Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance.

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.

Clinical effects of conjunctiva-Müller muscle resection in anophthalmic ptosis.

PURPOSE: To evaluate the clinical effects of conjunctiva-Muller muscle resection through conjunctival incision in anophthalmic patients with mild ptosis. METHODS: Conjunctiva-Müller muscle resection was performed by one surgeon in 8 patients (8 eyes) who had received evisceration or enucleation and responded to 10% phenylephrine solution to correct ptosis. The average age of the patients was 35.87+/-13.4 years. Ptosis was seen from 1 to 34 months after evisceration or enucleation. The preoperative MRD 1 was -2 to 0.5 mm (average: -0.25+/-1.10 mm) and the difference of MRD 1 between before and after 10% phenylephrine use was 2.56+/-0.98 mm. The Müller muscle was resected 7.5 to 9 mm through conjunctival incision during surgery to match the MRD 1 of sound eye. Mean follow-up period after the operation was 2 to 16 months (average: 8.1 months). RESULTS: Postoperatively, the MRD 1 increased by 1.81+/-0.88 mm on the average, corresponding to the improvement in lid elevation after the use of 10% phenylephrine performed before resection. Surgery was successful in most patients, and postoperative difference in MRD 1 was less than 1 mm from the sound eye. No special postoperative complication was observed. CONCLUSIONS: Conjunctiva-Müller muscle resection is one of the effective methods of correcting mild ptosis in anophthalmic patients.

Beta ig-h3 promotes renal proximal tubular epithelial cell adhesion, migration and proliferation through the interaction with alpha3beta1 integrin.

Betaig-h3 (betaig-h3) is a secretory protein composed of fasciclin I-like repeats containing sequences that allows binding of integrins and glycosaminoglycans in vivo. Expression of betaig-h3 is responsive to TGF-Beta and the protein is found to be associated with extracellular matrix (ECM) molecules, implicating betaig-h3 as an ECM adhesive protein of developmental processes. We previously observed predominant expression of betaig-h3 expression in the basement membrane of proximal tubules of kidney. In this study, the physiological relevance of such localized expression of betaig-h3 was examined in the renal proximal tubular epithelial cells (RPTEC). RPTEC constitutively expressed betaig-h3 and the expression was dramatically induced by exogenous TGF-Beta1 treatment. betaig-h3 and its second and fourth FAS1 domain were able to mediate RPTEC adhesion, spreading and migration. Two known alpha3beta1 integrin-interaction motifs including aspartatic acid and isoleucine residues, NKDIL and EPDIM in betaig-h3 were responsible to mediate RPTEC adhesion, spreading, and migration. By using specific antibodies against integrins, we confirmed that alpha3beta1 integrin mediates the adhesion and migration of RPTECs on betaig-h3. In addition, it also enhanced proliferation of RPTECs through NKDIL and EPDIM. These results indicate that betaig-h3 mediates adhesion, spreading, migration and proliferation of RPTECs through the interaction with alpha3beta1 integrin and is intimately involved in the maintenance and the regeneration of renal proximal tubular epithelium.

Elevation of urinary betaig-h3, transforming growth factor-beta-induced protein in patients with type 2 diabetes and nephropathy.

Transforming growth factor-beta (TGF-beta) is a pro-sclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. betaig-h3 is an extracellular matrix protein which is induced in many cells by TGF-beta. This study examined urinary betaig-h3 excretion in diabetic patients with elevated urinary albumin excretion and the clinical application of urinary betaig-h3 as a marker of diabetic nephropathy. Urinary and serum betaig-h3 levels were determined by enzyme-linked immunosorbent assay in 163 type 2 diabetic patients and 101 healthy control subjects of comparable age and weight. The ratio of urinary betaig-h3 and TGF-beta to creatinine was analyzed in patients with different degree of nephropathy. The betaig-h3 to creatinine ratio in urine was elevated in all groups of type 2 diabetics with normoalbuminuria (101.6 +/- 9.27), microalbuminuria (120.2 +/- 14.48), and overt proteinuria (146.3 +/- 16.34), when compared with control subjects (64.8 +/- 7.14) (P < 0.01). There was a positive correlation between urinary betaig-h3 and TGF-beta excretion rate and a positive correlation between urinary betaig-h3 and albumin excretion rate (AER). These data show that urinary levels of betaig-h3 are elevated in type 2 diabetic patients with nephropathy and may be used as a marker of diabetic nephropathy.

Hydrophilic acrylic intraocular lens optic opacification in a diabetic patient.

PURPOSE: To report clinicopathologic and ultrastructural feature of one opacified hydrophilic acrylic intraocular lens (IOL) explanted from a diabetic patient. METHODS: A 48-year-old man underwent trans pars plana vitrectomy and phacoemulsification with implantation of a hydrophilic acrylic lens OS in November 2008. The patient complained of a marked decrease in visual acuity in May 2009 as a result of a milky opalescence of the IOL. Intraocular lens explantation and exchange were performed in August 2009, and the explanted IOL was submitted to our center for detailed pathologic, histochemical and ultrastructural evaluation. It was stained by the von Kossa method for calcium, and also underwent scanning electron microscopy and energy dispersive radiograph spectroscopy to ascertain the nature of the deposits leading to opacification. RESULTS: Opacification of the IOL was found to be the cause of the decreased visual acuity. The opacification involved only the IOL optic, and the haptics was clear. Histochemical and ultrastructural analyses revealed that the opacity was caused by deposition of calcium and phosphate within the lens optic. CONCLUSION: We believe this report of calcification of the Akreos(®) MI-60 IOL is of clinicopathological importance. Long-term follow-up of diabetic patients implanted with this IOL should be maintained by surgeons and manufacturers.

Prevalence of Diabetes Mellitus and Prediabetes in Dalseong-gun, Daegu City, Korea.

BACKGROUND: The aim of the present study was to determine the population-based prevalence of diabetes mellitus (DM) and prediabetes in a rural district of Daegu City, Korea. METHODS: Between August and November 2003, a community-based health survey of adults aged 20 years and older was performed in the rural district of Dalseong-gun in Daegu City. A total of 1,806 of all eligible individuals agreed to participate. Fasting plasma glucose was measured in all participants. Two hour oral glucose tolerance was measured in the 1,773 participants for whom there was neither an established diagnosis of DM nor evidence of DM according to fasting glucose levels. The prevalence of DM and prediabetes was determined according to the 2003 criteria of the American Diabetes Association. Subjects with prediabetes were classified into one of three categories of glucose intolerance: isolated impaired fasting glucose (IFG); isolated impaired glucose tolerance (IGT); or combined IFG and IGT. RESULTS: The prevalence of DM was 12.2%. The highest prevalence rates were observed in subjects in their seventies. A total of 34.7% of all subjects who were assigned a diagnosis of DM in the present study had not been diagnosed previously. The prevalence of prediabetes was 22.7%. The highest prevalence rates were observed in subjects in their fifties. CONCLUSION: The present study identified prevalence rates of 12.2% for DM (age-standardized prevalence rate [ASR], 6.8%), and 22.7% for prediabetes (ASR 18.5%). These results emphasize the need for community health promotion strategies to prevent or delay the onset of DM in individuals with prediabetes.

Factors that Affect Medication Adherence in Elderly Patients with Diabetes Mellitus.

BACKGROUND: This study was conducted to evaluate the factors affecting medication adherence in geriatric diabetic patients treated at private clinics and tertiary hospitals. We compared the factors affecting medication adherence between these two patient groups. METHODS: We included 108 diabetic patients older than 65 years treated at one tertiary hospital and 157 patients older than 65 years treated at two private clinics. We conducted an interview survey based on the Health Belief Model, and used a questionnaire that included the self-efficacy variable. For the medication adherence, Morisky's self-report was used. RESULTS: The medication adherence based on Morisky's self-report was significantly higher in tertiary hospital patients (61.1%) compared to private clinic patients (43.2%) (P < 0.01). The results showed that drug storage and self-efficacy were factors affecting adherence to medication in tertiary hospital patients (P < 0.05). The adherence was high in cases of proper drug storage (odds ratio [OR], 5.401) and in cases with high self-efficacy (OR, 13.114). In private clinic patients, financial level (P < 0.05), recognition of the seriousness of diabetes complications (P < 0.05) and self-efficacy (P < 0.01) were associated with medication adherence. The medication adherence was significantly lower in patients whose financial state were moderate than those with lower (OR, 0.410), and medication adherence was significantly higher in patients who had higher perceived severity (OR, 2.936) and in patients with higher self-efficacy (OR, 4.040). CONCLUSION: Different strategies should be used to increase medication adherence in geriatric diabetic patients, depending on institutions whether they are treated.

TGF-beta-induced protein beta ig-h3 is upregulated by high glucose in vascular smooth muscle cells.

TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule that interacts with integrins. Because TGF-beta plays an important role in diabetic complications and beta ig-h3 serves as a cell substrate, we hypothesized that diabetic conditions might increase beta ig-h3 synthesis in vascular smooth muscle cells (VSMCs), which may subsequently contribute to the pathogenesis of diabetic angiopathy. The concentrations of beta ig-h3 and TGF-beta were measured in conditioned media using an enzyme-linked immunosorbent assay. An immunohistochemical study showed that beta ig-h3 was expressed in the VSMCs and the matrix of rat aortas. TGF-beta stimulated beta ig-h3 production, and high glucose induced beta ig-h3 as well as TGF-beta production in the VSMCs. The high glucose-induced beta ig-h3 expression was almost entirely blocked by an anti-TGF-beta antibody. beta ig-h3 protein mediated the adhesion, spreading, migration, and proliferation of rat VSMCs. These results suggest that the high glucose-induced beta ig-h3 in VSMCs regulates VSMC functions and may play an important role in diabetic angiopathy.

Expression of TGF-beta-induced matrix protein betaig-h3 is up-regulated in the diabetic rat kidney and human proximal tubular epithelial cells treated with high glucose.

BACKGROUND: betaig-h3 is an extracellular matrix protein whose expression in several cell types is greatly increased by transforming growth factor-beta (TGF-beta). TGF-beta is believed to be involved in the development of diabetic nephropathy and thus we have assessed the possibility that betaig-h3 may be a downstream molecule in this pathogenic process. METHODS: Immunoblotting and immunohistochemistry were done using an antibody against mouse betaig-h3 protein. betaig-h3 and TGF-beta concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Cell adhesion and migration were assessed by measuring activity of N-acetyl-beta-d-glucosaminidase and using a transwell plate, respectively. RESULTS: Immunohistochemistry revealed that betaig-h3 occurs mainly in the basement membrane of proximal tubules, particularly the S3 segment but also to lesser extents in the basement membranes of the cortical thick ascending limb cells and the parietal glomerular epithelial cells in Bowman's capsule. Immunoblotting revealed that approximately 68 kD bands were seen only in the cortex + the outer stripe of the outer medulla. Rats with streptozotocin (STZ)-induced diabetes exhibited a marked and sustained increase in renal betaig-h3 abundance. This was mirrored by urinary betaig-h3 levels. In vitro experiments with human primary renal proximal tubular epithelial cells revealed that their expression of betaig-h3 was greatly increased by either TGF-beta or glucose. High glucose levels also stimulated TGF-beta production by renal proximal tubular epithelial cells and the high glucose-induced betaig-h3 expression was almost completely blocked by anti-TGF-beta antibody. betaig-h3 mediated renal proximal tubular epithelial cells adhesion and migration. CONCLUSION: betaig-h3 may be important in the development of diabetic nephropathy. Furthermore, the level of urinary betaig-h3 may be useful as an early marker reflecting disease onset and progression.