Migrated guidewire: an unusual cause for recurrent aural polyps

Aural polyps are secondary to multiple ear pathologies, most commonly inflammatory or cholesteatoma related. Here, we present a rare case of recurrent aural polyps caused by guidewire migration into the middle ear with serious systemic complications and our attempts at removal

X-Box Binding Protein 1 Is Essential for Insulin Regulation of Pancreatic α-Cell Function

Patients with type 2 diabetes (T2D) often exhibit hyperglucagonemia despite hyperglycemia, implicating defective α-cell function. Although endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in α-cell biology remains unclear. X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), and its deficiency in β-cells has been reported to impair insulin secretion, leading to glucose intolerance. To evaluate the role of XBP1 in α-cells, we created complementary in vivo (α-cell–specific XBP1 knockout [αXBPKO] mice) and in vitro (stable XBP1 knockdown α-cell line [αXBPKD]) models. The αXBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. αXBPKD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun NH2-terminal kinase. Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) (pY896) and phosphorylation of Akt while enhancing serine phosphorylation (pS307) of IRS1. Consequently, the αXBPKD cells exhibited blunted suppression of glucagon secretion after insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion

Insulin Signaling Regulates Mitochondrial Function in Pancreatic β-Cells

Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in β-cells that included glucokinase (GK), and the pro-apoptotic protein, BADS. Mitochondria isolated from β-cells derived from β-cell specific insulin receptor knockout (βIRKO) mice exhibited reduced BADS, GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in βIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BADS. The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in βIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for β-cell dysfunction in type 2 diabetes

Impaired Thermogenesis and Adipose Tissue Development in Mice with Fat-Specific Disruption of Insulin and IGF-1 Signalling

Insulin and insulin-like growth factor 1 (IGF-1) play important roles in adipocyte differentiation, glucose tolerance and insulin sensitivity. Here, to assess how these pathways can compensate for each other, we created mice with a double tissue-specific knockout of insulin and IGF-1 receptors to eliminate all insulin/IGF-1 signaling in fat. These FIGIRKO mice had markedly decreased white and brown fat mass and were completely resistant to high fat diet (HFD) induced obesity and age- and HFD-induced glucose intolerance. Energy expenditure was increased in FIGIRKO mice despite a >85% reduction in brown fat mass. However, FIGIRKO mice were unable to maintain body temperature when placed at $4^{\circ}C$. Brown fat activity was markedly decreased in FIGIRKO mice but was responsive to $\beta3$-receptor stimulation. Thus, insulin/IGF-1 signaling has a crucial role in the control of brown and white fat development, and, when disrupted, leads to defective thermogenesis and a paradoxical increase in basal metabolic rate

Increasing Glucose 6-Phosphate Dehydrogenase Activity Restores Redox Balance in Vascular Endothelial Cells Exposed to High Glucose

Previous studies have shown that high glucose increases reactive oxygen species (ROS) in endothelial cells that contributes to vascular dysfunction and atherosclerosis. Accumulation of ROS is due to dysregulated redox balance between ROS-producing systems and antioxidant systems. Previous research from our laboratory has shown that high glucose decreases the principal cellular reductant, NADPH by impairing the activity of glucose 6-phosphate dehydrogenase (G6PD). We and others also have shown that the high glucose-induced decrease in G6PD activity is mediated, at least in part, by cAMP-dependent protein kinase A (PKA). As both the major antioxidant enzymes and NADPH oxidase, a major source of ROS, use NADPH as substrate, we explored whether G6PD activity was a critical mediator of redox balance. We found that overexpression of G6PD by pAD-G6PD infection restored redox balance. Moreover inhibition of PKA decreased ROS accumulation and increased redox enzymes, while not altering the protein expression level of redox enzymes. Interestingly, high glucose stimulated an increase in NADPH oxidase (NOX) and colocalization of G6PD with NOX, which was inhibited by the PKA inhibitor. Lastly, inhibition of PKA ameliorated high glucose mediated increase in cell death and inhibition of cell growth. These studies illustrate that increasing G6PD activity restores redox balance in endothelial cells exposed to high glucose, which is a potentially important therapeutic target to protect ECs from the deleterious effects of high glucose

The Islet Estrogen Receptor-α Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes

The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO−/−), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO−/− mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO−/− mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO−/− mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury

The islet estrogen receptor-alpha is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes

The female steroid, 17beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ERalpha, ERbeta, and the G-protein coupled ER (GPER). Using a pancreas-specific ERalpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERalphaKO (-)/(-)), we previously reported that islet ERalpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERalpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ERalpha to beta-cell survival in vivo, without the contribution of ERalpha in other tissues is still unclear. Using the PERalphaKO (-)/(-) mouse, we show that ERalpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERalpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERalphaKO (-)/(-) mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PERalphaKO (-)/(-) mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ERalpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERalpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERalpha expression acts to naturally protect beta-cells against oxidative injury

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulin-resistant states

Ablation of TRIP-Br2, a novel regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance

SUMMARY Obesity develops due to altered energy homeostasis favoring fat storage. Here we describe a novel transcription co-regulator for adiposity and energy metabolism, TRIP-Br2 (also called SERTAD2). TRIP-Br2 null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of the knockout (KO) mice exhibited greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The KOs also exhibit higher energy expenditure due to increased adipocyte thermogenesis and oxidative metabolism by up-regulating key enzymes in respective processes. Our data show for the first time that a cell cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data together with the observation that TRIP-BR2 expression is selectively elevated in visceral fat in obese humans suggests that this transcriptional co-regulator is a novel therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function