Minoru Yasujima

Role of Advanced Glycation End Products in Diabetic Neuropathy

Diabetic neuropathy is the commonest form of peripheral neuropathy in the developed countries of the world. In diabetic patients, the presence of peripheral neuropathy increases their risks for developing foot ulceration and subsequent necrosis that necessitates lower limb amputation. Although the precise mechanisms underlying diabetic neuropathy remain unclear, there is evidence that hyperglycemia-induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy; AGE-modified peripheral nerve myelin is susceptible to phagocytosis by macrophages and contributes to segmental demyelination; modification of major axonal cytoskeletal proteins such as tubulin, neurofilament, and actin by AGEs results in axonal atrophy/degeneration and impaired axonal transport; and glycation of extracellular matrix protein laminin leads to impaired regenerative activity in diabetic neuropathy. Recently, the receptor for AGEs (RAGE) has been found to colocalize with AGEs in diabetic peripheral nerves. This suggests that, in diabetic neuropathy, AGEs and AGE/RAGE interactions induce oxidative stress, result in upregulation of nuclear factor (NF)-kappaB and various NF-kappaB-mediated proinflammatory genes, and exaggerate neurological dysfunction, including altered pain sensation. Additionally, AGE/RAGE-induced oxidative stress further accelerates formation of glycoxidation products such as Nepsilon-(carboxymethyl)lysine and pentosidine. Although new drugs that inhibit the formation of AGEs and block the AGE-RAGE interaction are being studied, no effective treatment modalities against AGE-induced nerve injury are currently available clinically. A therapeutic strategy to prevent and ameliorate diabetic neuropathy using anti-AGE agents needs to be established. In this review, the current issues involved in the role of the glycation process and the potential treatment options for diabetic neuropathy are explored.

Early Changes in Insulin Receptor Signaling and Pain Sensation in Streptozotocin-Induced Diabetic Neuropathy in Rats

UNLABELLEDnThe objective of the present study was to evaluate the time course of changes in peripheral nerve insulin receptor (IR) signaling and compare observed findings with behavioral responses to noxious mechanical and thermal stimuli in streptozotocin (STZ)-diabetic rats over 12 weeks of diabetes. Diabetic rats developed mechanical hyperalgesia, as indicated by decreased paw withdrawal thresholds to mechanical stimuli that were detectable after 2 weeks of diabetes; they also developed thermal hypoalgesia, as indicated by increased tail flick latencies to thermal stimuli that were detectable at 1 week of diabetes. Western blot analysis revealed decreased phosphorylated: total IR protein ratio that was detectable as early as 2 weeks of diabetes, whereas phosphorylated:total Akt protein ratio was decreased at 2 weeks and increased at 12 weeks of diabetes with unchanged PI-3K protein levels. To our knowledge, the present study is the first to demonstrate that impaired peripheral nerve IR signaling, as indicated by decreased phosphorylated:total IR protein ratio, coincides with early mechanical hyperalgesia and thermal hypoalgesia in STZ-diabetic rats. This finding may improve understanding of how altered pain sensation develops rapidly in this model.nnnPERSPECTIVEnThis study examined peripheral nerve IR signaling during the early course of altered nociception in STZ-diabetic rats. In diabetic rats, impaired peripheral nerve IR signaling is observed shortly after STZ injection, as is altered nociception. This finding suggests a possible role of impaired IR signaling in diabetic sensory neuropathy.

Elevated plasma brain natriuretic peptide levels independent of heart disease in acute ischemic stroke: correlation with stroke severity.

We tested the hypothesis that plasma brain natriuretic peptide (BNP) levels are elevated in patients with acute cerebrovascular diseases (CVD) independent of heart disease, and reflect CVD severity. After careful evaluations for heart disease, the study included 79 consecutive patients with CVD without any evidence of heart disease admitted within 48 h after onset (71±10 years), and 26 control subjects without CVD (CT, 67±12 years). Ischemic stroke subtypes were defined by the TOAST classification. Large-artery atherosclerosis (LAA, n=27), small-artery occlusion (SAO, n=27), and intracerebral hemorrhage (ICH, n=25) were included. The plasma BNP levels were measured at admission and 1 month later. Stroke severity and brain infarct volume were evaluated. There were no significant differences in the clinical profiles including echocardiographic parameters among the groups. The plasma BNP level (pg/mL) upon admission was higher in LAA (70.6±53.9) than in SAO (38.2±28.4) and CT (28.5±19.9) (both p<0.05). The level in ICH (47.3±28.6) was not significantly different from that in CT. The BNP level in ischemic stroke was positively correlated with the NIH Stroke Scale (NIHSS) (ρ=0.42, p<0.05) and infarct volume (r=0.34, p<0.05). Brain infarct volume and NIHSS were independent contributors to the plasma BNP level in ischemic stroke. One month later, the BNP level was significantly decreased and was similar in all CVD groups. The plasma BNP level transiently increased in patients with LAA independently of heart disease, and reflected infarct volume and the severity of acute ischemic stroke.

Time course of pain sensation in rat models of insulin resistance, type 2 diabetes, and exogenous hyperinsulinaemia

Small sensory fibre dysfunction has been recently recognized as a component of impaired glucose tolerance and insulin resistance (IR) syndrome. However, few studies have investigated whether small sensory fibre dysfunction develops in normoglycaemic or pre‐diabetic animal models of IR and/or hyperinsulinaemia. In addition, scant information is available on the metabolic features of IR in relation to small sensory fibre dysfunction due to the progressive failure of beta cells to compensate for IR during the development of frank diabetes.

Quantification of cystatin C in cerebrospinal fluid from various neurological disorders and correlation with G73A polymorphism in CST3

Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimers disease (AD), Parkinsons disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype.

A case of multiple endocrine neoplasia type II accompanied by thyroid medullary carcinoma and pheochromocytomas expressing corticotropin-releasing factor and urocortins.

A 38-year-old woman with RET gene mutation presented with tumors in her thyroid and bilateral adrenal glands. I-metaiodobenzylguanidine scintigraphy revealed accumulation of the radioisotope in both adrenal glands. Both plasma adrenaline and noradrenaline levels were elevated. The circadian rhythms for plasma adrenocorticotropic hormone (ACTH) and cortisol levels were disturbed. Plasma ACTH and cortisol levels failed to be suppressed by an overnight dexamethasone test, suggesting autonomic secretion of ACTH and cortisol, although the patient had no typical Cushingoid features, hypertension, or impaired glucose tolerance. Pathological examination showed that these tumors were pheochromocytoma and thyroid medullary carcinoma, respectively, both of which highly expressed corticotropin-releasing factor, urocortin1, and urocortin3. Together with the endocrinological and pathological observations, the patient was diagnosed as multiple endocrine neoplasia type II with corticotropin-releasing factor- and urocortin-producing tumors that stimulated ACTH and glucocorticoid secretion.

Association of novel promoter single nucleotide polymorphisms in vasopressin V1a receptor gene with essential hypertension in nonobese Japanese.

We studied the association between four novel single nucleotide polymorphisms (SNPs) in the promoter region of V1aR gene and essential hypertension in 620 Japanese subjects (365 hypertensives and 255 healthy). A significant association was found between one of the genotypes and alleles at SNP -6951 and hypertension in a subsample of nonobese individuals. This association demonstrated an independent risk for nonobese hypertension.

Growth hormone-releasing peptide-2 stimulates secretion and synthesis of adrenocorticotropic hormone in mouse pituitary

Growth hormone (GH)-releasing peptides (GHRPs) are synthetic peptides which induce strong GH release in both animals and humans. Among them, GHRP-2 is known to stimulate GH release by acting at both hypothalamic and pituitary sites, but also induces adrenocorticotropic hormone (ACTH) release in healthy subjects. GHRP-2 may stimulate ACTH release directly via GHRP receptor type 1a in ACTH-producing tumors. GHRP-2 increases ACTH secretion in rat in vivo, but not ACTH release from rat primary pituitary cells. In the present study, in order to elucidate the mechanism underlying ACTH secretion by GHRPs, mouse pituitary cells were stimulated by GHRP-2. GHRP receptor mRNA was expressed in the mouse pituitary, and GHRP-2 directly stimulated secretion and synthesis of ACTH in the mouse anterior pituitary cells. GHRP-2 increased intracellular cyclic AMP production. H89, a potent protein kinase A (PKA) inhibitor, and bisindolylmaleimide I, a selective protein kinase C (PKC) inhibitor, inhibited the GHRP-2-induced ACTH release, and that H89, but not bisindolylmaleimide I, inhibited the GHRP-2-induced proopiomelanocortin mRNA levels. Together, the GHRP-2-induced ACTH release was regulated via both PKA and PKC pathways in the mouse pituitary cells, while ACTH was synthesized by GHRP-2 only via the PKA pathway.

A case of thyrotropin-producing pituitary adenoma, accompanied by an increase in anti-thyrotropin receptor antibody after tumor resection

We describe a rare, but interesting, case of TSH-producing adenoma (TSHoma), accompanied by increases in both anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) after tumor resection. A 21-yr-old woman was referred to our department for further evaluation of pituitary tumor. In a nearby hospital, she had been diagnosed as having pituitary tumor. Her serum free T4, free T3, and TSH levels were all elevated concomitantly. On the basis of a diagnosis of pituitary adenoma with TSH production, transsphenoidal resection of the pituitary adenoma was performed. Two weeks after the operation, the blood concentrations of TSH were undetectable, whereas both TRAb and TSAb levels were elevated. TSAb levels gradually increased further from 2 weeks to 3 months after the operation, accompanied by an increase in TSH and free T4 levels. TSH is an important hormone in maintaining physiology and regulating immunomodulators in thyrocytes, as it can influence a variety of immune-regulating cytokine-like activities and inhibit expressions of Fas antigen, intracellular adhesion molecule-1, and class II trans-activator. Changes in TSH would modulate the immune circumstances in the thyroid, and then induce TRAb and TSAb. Autoimmune parameters with thyroid function should be observed carefully when managing patients with TSHoma.