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Diabetes Complications



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Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function

2018-03-20T12:00:37-07:00

Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern the podocyte cytoskeletal rearrangement remain unclear. Through analyzing the transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO GTPase-activating protein 2a (SRGAP2a) as one of the main hub genes strongly associated with proteinuria and glomerular filtration in type 2 DN. Immunofluorescence staining and Western blot analysis revealed that human and mouse SRGAP2a is primarily localized at podocytes and largely colocalized with synaptopodin. Moreover, podocyte SRGAP2a is downregulated in patients with DN and db/db mice at both the mRNA and the protein level. SRGAP2a reduction is observed in cultured podocytes treated with tumor growth factor-β or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocyte motility through inactivating RhoA/Cdc42 but not Rac1. The protective role of SRGAP2a in podocyte function also is confirmed in zebrafish, in which knockdown of SRGAP2a, a SRGAP2 ortholog in zebrafish, recapitulates podocyte foot process effacement. Finally, increasing podocyte SRGAP2a levels in db/db mice through administration of adenovirus-expressing SRGAP2a significantly mitigates podocyte injury and proteinuria. The results demonstrate that SRGAP2a protects podocytes by suppressing podocyte migration.




Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b

2018-03-20T12:00:38-07:00

Transforming growth factor-β/Smad signaling plays an important role in diabetic nephropathy. The current study identified a novel Smad3-dependent long noncoding RNA (lncRNA) Erbb4-IR in the development of type 2 diabetic nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and specifically induced by advanced glycosylation end products (AGEs) via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN, such as elevated microalbuminuria, serum creatinine, and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR–microRNA (miR)-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3' untranslated region of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased miR-29b and therefore protected the kidney from progressive renal injury in db/db mice and prevented mTECs and mMCs from AGE-induced loss of miR-29b and fibrotic response in vitro. Collectively, we identify that Erbb4-IR is a Smad3-dependent lncRNA that promotes renal fibrosis in T2DN by suppressing miR-29b. Targeting Erbb4-IR may represent a novel therapy for T2DN.




Sirt1: A Guardian of the Development of Diabetic Retinopathy

2018-03-20T12:00:38-07:00

Diabetic retinopathy is a multifactorial disease, and the exact mechanism of its pathogenesis remains obscure. Sirtuin 1 (Sirt1), a multifunctional deacetylase, is implicated in the regulation of many cellular functions and in gene transcription, and retinal Sirt1 is inhibited in diabetes. Our aim was to determine the role of Sirt1 in the development of diabetic retinopathy and to elucidate the molecular mechanism of its downregulation. Using Sirt1-overexpressing mice that were diabetic for 8 months, structural, functional, and metabolic abnormalities were investigated in vascular and neuronal retina. The role of epigenetics in Sirt1 transcriptional suppression was investigated in retinal microvessels. Compared with diabetic wild-type mice, retinal vasculature from diabetic Sirt1 mice did not present any increase in the number of apoptotic cells or degenerative capillaries or decrease in vascular density. Diabetic Sirt1 mice were also protected from mitochondrial damage and had normal electroretinography responses and ganglion cell layer thickness. Diabetic wild-type mice had hypermethylated Sirt1 promoter DNA, which was alleviated in diabetic Sirt1 mice, suggesting a role for epigenetics in its transcriptional suppression. Thus strategies targeted to ameliorate Sirt1 inhibition have the potential to maintain retinal vascular and neuronal homeostasis, providing opportunities to retard the development of diabetic retinopathy in its early stages.




Diabetes Reduces Severity of Aortic Aneurysms Depending on the Presence of Cell Division Autoantigen 1 (CDA1)

2018-03-20T12:00:38-07:00

Diabetes is a negative risk factor for aortic aneurysm, but the underlying explanation for this phenomenon is unknown. We have previously demonstrated that cell division autoantigen 1 (CDA1), which enhances transforming growth factor-β signaling, is upregulated in diabetes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wild-type, CDA1 knockout (KO), apolipoprotein E (ApoE) KO, and CDA1/ApoE double-KO (dKO) mice were rendered diabetic. Whereas aneurysms were not observed in diabetic ApoE KO and wild-type mice, 40% of diabetic dKO mice developed aortic aneurysms. These aneurysms were associated with attenuated aortic transforming growth factor-β signaling, reduced expression of various collagens, and increased aortic macrophage infiltration and matrix metalloproteinase 12 expression. In the well-characterized model of angiotensin II–induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated suprarenal aortic expansion, changes not seen in dKO mice. Furthermore, aortic CDA1 expression was downregulated ~70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 deletion in diabetic mice promotes aneurysm formation provides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.




ELOVL4-Mediated Production of Very Long-Chain Ceramides Stabilizes Tight Junctions and Prevents Diabetes-Induced Retinal Vascular Permeability

2018-03-20T12:00:38-07:00

Tight junctions (TJs) involve close apposition of transmembrane proteins between cells. Although TJ proteins have been studied in detail, the role of lipids is largely unknown. We addressed the role of very long-chain (VLC ≥26) ceramides in TJs using diabetes-induced loss of the blood-retinal barrier as a model. VLC fatty acids that incorporate into VLC ceramides are produced by elongase elongation of very long-chain fatty acids protein 4 (ELOVL4). ELOVL4 is significantly reduced in the diabetic retina. Overexpression of ELOVL4 significantly decreased basal permeability, inhibited vascular endothelial growth factor (VEGF)– and interleukin-1β–induced permeability, and prevented VEGF-induced decrease in occludin expression and border staining of TJ proteins ZO-1 and claudin-5. Intravitreal delivery of AAV2-hELOVL4 reduced diabetes-induced increase in vascular permeability. Ultrastructure and lipidomic analysis revealed that -linked acyl-VLC ceramides colocalize with TJ complexes. Overall, normalization of retinal ELOVL4 expression could prevent blood-retinal barrier dysregulation in diabetic retinopathy through an increase in VLC ceramides and stabilization of TJs.




Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts

2018-02-20T12:50:31-08:00

Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy (DCM), but the mechanism remains largely unclear. We found that diabetic hearts exhibited decreased phosphorylation of total Akt and isoform Akt2 but not Akt1 in wild-type (WT) male FVB mice, which was accompanied by attenuation of Akt downstream glucose metabolic signal. All of these signal changes were not observed in metallothionein cardiac-specific transgenic (MT-TG) hearts. Furthermore, insulin-induced glucose metabolic signals were attenuated only in WT diabetic hearts. In addition, diabetic hearts exhibited increased Akt-negative regulator tribbles pseudokinase 3 (TRB3) expression only in WT mice, suggesting that MT may preserve Akt2 function via inhibiting TRB3. Moreover, MT prevented tert-butyl hydroperoxide (tBHP)–reduced insulin-stimulated Akt2 phosphorylation in MT-TG cardiomyocytes, which was abolished by specific silencing of Akt2. Specific silencing of TRB3 blocked tBHP inhibition of insulin-stimulated Akt2 phosphorylation in WT cardiomyocytes, whereas overexpression of TRB3 in MT-TG cardiomyocytes and hearts abolished MT preservation of insulin-stimulated Akt2 signals and MT prevention of DCM. Most importantly, supplementation of Zn to induce MT preserved cardiac Akt2 signals and prevented DCM. These results suggest that diabetes-inhibited cardiac Akt2 function via TRB3 upregulation leads to aberrant cardiac glucose metabolism. MT preservation of cardiac Akt2 function by inhibition of TRB3 prevents DCM.




DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring

2018-02-20T12:50:31-08:00

Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial-mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes.




Photobiomodulation Inhibits Long-term Structural and Functional Lesions of Diabetic Retinopathy

2018-01-22T12:00:28-08:00

Previous studies demonstrated that brief (3 to 4 min) daily application of light at 670 nm to diabetic rodents inhibited molecular and pathophysiologic processes implicated in the pathogenesis of diabetic retinopathy (DR) and reversed diabetic macular edema in small numbers of patients studied. Whether or not this therapy would inhibit the neural and vascular lesions that characterize the early stages of the retinopathy was unknown. We administered photobiomodulation (PBM) therapy daily for 8 months to streptozotocin-diabetic mice and assessed effects of PBM on visual function, retinal capillary permeability, and capillary degeneration using published methods. Vitamin D receptor and Cyp24a1 transcripts were quantified by quantitative real-time PCR, and the abundance of c-Kit+ stem cells in blood and retina were assessed. Long-term daily administration of PBM significantly inhibited the diabetes-induced leakage and degeneration of retinal capillaries and also significantly inhibited the diabetes-induced reduction in visual function. PBM also inhibited diabetes-induced reductions in retinal Cyp24a1 mRNA levels and numbers of circulating stem cells (CD45/c-Kit+), but these effects may not account for the beneficial effects of PBM on the retinopathy. PBM significantly inhibits the functional and histopathologic features of early DR, and these effects likely are mediated via multiple mechanisms.




Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy

2017-12-20T12:06:27-08:00

AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. In this study, we discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Metformin induced a dose-dependent inhibition of TRPA1-mediated calcium influx. Conversely, in diabetic db/db mice, AMPK activity was impaired in DRG neurons, and this was associated with a concomitant increase in membrane-associated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changes were normalized following treatment with AMPK activators. Moreover, high-glucose exposure decreased activated AMPK levels and increased agonist-evoked TRPA1 currents in cultured DRG neurons, and these effects were prevented by treatment with AMPK activators. Our results identify AMPK as a previously unknown regulator of TRPA1 channels. AMPK modulation of TRPA1 could thus serve as an underlying mechanism and potential therapeutic molecular target in painful diabetic neuropathy.




Deletion of the Akt/mTORC1 Repressor REDD1 Prevents Visual Dysfunction in a Rodent Model of Type 1 Diabetes

2017-12-20T12:06:27-08:00

Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.




Thioredoxin-1 Overexpression in the Ventromedial Nucleus of the Hypothalamus Preserves the Counterregulatory Response to Hypoglycemia During Type 1 Diabetes in Male Rats

2017-12-20T12:06:27-08:00

We previously showed that the glutathione precursor, N-acetylcysteine (NAC), prevented hypoglycemia-associated autonomic failure (HAAF) and impaired activation of ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons by low glucose after recurrent hypoglycemia (RH) in nondiabetic rats. However, NAC does not normalize glucose sensing by VMH GI neurons when RH occurs during diabetes. We hypothesized that recruiting the thioredoxin (Trx) antioxidant defense system would prevent HAAF and normalize glucose sensing after RH in diabetes. To test this hypothesis, we overexpressed Trx-1 (cytosolic form of Trx) in the VMH of rats with streptozotocin (STZ)-induced type 1 diabetes. The counterregulatory response (CRR) to hypoglycemia in vivo and the activation of VMH GI neurons in low glucose using membrane potential sensitive dye in vitro was measured before and after RH. VMH Trx-1 overexpression normalized both the CRR and glucose sensing by VMH GI neurons in STZ rats. VMH Trx-1 overexpression also lowered the insulin requirement to prevent severe hyperglycemia in STZ rats. However, like NAC, VMH Trx-1 overexpression did not prevent HAAF or normalize activation of VMH GI neurons by low glucose in STZ rats after RH. We conclude that preventing HAAF in type 1 diabetes may require the recruitment of both antioxidant systems.




Evidence That Differences in Fructosamine-3-Kinase Activity May Be Associated With the Glycation Gap in Human Diabetes

2017-12-20T12:06:27-08:00

The phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors but can be measured as the glycation gap (GGap). This GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). We hypothesized that variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the GGap. We measured erythrocyte FN3K concentrations and enzyme activity in a population dichotomized for a large positive or negative GGap. FN3K protein was higher and we found a striking threefold greater activity (323%) at any given FN3K protein level in the erythrocytes of the negative-GGap group compared with the positive-GGap group. This was associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). We conclude that FN3K may play a key role in the GGap and thus diabetes complications such that FN3K may be a potential predictor of the risk of diabetes complications. Pharmacological modifications of its activity may provide a novel approach to their prevention.