Dianabol Cycle: FAQs And Harm Reduction Protocols The Interplay Between SARS‑CoV‑2 Infection and Diabetes: A Narrative Review

1. Introduction
   

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) in late 2019, millions of people worldwide have been infected with COVID‑19. While the respiratory manifestations are well known, accumulating evidence demonstrates that SARS‑CoV‑2 infection is not limited to the lungs and that it can profoundly influence metabolic homeostasis. Diabetes mellitus—both type 1 (T1D) and type 2 (T2D)—has emerged as a major risk factor for severe disease and mortality in COVID‑19, and conversely, acute glycaemic disturbances are common in infected patients.

This review critically examines the current understanding of how SARS‑CoV‑2 infection interacts with diabetes. We focus on the pathophysiological mechanisms underlying altered glucose metabolism during infection, the impact of pre‑existing diabetes on disease progression and outcomes, and potential therapeutic strategies to mitigate these complications.

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1 Pathophysiology of Glucose Dysregulation During SARS‑CoV‑2 Infection

1.1 Cytokine‑Mediated Insulin Resistance

Severe COVID‑19 is characterised by a hyperinflammatory response often referred to as a "cytokine storm". Pro‑inflammatory cytokines such as interleukin‑6 (IL‑6), tumour necrosis factor‑α (TNF‑α), and interferon‑γ are markedly elevated. These mediators interfere with insulin signalling pathways in adipose tissue, skeletal muscle, and liver cells.
IL‑6 activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, leading to serine phosphorylation of insulin receptor substrate‑1 (IRS‑1), impairing downstream phosphatidylinositol 3‑kinase (PI3K)/Akt signalling. TNF‑α induces expression of suppressor of cytokine signalling‑3 (SOCS‑3) and inhibits IRS‑1 via serine phosphorylation.

The net effect is insulin resistance: diminished glucose uptake by peripheral tissues, necessitating higher circulating insulin levels to maintain euglycaemia. Elevated insulin further stimulates lipogenesis in the liver, exacerbating hepatic steatosis and systemic inflammation.

2.2 Inflammatory Signalling Pathways (NF‑κB, MAPK)

SARS‑CoV‑2 infection of host cells activates innate immune sensors (TLR3/7/8, RIG‑I) that trigger downstream pathways:
Nuclear Factor κB (NF‑κB): Phosphorylation and degradation of IκBα releases NF‑κB to translocate into the nucleus and upregulate pro‑inflammatory cytokines (IL‑6, TNF‑α). Chronic activation leads to a "cytokine storm," contributing to endothelial dysfunction and coagulopathy. Mitogen‑Activated Protein Kinases (MAPK): ERK1/2, p38, and JNK pathways further amplify inflammatory signaling and influence apoptosis.

These pathways also intersect with metabolic regulation:

NF‑κB activation can inhibit insulin receptor substrate phosphorylation, exacerbating insulin resistance. MAPK-mediated phosphorylation of transcription factors such as FOXO3 modulates expression of antioxidant enzymes (e.g., SOD2), affecting oxidative stress response.

4. Integrated Pathway Diagram

Below is a schematic representation that integrates the key genes and signaling pathways described above. The diagram highlights:
Primary Signaling Cascades: Activation of NF‑κB, MAPK, PI3K/Akt, JAK/STAT. Cross‑Talk Between Inflammation &amp