Paradoxical Hepato-Peripheral Glucoregulatory Dissociation Syndrome (HPGDS): A Novel Framework for Multi-Drug Refractory Type 2 Diabetes

Abstract

Background: Hepato-Peripheral Glucoregulatory Dissociation Syndrome (HPGDS) is a severe phenotype of refractory type 2 diabetes characterized by unsuppressed hepatic glucose production and peripheral insulin resistance.

Objective: To investigate the physiological mechanisms driving hepatic insulin resistance and skeletal muscle microvascular impairment in HPGDS.

Methods: A multi-center clinical investigation evaluated 127 participants (42 HPGDS, 45 type 2 diabetes controls, and 40 healthy metabolic controls) using 6,6-[²H₂] glucose stable isotope tracer kinetics during a 120-minute hyperinsulinemic-euglycemic clamp, MRI-derived proton density fat fraction (MRI-PDFF) for hepatic fat quantification, and contrast-enhanced ultrasound (CEUS) for skeletal muscle microvascular recruitment.

Results: HPGDS patients exhibited severe glycemic failure (HbA1c 9.8%) despite high basal-bolus insulin regimens (1.85 U/kg/day). Tracer kinetics revealed profound hepatic insulin resistance with minimal suppression of endogenous glucose production (clamp Ra 18.9 µmol/kg/min; suppression rate 11.7%). MRI-PDFF demonstrated marked hepatic steatosis (24.6%), which correlated robustly with clamp Ra ($r = 0.84, p < 0.001$). Furthermore, CEUS revealed severe impairment in skeletal muscle microvascular blood flow ($0.14\text{ AU}$), showing strong inverse correlations with HbA1c ($r = -0.76, p < 0.001$) and circulating glucagon ($r = -0.68, p < 0.001$).

Conclusion: HPGDS is driven by a dual pathophysiological failure combining autonomous hepatic glucose output and peripheral microvascular dysfunction, providing a mechanistic explanation for severe treatment refractoriness.