Both cardio- and microvascular complications adversely affect the life quality of patients with diabetes and have been the leading cause of mortality and morbidity in this population. Cardiovascular ...pathologies of diabetes have an effect on microvenules, arteries, and myocardium. It is believed that hyperglycemia is one of the most important metabolic factors in the development of both micro- and macrovascular complications in diabetic patients. Several prominent hypotheses exist to explain the adverse effect of hyperglycemia. One of them is the chronic activation by hyperglycemia of protein kinase (PK)C, a family of enzymes that are involved in controlling the function of other proteins. PKC has been associated with vascular alterations such as increases in permeability, contractility, extracellular matrix synthesis, cell growth and apoptosis, angiogenesis, leukocyte adhesion, and cytokine activation and inhibition. These perturbations in vascular cell homeostasis caused by different PKC isoforms (PKC-α, -β1/2, and PKC-δ) are linked to the development of pathologies affecting large vessel (atherosclerosis, cardiomyopathy) and small vessel (retinopathy, nephropathy and neuropathy) complications. Clinical trials using a PKC-β isoform inhibitor have been conducted, with some positive results for diabetic nonproliferative retinopathy, nephropathy, and endothelial dysfunction. This article reviews present understanding of how PKC isoforms cause vascular dysfunctions and pathologies in diabetes.
The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin ...(HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic β-cell failure. Histopathological analyses combined to
F-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic β-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Poor glycemic control profoundly affects protein expression and the cell signaling action that contributes to glycemic memory and irreversible progression of diabetic nephropathy (DN). We demonstrate ...that SHP-1 is elevated in podocytes of diabetic mice, causing insulin unresponsiveness and DN. Thus, sustained SHP-1 expression caused by hyperglycemia despite systemic glucose normalization could contribute to the glycemic memory effect in DN. Microalbuminuria, glomerular filtration rate, mesangial cell expansion, and collagen type IV and transforming growth factor-β expression were significantly increased in diabetic Ins2
mice compared with nondiabetic Ins2
mice and remained elevated despite glucose normalization with insulin implants. A persistent increase of SHP-1 expression in podocytes despite normalization of systemic glucose levels was associated with sustained inhibition of the insulin signaling pathways. In cultured podocytes, high glucose levels increased mRNA, protein expression, and phosphatase activity of SHP-1, which remained elevated despite glucose concentration returning to normal, causing persistent insulin receptor-β inhibition. Histone posttranslational modification analysis showed that the promoter region of SHP-1 was enriched with H3K4me1 and H3K9/14ac in diabetic glomeruli and podocytes, which remained elevated despite glucose level normalization. Hyperglycemia induces SHP-1 promoter epigenetic modifications, causing its persistent expression and activity and leading to insulin resistance, podocyte dysfunction, and DN.
In the oligotrophic tropical marine environment resources are usually more patchily distributed and less abundant to top predators. Thus, spatial and trophic competition can emerge, especially ...between related seabird species belonging to the same ecological guild. Here we studied the foraging ecology of two sympatric species-brown booby (BRBO) Sula leucogaster (breeding) and red-footed boobies (RFBO) Sula sula (non-breeding)-at Raso islet (Cabo Verde), across different seasons. Sexual segregation was only observed during Jun-Oct, when RFBO were present, with larger females BRBO remaining closer to the colonies, while males and RFBO travelled further and exploited different habitats. Overall, species appeared to prefer areas with specific oceanic features, particularly those related with oceanic currents and responsible for enhancing primary productivity in tropical oceanic areas (e.g. Sea Surface Height and Ocean Mixed Layer Thickness). Female BRBOs showed high foraging-site fidelity during the period of sympatry, while exploiting the same prey species as the other birds. However, during the months of co-existence (Jun.-Oct.), isotopic mixing models suggested that female BRBO would consume a higher proportion of epipelagic fish, whereas female RFBO would consume more squid compared to the other birds, possibly due to habitat-specific prey availability and breeding energy-constraints for BRBO. We conclude that divergent parental roles, environmental conditions, habitat preference and competition could be mechanisms simultaneously underlying sexual segregation for BRBO during a period of co-existence, while inter-specific foraging differences appear to be more affected by habitat preference and different breeding stages. These results support previous statements that BRBO can adapt their foraging ecology to different circumstances of environmental conditions and competition, and that marine physical features play an important role in foraging decisions of boobies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic nephropathy (DN) remains the major cause of end‐stage renal disease (ESRD). We used high‐fat/high‐sucrose (HFHS)‐fed LDLr‐/‐/ApoB100/100 mice with transgenic overexpression of IGFII in ...pancreatic β‐cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega‐3 polyunsaturated fatty acids LCω3FA‐rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)‐derived pro‐resolving lipid mediators, 17‐hydroxy‐DHA (17‐HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS‐fed vehicle‐treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17‐HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LCω3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or ...conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
► Insulin decreases VCAM-1 protein expression in endothelial cells ► Knockout of endothelial insulin receptors increases leukocyte adhesion by 4-fold ► Loss of insulin signaling causes increase in atherosclerotic lesion area by >2-fold
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nephrin, a critical podocyte membrane component that is reduced in diabetic nephropathy, has been shown to activate phosphotyrosine signaling pathways in human podocytes. Nephrin signaling is ...important to reduce cell death induced by apoptotic stimuli. We have shown previously that high glucose level exposure and diabetes increased the expression of SHP-1, causing podocyte apoptosis. SHP-1 possesses two Src homology 2 domains that serve as docking elements to dephosphorylate tyrosine residues of target proteins. However, it remains unknown whether SHP-1 interacts with nephrin and whether its elevated expression affects the nephrin phosphorylation state in diabetes. Here we show that human podocytes exposed to high glucose levels exhibited elevated expression of SHP-1, which was associated with nephrin. Coexpression of nephrin-CD16 and SHP-1 reduced nephrin tyrosine phosphorylation in transfected human embryonic kidney 293 cells. A single tyrosine-to-phenylalanine mutation revealed that rat nephrin Tyr1127 and Tyr1152 are required to allow SHP-1 interaction with nephrin. Overexpression of dominant negative SHP-1 in human podocytes prevented high glucose-induced reduction of nephrin phosphorylation. In vivo, immunoblot analysis demonstrated that nephrin expression and phosphorylation were decreased in glomeruli of type 1 diabetic Akita mice (Ins2+/C96Y) compared with control littermate mice (Ins2+/+), and this was associated with elevated SHP-1 and cleaved caspase-3 expression. Furthermore, immunofluorescence analysis indicated increased colocalization of SHP-1 with nephrin in diabetic mice compared with control littermates. In conclusion, our results demonstrate that high glucose exposure increases SHP-1 interaction with nephrin, causing decreased nephrin phosphorylation, which may, in turn, contribute to diabetic nephropathy.Elevated expression of SHP-1 in diabetic podocytes may potentially interact with nephrin phosphorylation.
Rat nephrin Tyr1127 and Tyr1152 are essential for SHP-1 induced nephrin dephosphorylation under high-glucose conditions.
SHP-1 contributes to nephrin deactivation in podocytes exposed to high glucose levels.
Reduction of SHP-1 may serve as potential therapeutic target to prevent glomerular pathology in diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central ...event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse podocytes exposed to palmitic acid for 24 h followed by an insulin stimulation. Renal function and pathology were evaluated at 25 weeks of age to confirm the DN development. Our results demonstrate that saturated FFA activated the serine/threonine kinases IκB kinase (IKK)β/IκBα and mTORC1/S6K1, but not protein kinase C and c-jun N-terminal kinase, in podocytes and glomeruli of db/db mice. Activation of both kinases promoted serine 307 phosphorylation of IRS1, a residue known to provoke IRS1 inhibition. Using IKK, mTORC1 and ceramide production inhibitors, we were able to blunt IRS1 serine 307 phosphorylation and restore insulin stimulation of Akt. In conclusion, our results indicate that FFA and diabetes contribute to insulin resistance through the activation of IKKβ and S6K1 leading to podocyte dysfunction and DN.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Peripheral artery disease is caused by atherosclerosis of lower extremity arteries leading to the loss of blood perfusion and subsequent critical ischemia. The presence of diabetes mellitus is an ...important risk factor that greatly increases the incidence, the progression and the severity of the disease. In addition to accelerated disease progression, diabetic patients are also more susceptible to develop serious impairment of their walking abilities through an increased risk of lower limb amputation. Hyperglycemia is known to alter the physiological development of collateral arteries in response to ischemia. Deregulation in the production of several critical pro-angiogenic factors has been reported in diabetes along with vascular cell unresponsiveness in initiating angiogenic processes. Among the multiple molecular mechanisms involved in the angiogenic response, protein tyrosine phosphatases are potent regulators by dephosphorylating pro-angiogenic tyrosine kinase receptors. However, evidence has indicated that diabetes-induced deregulation of phosphatases contributes to the progression of several micro and macrovascular complications. This review provides an overview of growth factor alterations in the context of diabetes and peripheral artery disease, as well as a description of the role of phosphatases in the regulation of angiogenic pathways followed by an analysis of the effects of hyperglycemia on the modulation of protein tyrosine phosphatase expression and activity. Knowledge of the role of phosphatases in diabetic peripheral artery disease will help the development of future therapeutics to locally regulate phosphatases and improve angiogenesis.
Pelagic seabirds exhibit plasticity in foraging characteristics in relation to oceanographic conditions. This should be particularly relevant in tropical marine environments where food resources are ...naturally more unpredictable. We studied how inter-annual variations (2013–2018) in tropical oceanographic conditions (driver of oceanic productivity) can influence the spatial and trophic ecology of Cape Verde shearwater (Calonectris edwardsii) during the breeding season. During years of poor oceanographic conditions around the colony, birds engaged in longer trips to West Africa, showed higher spatial and behavioural consistency, and presented a wider isotopic niche. Opposite patterns were generally found for years of good oceanographic conditions, when birds foraged more on their colony surroundings. New foraging areas off West Africa were highlighted as relevant, especially during years of poor environmental conditions. This study highlights the need for long-term studies to assess variation in foraging areas and foraging decisions by seabird populations.
•Despite shifts in oceanographic conditions C. edwardsii showed foraging consistency.•Under poor oceanographic conditions birds increased their spatial consistency.•New foraging hotspots off West Africa were highlighted during this 6-year study.•This key information should support an informed design of MPAs in this tropical area.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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