Metabolic and Non-metabolic Roles of Pyruvate Kinase M2 Isoform in Diabetic Retinopathy

Rajala, Ammaji; Soni, Krutik; Rajala, Raju V S

doi:10.1038/s41598-020-64487-2

Cited by 12 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study reported a decrease in retinal PKM2 expression in 10-week-old type 2 diabetic obese db/db mice with no change in the other isoform, PKM1. Interestingly, the same study could not detect a change in PKM1 or PKM2 in type 1 diabetic mouse retinas from STZ diabetic mice that were diabetic for 6 weeks but PDH was increased in these mice ( 39 ).…”

Section: Discussionmentioning

confidence: 91%

Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice

Shosha

Qin

Lemtalsi

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is the leading cause of vision loss in working age adults. Understanding the retinal metabolic response to circulating high glucose levels in diabetic patients is critical for development of new therapeutics to treat DR. Measuring retinal metabolic function using the Seahorse analyzer is a promising technique to investigate the effect of hyperglycemia on retinal glycolysis and mitochondrial respiration. Here, we analyzed the retinal metabolic function in young and old diabetic and control mice. We also compared the expression of key glycolytic enzymes between the two groups. The Seahorse XF analyzer was used to measure the metabolic function of retina explants from young and old type 1 diabetic Akita (Ins2Akita) mice and their control littermates. Rate-limiting glycolytic enzymes were analyzed in retina lysates from the two age groups by Western blotting. Retinas from young adult Akita mice showed a decreased glycolytic response as compared to control littermates. However, this was not observed in the older mice. Western blotting analysis showed decreased expression of the glycolytic enzyme PFKFB3 in the young Akita mice retinas. Measurement of the oxygen consumption rate showed no difference in retinal mitochondrial respiration between Akita and WT littermates under normal glucose conditions ex vivo despite mitochondrial fragmentation in the Akita retinas as examined by electron microscopy. However, Akita mice retinas showed decreased mitochondrial respiration under glucose-free conditions. In conclusion, diabetic retinas display a decreased glycolytic response during the early course of diabetes which is accompanied by a reduction in PFKFB3. Diabetic retinas exhibit decreased mitochondrial respiration under glucose deprivation.

show abstract

Section: Discussionmentioning

confidence: 91%

Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice

Shosha

Qin

Lemtalsi

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…The FAO activity assay is based on the oxidation of octanoyl-CoA, which is coupled to NADH-dependent reduction of INT to INT-formazan, and exhibits an absorption maximum at 492 nm [ 59 ]. NAD, NADH, NADP, and NADPH levels were measured as described [ 60 ]. ATP concentration was determined using an EnzyLight™ ATP Assay Kit from BioAssay Systems (Hayward, CA).…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor 1 receptor mediates photoreceptor neuroprotection

et al. 2022

Self Cite

View full text Add to dashboard Cite

Insulin-like growth factor I (IGF-1) is a neurotrophic factor and is the ligand for insulin-like growth factor 1 receptor (IGF-1R). Reduced expression of IGF-1 has been reported to cause deafness, mental retardation, postnatal growth failure, and microcephaly. IGF-1R is expressed in the retina and photoreceptor neurons; however, its functional role is not known. Global IGF-1 KO mice have age-related vision loss. We determined that conditional deletion of IGF-1R in photoreceptors and pan-retinal cells produces age-related visual function loss and retinal degeneration. Retinal pigment epithelial cell-secreted IGF-1 may be a source for IGF-1R activation in the retina. Altered retinal, fatty acid, and phosphoinositide metabolism are observed in photoreceptor and retinal cells lacking IGF-1R. Our results suggest that the IGF-1R pathway is indispensable for photoreceptor survival, and activation of IGF-1R may be an essential element of photoreceptor and retinal neuroprotection.

show abstract

“… 47 Reductions in PKM2 protein expression can impair transcriptional co-activator activity, leading to reduced Pde6β expression, whereas a loss of Pde6β can impair the function of rod photoreceptors and compromise normal retinal anabolic activity. 47–49 Rajala et al 50 employed a mouse model of type 2 diabetic mouse model to explore the importance of PKM2 in the context of DR, and found that retinal PKM2 protein levels declined in db/db mice whereas PKM1 expression was unaffected, with corresponding reductions in retinal Pde6β expression and the impairment of rod cell function. Retinal pyruvate kinase activity increased in these db/db mice, while the redox/reduction ratio declined.…”

Section: The Role Of Pkm2 In Diabetic Retinopathymentioning

confidence: 99%

The Role of PKM2 in Diabetic Microangiopathy

Tu¹,

Wang²,

Wei³

2022

DMSO

View full text Add to dashboard Cite

Diabetic microangiopathy is among the most common complications affecting patients with diabetes, and includes both diabetic retinopathy (DR) and diabetic nephropathy (DKD). Diabetic microangiopathy remains a persistent threat to the health and quality of life of affected patients. Mechanistically, the severity of DR and DKD is tied to mitochondrial and glucose metabolism abnormalities, with the activation of the glycolytic enzyme pyruvate kinase M2 (PKM2) contributing to mitochondrial and glomerular dysfunction, abnormal renal hemodynamics, and retinopathy. PKM2 can activate inflammatory bodies in macrophages to promote the release of inflammatory mediators, and serves as a key regulator of inflammatory factors, chemokines and adhesion molecules. As such, there is sufficient evidence that PKM2 can be used as a biomarker for the diagnosis of diabetes and diabetic microangiopathy. Here, we survey the mechanisms whereby PKM2 contributes to diabetes-related microvascular diseases, associated regulatory roles, post-translational modifications, and the potential utility of PKM2 as a therapeutic target. Through this literature review, we have determined that PKM2 offers promise as both a diagnostic marker and therapeutic target with direct relevance to research pertaining to diabetic microangiopathy.

show abstract

Metabolic and Non-metabolic Roles of Pyruvate Kinase M2 Isoform in Diabetic Retinopathy

Cited by 12 publications

References 33 publications

Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice

Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice

Insulin-like growth factor 1 receptor mediates photoreceptor neuroprotection

The Role of PKM2 in Diabetic Microangiopathy

Contact Info

Product

Resources

About