MON-630 - Severe Insulin Resistance and Accelerated Metabolic Dysfunction in Alström Syndrome: A Case of Extraordinary Insulin Requirements

Background: Alström syndrome (ALMS) is a rare autosomal recessive ciliopathy caused by ALMS1 mutations, characterized by progressive multiorgan dysfunction, including early-onset obesity, diabetes mellitus, and hepatic disease. We report a case demonstrating the profound insulin resistance and treatment-refractory hyperglycemia characteristic of this condition.

Case Presentation: An 18-year-old female, offspring of consanguineous parents with two similarly affected siblings, initially presented at age 4 with blindness, nystagmus, acanthosis nigricans, and severe early-onset obesity (weight 39.0 kg, >>95th percentile). Genetic testing confirmed ALMS with loss of heterozygosity at 2p13 involving ALMS1. Diabetes mellitus was diagnosed at age 11 (HbA1c 7.2%), initially managed with metformin 500 mg daily, subsequently escalated to 1 gram daily with basal insulin 15 units. Despite progressive therapeutic intensification, metabolic deterioration continued. By age 18, her regimen required U-500 regular insulin (300 units daily: 100 units TID with meals, 70 units TID when fasting), metformin 1000 mg BID, and pioglitazone 30 mg daily, yet glycemic control remained suboptimal (HbA1c 13.3%, GMI 10.4%). Dulaglutide was briefly trialed but discontinued due to pancreatitis. Hepatic disease progressed from mild steatosis with transaminitis at diabetes diagnosis to cirrhosis by age 18.

Discussion: ALMS-associated insulin resistance exceeds that of BMI-matched controls by more than fivefold, with tenfold higher metabolic syndrome prevalence. This disproportionate resistance stems from relative failure of adipose tissue and from ALMS1-mediated defects in GLUT4 trafficking, independent of AKT activation. Progressive hepatic dysfunction compounds peripheral insulin resistance, creating a self-perpetuating cycle of metabolic deterioration.

Conclusion: The extraordinary insulin requirements (300 units/day) despite triple therapy underscore that ALMS-associated diabetes represents progressive beta-cell dysfunction superimposed on severe peripheral and hepatic insulin resistance, potentially warranting earlier, more aggressive insulin therapy than standard protocols recommend.

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