Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat.

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model.

Minimal Change Disease Following the Pfizer-BioNTech COVID-19 Vaccine.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

A novel mutation in the NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (Ndufa4) gene links mitochondrial dysfunction to the development of diabetes in a rodent model.

The mechanisms underlying diabetes remain unresolved. The Cohen diabetic rat represents a model of diet-induced diabetes, in which the disease is induced after exposure to a diabetogenic diet (DD) in the diabetes-sensitive (CDs/y) but not in the -resistant (CDr/y) strain. Diet imposes a metabolic strain that leads to diabetes in the appropriate genetic background. We previously identified, through whole-genome linkage analysis, a diabetes-related quantitative trait locus on rat chromosome 4 (RNO4), which incorporates NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (Ndufa4), a nuclear gene that affects mitochondrial function. Here, we sequenced the gene and found a major deletion in CDs/y that leads to lack of expression of the NDUFA4 protein that has been reported to be involved in the activities of mitochondrial complexes I and IV. In the absence of NDUFA4 in the diabetic CDs/y on DD, complex I activity is reduced in comparison to that in nondiabetic CDs/y on regular diet and CDr/y on either diet; complex IV activity is reduced in both strains provided DD, and thus as a result of diet and unrelated to the gene mutation. ATP fails to increase in diabetic CDs/y in response to DD, in comparison to nondiabetic CDr/y on DD. Plasma malondialdehyde levels are elevated in CDs/y on DD, whereas SOD1 and SOD2 levels fail to increase, indicating increased oxidative stress and inability of the pancreas to generate an appropriate antioxidative stress response. These findings suggest that the Ndufa4 mutation in CDs/y on DD is directly associated with mitochondrial dysfunction, which we attribute to the lack of expression of NDUFA4 and to diet, and which prevents the anticipated increase in ATP production. The resulting enhanced oxidative stress impairs the ability of the pancreas to secrete insulin, leading to the development of diabetes. This is the first demonstration of an inherited mutation in a nuclear gene that adversely affects mitochondrial function and promotes diet-induced diabetes.