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oai:figshare.com:article/34020561 2026-09-29T03:02:24Z category_24499 category_24718 category_24721 category_24514 category_24658 item_type_12 month_year_09_2026

Metabolic–osmoregulatory coupling in insulin physiology: revisiting Epple and Brinn fifty years later Kathleen Bell (23640910) Endocrinology Systems physiology Medical physiology not elsewhere classified Medical genetics (excl. cancer genetics) Metabolic medicine insulin glucose metabolism osmoregulation metabolic-osmoregulatory coupling hydromineral physiology sodium homeostasis water balance cell volume regulation vasopressin arginine vasopressin IRAP LNPEP insulin-regulated aminopeptidase GLUT4 SGLT2 SWELL1 LRRC8A type 2 diabetes beta-cell physiology TBC1D4 FXYD2 MAP3K15 ASK3 metabolic physiology diabetes mellitus insulin resistance Hypothesis and evidence-synthesis preprint, Audited v1.3.2, 28 September 2026.This work reassesses the relationship between glucose–insulin physiology and osmotic, ionic, water-balance and cell-volume physiology, fifty years after August Epple and Jack E. Brinn proposed a broader metabolic–osmoregulatory interpretation of the pancreatic islet organ. The central synthesis is that glucose–insulin physiology is demonstrably interconnected with hydromineral physiology through renal electrolyte handling, cellular-volume regulation, microvascular delivery, β-cell volume-sensitive secretion, ion-transporter trafficking, and insulin-regulated aminopeptidase (IRAP/LNPEP)–dependent peptide processing. These relationships establish physiological coupling but do not establish a single adaptive programme, an osmotic cause of type 2 diabetes, or a treatment effect.Evidence considered includes human insulin-dependent renal antinatriuresis; partial dissociation of glucose, sodium and potassium responses; SGK1, WNK1 and SWELL1/LRRC8A physical-state-sensitive pathways; β-cell swell–secretion coupling; insulin-responsive KCC1 and PIT2 trafficking; GLUT4–IRAP co-trafficking; insulin-dependent acceleration of intact vasopressin disappearance in mice; IRAP-dependent water-excretion phenotypes; positive and null human osmotic and hydration interventions; pharmacological intersections involving SGLT2 inhibition, GLP-1 receptor agonism, thiazolidinediones, insulin and historical chlorpropamide; and genetic evidence involving TBC1D4, FXYD2, MAP3K15/ASK3, PPARG, SLC5A1/SGLT1 and selected pharmacogenetic studies.The manuscript distinguishes demonstrated mechanisms from supported inference and from hypothesis. Human hydration and osmotic studies produce both positive and null metabolic findings. Moderate extracellular glucose elevations can provide limited effective-tonicity support after transcellular water redistribution, but the manuscript does not claim that glucose is a universally beneficial osmolyte. SGLT2-associated natriuresis and volume effects are treated as state- and time-dependent rather than uniformly sustained. Genetic susceptibility is separated from direct genotype-by-hydromineral exposure interaction, and threshold crossing, effect modification and disease progression are treated as distinct questions.The principal experimental proposal is a paired mechanistic study measuring native surface GLUT4, glucose transport, native surface IRAP/LNPEP, LNPEP-dependent intact-vasopressin disappearance and cell-volume recovery under controlled ionic and osmotic conditions, followed by selective disruption and rescue. A complementary human programme would test whether objectively measured hydromineral exposures causally modify glucose appearance, disposal or secretion. The practical hypothesis is that some abnormal glucose–insulin handling may depend on a modifiable hydromineral context; this remains to be demonstrated experimentally.No new human or animal experiments, participant-level genetic analyses or clinical interventions were performed for this work. This is a hypothesis and evidence-synthesis preprint and does not provide medical or dietary treatment recommendations.Files in this deposit: the audited release manuscript in PDF and DOCX formats; the audited supplementary genetics evidence note in PDF and DOCX formats; an independent AI-assisted claim-to-source audit report; and a release provenance note. The main manuscript contains 114 references. The genetics supplement contains 45 references and four supplementary tables. The independent audit checked the main manuscript reference-by-reference, independently recomputed the illustrative glucose/tonicity compartment calculation, and identified source-attribution and statistical-wording corrections that were incorporated into Audited v1.3.2. The genetics supplement subsequently underwent a separate bounded source audit and its required corrections were also implemented. The audit is documentary source checking and is not peer review.Research provenance: this work originated as a side branch of the author's separate research programme investigating the “Sodium Struggle hypothesis of autism”, which considers compensatory physiology involving sodium and water balance, cellular volume, vascular tone, effective circulating volume and related neuroendocrine regulation. Repeated intersections with glucose and insulin physiology prompted the independent question examined here. The present preprint does not test autism aetiology, and none of its scientific conclusions depends on the Sodium Struggle hypothesis of autism being correct. 2026-09-29T03:02:24Z Text Preprint 10.6084/m9.figshare.34020561.v1 https://figshare.com/articles/preprint/Metabolic_osmoregulatory_coupling_in_insulin_physiology_revisiting_Epple_and_Brinn_fifty_years_later/34020561 CC BY 4.0