Introduction: Non-diabetic hypoglycemia in older adults warrants careful evaluation across insulin-mediated and noninsulin-mediated causes. We present a challenging case of insulin autoimmune syndrome (IAS; Hirata’s syndrome). Case: An 85-year-old female presented with severe hypoglycemia (capillary blood glucose [CBG] 1.8 mmol/L) with reduced consciousness, preceded by 2 months of recurrent dizziness relieved by food intake. Appetite and weight were stable. Past medical history included stage 3 chronic kidney disease and osteoporosis, but no diabetes. Medication review revealed a recent 2-week course of traditional supplement, long-term Neurobion®, but no agents with recognized hypoglycemic potential. Physical examination showed a moderately built elderly female with a body mass index of 24.3 kg/m² and no Cushingoid features. Recurrent hypoglycemia (CBG nadir 1.5 mmol/L) occurred in both fasting and postprandial states, fulfilling Whipple’s triad. Baseline investigations showed an estimated glomerular filtration rate of 42 mL/min/1.73 m², AM cortisol of 700 mmol/L, and unremarkable liver and thyroid function tests. During a hypoglycemic episode (CBG 2.3 mmol/L), plasma insulin and C-peptide were inappropriately raised at 203.6 mU/L (reference interval [RI]: 3.0– 25.0) and 33 ng/mL (RI: 0.9–7.1), respectively, confirming endogenous hyperinsulinemic hypoglycemia. Polyethylene glycol precipitation showed 21% insulin recovery, raising suspicion for an autoimmune cause. Elevated insulin autoantibodies (175 AU/mL; RI <20) confirmed IAS. Computed tomography of the abdomen and endoscopic ultrasound excluded a pancreatic neuro-endocrine tumor. Nutritional management comprising frequent low glycemic index feeds and uncooked cornstarch was commenced. Diazoxide 100 mg TDS caused fluid overload and severe hyponatremia, while hypoglycemia persisted at lower doses, necessitating discontinuation. Subcutaneous octreotide 100 mg QID was required to control hypoglycemia. Prednisolone 30 mg BD improved glycemic stability. Insulin autoantibodies titer remained 175 AU/mL at 2 weeks; reassessment was conducted at 4 weeks with consideration for biologics if persistent. : doses, necessitating discontinuation. Subcutaneous octreotide 100 mg QID was required to control hypoglycemia. Prednisolone 30 mg BD improved glycemic stability. Insulin autoantibodies titer remained 175 AU/mL at 2 weeks; reassessment was conducted at 4 weeks with consideration for biologics if persistent. Conclusion Endogenous hyperinsulinemic hypoglycemia, after excluding insulinoma, should raise suspicion for IAS. Management includes removing triggers, supportive care, and immunomodulatory therapy in severe cases.

Introduction: Vitamin D-dependent rickets type 2 (VDDR2) is traditionally defined by biallelic vitamin D receptor (VDR) mutations causing resistance to 1,25(OH)₂D. We describe a case of the classical VDDR2 phenotype with a single VDR mutation and an interesting physiological adaptation. Case: A female diagnosed with rickets at age three presented with a femoral fracture, severe short stature, hypocalcemia (2.1 mmol/L; NR 2.35–2.70), hypophosphatemia (0.8 mmol/L; NR 1.5–2.10), and evidence of renal phosphate wasting (TMP/GFR 0.5 mmol/L; NR 1.5–2.4). Biochemistry showed markedly elevated alkaline phosphatase (1,227 IU/L; NR 50–136) and secondary hyperparathyroidism (20.7 pmol/L; NR 0.8–7.8). Despite hypocalcemia, 1,25(OH)₂D was significantly elevated (>450 pmol/L; NR 60–150), consistent with VDDR2. There was no initial family history; however, subsequent evaluation of her mother—prompted by the patient’s diagnosis—revealed a similar biochemical profile, along with short stature (142 cm) and a history of multiple fractures. Genetic analysis in both individuals identified a heterozygous missense mutation in exon 10 of the VDR gene, affecting the ligand-binding domain, supporting a pattern of dominant inheritance. The patient was treated with cholecalciferol (1,200 IU daily), calcitriol (5–6 µg daily), and calcium carbonate (2,000 mg daily). Although biochemical responsiveness to therapy was evident, poor adherence resulted in suboptimal metabolic control throughout childhood and adolescence, including a second fracture at age 15 and a final adult height of 124 cm. Notably, calcium and phosphate levels progressively normalized after puberty, with sustained biochemical stability despite the patient omitting the treatment. Conclusion This case provides two important insights. First, it represents the fourth reported case worldwide demonstrating a dominant-negative effect of a VDR gene mutation, whereby a single mutant receptor interferes with wildtype VDR function. Second, it highlights postpubertal calcium adaptation, in which vitamin D–independent intestinal absorption may restore mineral homeostasis, and disease severity can attenuate over time through adaptive physiological mechanisms.
Calcium ; Mutation ; Vitamin D ; Rickets

People with type 2 diabetes mellitus have increased risk of chronic kidney disease and atherosclerotic cardiovascular disease. Improved care delivery and implementation of guideline-directed medical therapy have contributed to the declining incidence of atherosclerotic cardiovascular disease in high-income countries. By contrast, the global incidence of chronic kidney disease and associated mortality is either plateaued or increased, leading to escalating direct and indirect medical costs. Given limited resources, better risk stratification approaches to identify people at risk of rapid progression to end-stage kidney disease can reduce therapeutic inertia, facilitate timely interventions and identify the need for early nephrologist referral. Among people with chronic kidney disease G3a and beyond, the kidney failure risk equations (KFRE) have been externally validated and outperformed other risk prediction models. The KFRE can also guide the timing of preparation for kidney replacement therapy with improved healthcare resources planning and may prevent multiple complications and premature mortality among people with chronic kidney disease with and without type 2 diabetes mellitus. The present review summarizes the evidence of KFRE to date and call for future research to validate and evaluate its impact on cardiovascular and mortality outcomes, as well as healthcare resource utilization in multiethnic populations and different healthcare settings.