It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

The morbidity and mortality associated with diabetes is the result of the myriad complications related to the disease One of the most explored hypotheses to explain the onset of complications is a hyperglycemia-induced increase in oxidative stress Reactive oxygen species (ROS) are produced by oxidative phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase (NADPH), xanthine oxidase, the uncoupling of lipoxygenases, cytochrome P450 monooxygenases, and glucose autoxidation Once formed, ROS deplete antioxidant defenses, rendering the affected cells and tissues more susceptible to oxidative damage Lipid, DNA, and protein are the cellular targets for oxidation, leading to changes in cellular structure and function Recent evidence suggests ROS are also important as second messengers in the regulation of intracellular signaling pathways and, ultimately, gene expression This review explores the production of ROS and the propagation and consequences of oxidative stress in diabetes

The role of oxidative stress in diabetic complications.

Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.

/pdf/inflammation-in-diabetic-nephropathy-1e3jrnzjaz.pdf

Inflammation in Diabetic Nephropathy

https://repository.upenn.edu/cgi/viewcontent.cgi?article=1016&context=dental_papers

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways.

The epidemics of insulin resistance (IR) and type 2 diabetes (T2D) affect the first world as well as less-developed countries, and now affect children as well. Persistently elevated oxidative stress and inflammation (OS/Infl) precede these polygenic conditions. A hallmark of contemporary lifestyle is a preference for thermally processed nutrients, replete with pro-OS/Infl advanced glycation endproducts (AGEs), which enhance appetite and cause overnutrition. We propose that chronic ingestion of oral AGEs promotes IR and T2D. The mechanism(s) involved in these findings were assessed in four generations of C57BL6 mice fed isocaloric diets with or without AGEs [synthetic methyl-glyoxal-derivatives (MG+)]. F3/MG+ mice manifested increased adiposity and premature IR, marked by severe deficiency of anti-AGE advanced glycation receptor 1 (AGER1) and of survival factor sirtuin 1 (SIRT1) in white adipose tissue (WAT), skeletal muscle, and liver. Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. These features were absent in F3/MG− mice. MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-κB) p65 acetylation. Gene modulation revealed these effects to be coregulated by AGER1 and SIRT1. Thus, prolonged oral exposure to MG-AGEs can deplete host-defenses AGER1 and SIRT1, raise basal OS/Infl, and increase susceptibility to dysmetabolic IR. Because exposure to AGEs can be decreased, these insights provide an important framework for alleviating a major lifestyle-linked disease epidemic.

https://www.pnas.org/content/pnas/109/39/15888.full.pdf

Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1.

Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells

Highly reactive dicarbonyl compounds such as methylglyoxal (MG) form through the glycation reaction, causing so-called carbonyl stress under diabetic conditions. It has been hypothesized that MG potentially influences cell functions by itself in diabetic tissues in addition to its action as a precursor of several AGEs. We therefore investigated whether MG activated MAP kinase (MAPK) superfamily including JNK and p38 MAPK that was known to be activated in response to various cellular stresses, using primary culture of rat mesangial cells (RMC). Immunoblot analysis of RMC lysate revealed that MG induced phosphorylation and activation of JNK. On the other hand, p38 MAPK, another member of MAPK superfamily, was also activated in RMC by the incubation with MG. These findings suggest a potential role of MG-induced activation of MAPK superfamily signaling pathways in the development of diabetic complications including nephropathy.

Activation of MAP kinase superfamily signaling pathways by methylglyoxal

It has been suggested that decrease in the number of glomerular cells, including mesangial cells, occurs in the process of developing diabetic glomerulosclerosis. On the other hand, formation of methylglyoxal (MG), a highly reactive dicarbonyl compound, is accelerated through several pathways including the glycation reaction under diabetic conditions, presumably contributing to tissue injury in diabetes. We therefore examined if MG was capable of inducing cell death by apoptosis using cultured rat mesangial cells (RMC). Incubation of RMC with MG resulted in the dose-dependent induction of apoptosis, which was evaluated by both TUNEL analysis and detection of DNA laddering. These findings suggest that MG may play a potential role in the development of diabetic glomerulosclerosis through apoptosis of glomerular mesangial cells.

Osamu Muramoto

Papers

Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells

Activation of MAP kinase superfamily signaling pathways by methylglyoxal

Methylglyoxal induces apoptosis in rat mesangial cells