**Background:** Insulin and estrogen are two critical hormones that regulate metabolic homeostasis through distinct but interconnected signaling pathways. Insulin, secreted by pancreatic β-cells, controls macronutrient metabolism (glucose, lipid, protein) and mitochondrial function primarily through canonical IRS-PI3K-PDK1-Akt and non-canonical PDPK1-aPKCλ pathways, with FoxO transcription factors serving as key downstream effectors. Estrogen, mainly synthesized in ovaries and placenta, signals through ERα, ERβ, and GPER to regulate reproductive and non-reproductive tissue function, including mitochondrial homeostasis, autophagy, and epigenetic programming. Dysregulation of either hormone contributes to metabolic diseases such as diabetes, obesity, cardiovascular disease, NAFLD, and neurodegenerative disorders. This review provides an updated synthesis of insulin and estrogen signaling pathways and their crosstalk in metabolic regulation.
**Methods:** This is a narrative review synthesizing recent literature on insulin and estrogen signaling in metabolism. The authors discuss canonical and non-canonical insulin signaling pathways, estrogen receptor signaling mechanisms, and the molecular crosstalk between these hormonal systems via shared mediators including Sirt1, PI3K, mTOR, and FoxO transcription factors. Evidence is drawn from preclinical studies, clinical trials, and epidemiological data.
**Key Results:** Insulin signaling regulates macronutrient metabolism through FoxO-mediated control of gluconeogenic genes (PEPCK, G6Pase), glycogen synthesis via GSK3, glycolysis through glucokinase, protein synthesis via mTORC1, and lipogenesis through SREBP1c. Insulin also modulates mitochondrial biogenesis, dynamics (fusion/fission), and mitophagy through FoxO-dependent regulation of Tfam, NRF1, PGC1α, Mfn1/2, Drp1, miR-484, PINK1, and BNIP3. Diabetes affects more than 537 million adults worldwide (2021 data), with type 2 diabetes characterized by insulin resistance and hyperinsulinemia. Estrogen signaling through ERα regulates mitochondrial DNA content via Nr4a1 activation, mitochondrial dynamics and mitophagy through PKA-dependent mechanisms, and thermogenesis via Drp1 and Ucp1 in brown adipose tissue. The crosstalk between insulin and estrogen signaling occurs through: (1) Sirt1, which deacetylates ERα and IRS2 while also being transcriptionally regulated by ERα; (2) mTORC2-mediated Akt phosphorylation at Ser473; (3) FoxO-Sestrin-mTOR signaling; and (4) ERα-PI3K-Akt-FoxO1 activation independent of IRS1/2. Estrogen administration improves insulin sensitivity and glucose tolerance in both male and ovariectomized female mice, an effect absent in liver-specific FoxO1 knockout mice. Clinical data show early menopause (before age 40) confers a 2.6-fold increase in cardiovascular disease risk. A 12-month double-blind clinical trial of intranasal insulin in patients with amnestic mild cognitive impairment or Alzheimer's disease showed no cognitive or functional benefits in the primary intention-to-treat group.
**Clinical Implications:** The review highlights that biological sex significantly influences metabolic disease susceptibility, with premenopausal females showing lower risk than age-matched males due to estrogen's protective effects via PI3K-Akt-FoxO1 signaling. This sex difference is normalized after menopause. New therapeutic options discussed include GLP1/GIP receptor agonists (e.g., tirzepatide/Mounjaro approved for T2DM), β3-adrenergic receptor agonists (mirabegron), and agents targeting liver intermediary metabolism for NAFLD. The authors emphasize that clinical trials should be designed considering sex, age, and reproductive stage, as younger females may be more susceptible to certain metabolic diseases than males due to differences in insulin sensitivity and glucose disposal, a pattern that reverses after age 40. Understanding the molecular mechanisms of insulin-estrogen crosstalk, particularly the FoxO-Sestrin-mTOR cascade and ERα-PI3K-Akt signaling, may identify new therapeutic targets for hormone-related metabolic diseases.