By Max Bingham, PhD
Krüppel-Like Factor 6 and Podocyte Loss in Diabetic Kidney Disease
Podocyte-specific Krüppel-like factor 6, or KLF6, may play an important role in preventing mitochondrial injury and podocyte loss in diabetic kidney disease, according to Horne et al. (p. 2420). The conclusions come from a study of mice with a specific knockdown for podocyte-specific KLF6 and their respective controls both with and without streptozotocin-induced diabetes. The authors also examined isolated human podocyte cells under a series of conditions and quantified KLF6 protein expression in human kidney biopsies. They found that under conditions of diabetes, loss of KLF6 resulted in signs of diabetic kidney disease (the mice would not normally have had this outcome) and that KLF6 loss reduced expression of synthesis of cytochrome c oxidase 2 (SCO2), which is a key enzyme involved in respiratory chain function. The result of the loss increased mitochondrial injury, which in turn activated apoptosis. In human podocytes, they found under conditions representing diabetes (high glucose) that overexpression of KLF6 significantly reduced mitochondrial injury and apoptosis. In human kidney biopsies, reduction of KLF6 expression in glomerular and podocyte-specific cells was correlated with the progression of diabetic kidney disease as estimated by a renal pathologist. Although noting some limitations with the study and that further work will be needed, the authors suggest that KLF6 appears to be important in preventing podocyte loss and eventually may explain some of the gene expression changes involved in the development of diabetic kidney disease—and that means targets for therapy. Author Sandeep K. Mallipattu told Diabetes: “In recent years, as a community, we have made significant advances in understanding the critical role of mitochondrial dysfunction in diabetic kidney disease, the most common cause of chronic kidney disease in the U.S. This study demonstrates that KLF6, a key regulator of gene expression, is necessary to sustain mitochondrial function under diabetic conditions in the kidney. We hope these findings contribute to the identification of novel therapeutic targets for diabetic kidney disease in the future.”
Targeting Effector T Cells Extends Remission, Reverses New-Onset Type 1 Diabetes (in Mice)
Targeting effector T cells with an approach called “p53 potentiation with checkpoint abrogation” (PPCA) appears to preserve islet β-cells in new-onset type 1 diabetes, according to Carroll et al. (p. 2319). And, crucially, the approach appears not to affect other types of T cells, meaning that the wider immune system is not affected with the treatment approach. As a result, the authors suggest there is a basis for a potential immune intervention in type 1 diabetes. The conclusions come from a series of experiments in NOD mice that explored and tried to manipulate a key characteristic of effector T cells, namely that such cells are naturally poised on the edge of apoptosis due to DNA damage that occurs on activation and the subsequent damage that occurs to p53 regulation of the cell cycle. The authors hypothesized that small molecular inhibitors (previously discovered) might be able to tip such cells into apoptosis through potentiation of p53. They found that the PPCA combination of inhibitors they used (termed WEE1i and MDM2i) resulted in mice with new-onset diabetes capable of maintaining glycemic control for 50% of the days they were involved in the experiment. In comparison, untreated mice could only maintain control for 5%. When delivered at onset, the inhibitors significantly reduced diabetogenic effector T cells, did not affect other T cells, prolonged remission, and preserved functional islets. The authors also found that following islet transplantation into mice, PPCA treatment also protected the new islets from autoreactive T cells. Indeed, when challenged with such cells, all but one mouse receiving the PPCA treatment were protected against diabetes. In comparison, in mice that received vehicle, all but one developed diabetes within 30 days.
IgM for Prevention/Reversal of Type 1 Diabetes: In Vivo Mouse Studies
A previously unknown pathological process may exist in type 1 diabetes. It seems that natural IgM can protect against development of type 1 diabetes and, according to Wilson et al. (p. 2349), may hold the key to reversing the disease. Specifically, the authors suggest that natural IgM appears to be important in the regulation of B lymphocytes, connecting circulating IgM to thymic B-cell and regulatory T-cell (Treg) development. That, in turn, promotes normal immune homeostasis. With further work, they suggest that IgM might hold the key to immune therapy that supports defective immune systems, rather than the current poorly performing approaches that try to suppress immunity. The conclusions come from a series of experiments centered on the NOD mouse model in which the effects of IgM were assessed in terms of reversing diabetes. IgM was purified from serum of other NOD or Swiss Webster mice. Flow cytometry and histology approaches were then used to uncover the effects of the treatments. According to the authors, they found that treatment of NOD mice with purified IgM from the Swiss Webster mice (nIgMSW) managed to reverse new-onset diabetes and eliminated B lymphocytes and enhanced Treg numbers. In contrast, IgM from NOD mice did not restore endogenous regulation or reverse the diabetes. As a result, the authors say this represents a previously unknown process that is occurring in type 1 diabetes. Crucially, their last experiment involved IgM derived from a human donor, which they found was highly effective at preventing diabetes in NOD mice, reportedly for more than 12 weeks after treatment. In this case, the mice experienced moderate normalization of B lymphocytes and the expansion of Tregs. On the basis of the results, they carefully explain how IgM might be an alternative to current immunosuppressant approaches and might possibly translate as a clinical approach to preventing or reversing type 1 diabetes.
β-Cell Workload Explains Proinsulin-to-Insulin Ratio. But Does That Explain Insulin Resistance?
Using a rather drastic approach, partial pancreatectomy, Mezza et al. (p. 2389) examine the effects of a substantial reduction in pancreatic islet mass as a model to understand whether β-cell dysfunction or increased demands on β-cells for insulin explains the increased ratio of proinsulin to insulin in type 2 diabetes—a key feature that may explain insulin resistance in the disease. To investigate, the authors recruited nine patients due to undergo pancreatoduodenectomy due to ampullary carcinoma. Following recruitment, the patients (who did not have diabetes) then underwent a series of clamp tests 1 week prior to the surgical procedures. These were to assess insulin, glucose, and response to a mixed-meal test. Approximately 40 days later, after recovery, they then underwent the same clamp tests with a 50% reduced size of pancreas. Following the procedure, there were no changes observed in fasting proinsulin-to-insulin ratio, but fold-change in proinsulin-to-insulin ratios increased after the meal test in comparison to the same test results before surgery. Despite the low numbers of patients involved, the authors characterized about half of the subjects as insulin sensitive and the other half as insulin resistant. They found that whole-body insulin resistance appeared to be associated with underlying defects in proinsulin secretion, which they say only becomes detectable in the presence of increased insulin secretion demand. Author Andrea Giaccari commented: “Though all our subjects received the same 50% pancreatectomy, not all of them became diabetic after surgery. There are many reasons for this difference. Here, we reveal that some β-cell defects must be present even before surgery, accompanied and unmasked by the presence of insulin resistance. To really understand the pathogenesis of type 2 diabetes, research should be oriented towards examining the earliest phases of the disease. Our approach is just a shortcut to obtain changes in days, rather than in years.”