increased (from 33.0+/-3.6 to 1344.6+/-67.8 pmol/ml, P

Tumor necrosis factor-α (TNF-α) plays a critical role in the pathogenesis of vascular injury in diabetic patients (1). Increased circulating levels of TNF-α have been reported in diabetic patients (2,3). Hyperglycemia stimulates TNF-α secreted from monocytes and endothelial cells (4,5). Moreover, TNF-α may cause vascular injury by affecting the balance between coagulation and fibrinolysis. For example, TNF-α stimulates the expression of tissue factor that is the initiator of blood coagulation activation and the secretion of plasminogen activator inhibitor-1 that inhibits fibrinolysis (1). Activated protein C (APC) is a serine protease that inhibits activation of the blood coagulation system by proteolytically inactivating factors Va and VIIIa and by stimulating fibrinolysis (6,7). APC may indirectly promote fibrinolysis by inhibiting thrombin generation and by inhibiting the action of plasminogen activator inhibitor-1 (8). Recently, it was reported that APC has an anti-inflammatory effect and that it inhibits vascular injury induced by TNF-α …

Hypofibrinolysis is a common finding in patients with diabetes and a risk factor for the occurrence of micro- and macroangiopathy (1–3). Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI) was isolated from human plasma (4). It has been reported that the plasma levels of TAFI are increased in diabetic patients, and it may play an important role in the mechanism of hypofibrinolysis observed in these patients (5). Activated protein C (APC) is a serine protease that inhibits thrombin formation by proteolytically inactivating factors Va and VIIIa and by stimulating fibrinolysis (6,7). Thrombin stimulates the conversion of TAFI in its active form. APC may indirectly promote fibrinolysis by inhibiting thrombin generation and by inhibiting the action of plasminogen activator inhibitor-1 (7,8). Both TAFI and APC are regulated by thrombin-thrombmodulin complex on the plasma membrane of endothelium (6). This mechanism appears to be important for controlling the balance between coagulation and fibrinolysis in diabetic patients. In the present study, we investigated the plasma …