PKCα Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance.

Overexpression of PKCα has been linked to inhibit insulin signaling disrupting IRS-1 and Akt phosphorylations in skeletal muscle. PKCα inhibits IRS-1 and Akt phosphorylations, but not required for insulin-stimulated glucose transport in skeletal muscles. Inhibition of PKCα increased whereas in some studies decreased GLUT-4 levels at the plasma membrane in skeletal muscles and adipocytes. Controversial studies have reported opposite expression pattern of PKCα expression in insulin-resistant skeletal muscles. These findings indicate that the role of PKCα on insulin signaling is controversial and could be tissue specific. Evidently, studies are required to decipher the role of PKCα in regulating insulin signaling and preferably in other cellular systems. Utilizing neuronal cells, like Neuro-2a, SHSY-5Y and insulin-resistant diabetic mice brain tissues; we have demonstrated that PKCα inhibits insulin signaling, through IRS-Akt pathway in PP2A-dependent mechanism by an AS160-independent route involving 14-3-3ζ. Inhibition and silencing of PKCα improves insulin sensitivity by increasing GLUT-4 translocation to the plasma membrane and glucose uptake. PKCα regulates GSK3 isoforms in an opposite manner in insulin-sensitive and in insulin-resistant condition. Higher activity of PKCα aggravates insulin-resistant neuronal diabetic condition through GSK3ß but not GSK3α. Our results mechanistically explored the contribution of PKCα in regulating neuronal insulin resistance and diabetes, which opens up new avenues in dealing with metabolic disorders and neurodegenerative disorders.

PKCα: Prospects in Regulating Insulin Resistance and AD.

Protein kinase C alpha (PKCα) is known to participate in various signaling pathways due to its ubiquitous and dynamic characteristics. Previous studies report that PKCα abrogates peripheral insulin resistance, and recent publications show that it takes part in regulating Alzheimer's disease (AD). Based on evidence in the literature, we have highlighted how many of the substrates of PKCα in its signal transduction cascades are common in AD and diabetes and may have the capability to regulate both diseases simultaneously. Signaling pathways crosslinking these two diseases by PKCα have not been explored. Understanding the complexities of PKCα interactions with common molecules will deepen our understanding of its regulation of relevant pathophysiologies and, in the future, may broaden the possibility of using PKCα as a therapeutic target.

Type-2 diabetes, a co-morbidity in Covid-19: does insulin signaling matter?

Type-2 Diabetes is associated with one of the co-morbidities due to SARS-Coronavirus 2 (SARS-Cov2) infection. Clinical studies show out of control glucose levels in SARS-Cov2 infected patients with type-2 diabetes. There is no experimental evidence suggesting aberrant molecular pathway(s) that explains why SARS-Cov2 infected patients with type-2 diabetes have uncontrolled glucose homeostasis and are co-morbid. In this article, we have highlighted major proteins involved in SARS-Cov2 infection, like, ACE 2, proteases like, TMPRSS2, Furin and their connectivity to insulin signaling molecules like, PI3K, Akt, AMPK, MAPK, mTOR, those regulate glucose homeostasis and the possible outcome of that cross-talk. We also raised concerns about the effect of anti-SARS-Cov2 drugs on patients with type-2 diabetes with reference to insulin signaling and the outcome of their possible cross-talk. There are no studies to decipher the possibilities of these obvious cross-talks. The major objective of this article is to urge the scientific community to explore the possibility of determining whether derangement of insulin signaling could be one of the possible causes of the patients with type-2 diabetes being co-morbid due to SARS-Cov2 infection.

Protein Kinase C Attenuates Insulin Signalling Cascade in Insulin-Sensitive and Insulin-Resistant Neuro-2a Cells.

Protein kinase C (PKC) family of enzymes is known to be a feedback regulator of insulin signalling pathway in peripheral insulin-responsive tissues. Insulin signalling is reported to be required for maintaining cognitive abilities in brain. PKCs are involved in innumerable neuronal processes including differentiation, apoptosis, survival, maintaining synaptic plasticity, long-term potentiation and memory formation. In the present study, we made an attempt to elucidate the role of PKC, if any, in regulating insulin signalling and insulin resistance in Neuro-2a (N2a) cells in vitro. We show that phorbol 12-myristate 13-acetate (PMA) -activated PKC inhibited Akt activation in neuronal cell, N2a. In the process of inhibiting Akt, PMA-activated PKC decreased downstream insulin signalling proteins like Akt substrate 160 kDa (AS160) and glycogen synthase kinase (GSK3ß), followed by a decrease of glucose uptake in N2a cells. PKC activation caused insulin resistance in N2a cells and worsened the resistant state of already insulin-resistant cells. Hence, our study demonstrated that the activation of PKC attenuates insulin signalling cascade and make N2a cells insulin-resistant.

FIGO's PALM-COEIN Classification of Abnormal Uterine Bleeding: A Clinico-histopathological Correlation in Indian Setting.

INTRODUCTION: Abnormal uterine bleeding (AUB) is the commonest menstrual problem during perimenopause. The International Federation of Gynaecology and Obstetrics working group on menstrual disorders has developed a classification system (PALM-COEIN) for causes of the AUB in non-gravid women. The present study was conducted with the aim to study the two components of this system in clinical practice in general and to establish a clinico-pathological correlation of AUB with context of PALM component in particular. MATERIALS AND METHODS: Two hundred and thirty-six perimenopausal women (aged 40 years and above till 1 year beyond menopause) admitted with complaints of abnormal uterine bleeding were studied. After thorough history and examination, a clinical diagnosis was made as per PALM-COEIN classification. Relative contribution of various causes of PALM (structural) and COEIN (functional) components was analysed. After all indicated investigations, endometrial sampling and hysterectomy specimen were assessed by histology. A clinicopathological correlation was analysed statistically. RESULT: PALM and COEIN components contributed almost equally for AUB when assessed clinically. On the other hand, the histological examination revealed significantly more cases of PALM (structural or anatomical) component of AUB, i.e. 50.23 versus 63.98 % (p ≤ 0.05) The difference was mainly attributed to the detection of more cases of AUB-M (malignancy and hyperplasia) in highly significant proportions (p ≤ .01) and coexistent cases of AUB-A;L. AUB-L was the commonest (41.1 %) aetiology overall. CONCLUSION: The PALM-COEIN classification system should take into account both the clinical and histopathological diagnoses in women having AUB around perimenopause as the two diagnostic modalities are complementary to each other and clinical impression should be placed into proper perspective of this classification in order to optimise outcome.