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Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α–converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal–regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose–stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose–induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK–signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.

In order to identify small G protein (s) which contributes to the proliferation of vascular smooth muscle cells (VSMCs), we examined the effect of an HMG-CoA reductase inhibitor (cerivastatin), a farnesyltransferase inhibitor (FTI-277), a geranyl geranyl transferase inhibitor (GGTI-286) and a Rho kinase inhibitor (Y-27632) on the proliferation of cultured rat VSMCs stimulated with 20ng/ml platelet-derived growth factor (PDGF)-BB. Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced activation of extracellular signal related kinase (ERK1/2). The inhibitory effect of cerivastatin on the PDGF-BB-induced activation of ERK1/2 was fully recovered by the addition of geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP). Cerivastatin and GGTI-286, but not FTI-277, suppressed the PDGF-BB-induced [3H] thymidine incorporation and activation of ornitine decarboxylase (ODC), both of which were fully recovered by the addition of GGPP, but not FPP. These data indicate that the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs depend upon geranylgeranylated small G protein. Immunoblotting analysis revealed the upregulation of Rho A protein in the membrane fractions of VSMCs stimulated by PDGF-BB. Furthermore, Y-27632 suppressed the PDGF-BB-induced activation of ERK1/2 and proliferation of VSMCs. On the basis of these data, we conclude that PDGF-BB stimulates the proliferation of VSMCs via the activation of Rho A. Rho kinase plays an important role in this process as an effector of Rho A.

The Rho/Rho kinase pathway may be involved in the upregulation of VEGF expression in the diabetic retina, suggesting that fasudil might be useful for the prevention of diabetic retinopathy.

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Objective To investigate the relationship between homeostasis model assessment for insulin resistance (HOMA-R)

Abstract.A 75-year-old male showed combined anterior pituitary hormone deficiency (CPHD). Basal and TRHstimulated PRL levels were undetectable. Basal and GRH-stimulated GH levels were very low, and could barely be measured by means of an ultrasensitive enzyme immunoassay. In addition, basal TSH levels were under the normal limit, and TRH-stimulated TSH secretions were impaired. On the other hand, the secretions of ACTH, LH and FSH remained intact. There was no mutation of Pit-1 gene in this patient, and immunohistochemical studies using human pituitary and the patient's serum showed no positive staining. The HLA types frequently detected in lymphocytic hypophysitis were recognized, supporting the view that the CPHD in this case may be caused by lymphocytic hypophysitis, although magnetic resonance imaging of the pituitary gland showed no specific findings. Interestingly, a high titer of anti-glutamic acid decarboxylase antibody, suggested that the patient suffered from type 1 diabetes mellitus (DM). Five years ago, his thyroid function was normal and the treatment of DM with oral hypoglycemic agent was effective, indicating that the onset of both diseases at least occurred within the last half decade. We report here a rare case of SPIDDM with CPHD which might be caused by lymphocytic hypophysitis.

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