Exploring the therapeutic response to sodium-glucose cotransporter-2 inhibition in INSR-related insulin resistance monogenic diabetes: case-based analysis and narrative review.

backgroundINSR-related insulin resistance is a form of monogenic diabetes caused by pathogenic variants in the INSR gene, resulting in impaired insulin receptor signalling and a spectrum of insulin resistance. Conventional diabetes management strategies relying on insulin sensitisation or augmentation are often less effective and evidence to guide treatment in those with heterozygous INSR mutations remains limited. INDEX CASE ANALYSIS: A 63-year-old male diagnosed with type 2 diabetes aged 40 presented with a relatively stable fasting glucose and disproportionate postprandial hyperglycaemia despite prandial insulin. He had bilateral asymmetric mixed hearing loss (conductive/sensorineural) and early cardiovascular disease. C-peptide was preserved at 1.3 nmol/L with serum glucose at 7.1 mmol/L. Monogenic diabetes genetic testing identified a heterozygous likely pathogenic variant (i.e. mutation) in INSR (c.3473G > A, (p.Arg1158Gln)). Treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2 inhibitor) achieved 78% time-in-range (TIR). Subsequent SGLT2 inhibitor withdrawal for four months due to pyelonephritis led to TIR deterioration to 2% despite intensified basal insulin. Berberine initiation produced modest improvement (TIR 24%). Following re-introduction of the SGLT2 inhibitor, TIR rapidly improved to 85%, with restoration of a stable overnight profile. LITERATURE REVIEW: A narrative review identified eight cases with INSR-related insulin resistance (Donohue/Rabson-Mendenhall/type A insulin resistance) treated with a SGLT2 inhibitor. All reports documented clinically meaningful HbA1c reductions (1.4-3.6%) and, where available, improved CGM metrics.

conclusionsSGLT2 inhibitors provide insulin-independent glycaemic benefit in INSR-related insulin resistance. AMPK-activating strategies, including metformin, berberine, and exercise, may provide adjunctive benefit via cellular glucose uptake, although evidence remains limited. We propose a two-factor therapeutic framework targeting (1) insulin-independent glucosuria and (2) AMPK-mediated glucose uptake as a rational management approach for this rare form of diabetes.