Metformin paradoxically worsens insulin resistance in SHORT syndrome

Abstract

Background SHORT syndrome is an autosomal dominant condition associated severe insulin resistance (IR) and lipoatrophy due to post-receptor defect in insulin signaling involving phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), where no clear treatment guidelines are available. Methods We attempted to test the efficacy metformin in a female patient with SHORT syndrome by measuring glucose and insulin during an extended Oral Glucose Tolerance Test (OGTT) in a 21-year old patient (BMI 17.5 kg/m2), who presented for endocrine assessment with a history of amenorrhoea. Results She had lipid concentrations within the reference range, normal thyroid function tests, prolactin, gonadotropins, estradiol and androgens with Free Androgen Index 4.52. Extended Oral Glucose Tolerance Test was performed and showed severe IR. She was then started on metformin 850 mg twice a day, and had repeated OGTT. This showed dramatic worsening of glucose tolerance (e.g. glucose 96 mg/dl versus 187 mg/dl and 68 mg/dl versus 204 mg/dl at 120 and 150 min of OGTT, respectively). This was accompanied by a massive increase of already high insulin concentrations (e.g. from 488.6 to > 1000 µIU/ml, and from 246.8 to > 1000 µIU/ml at 120 and 150 min of OGTT, respectively). Insulin concentrations remained above upper assay detection limit also at 180 min of OGTT on metformin treatment (> 1000 µIU/ml versus 100.6 µIU/ml without metformin). Conclusions Metformin treatment may paradoxically lead to deterioration of insulin resistance and to development of glucose intolerance in SHORT syndrome. Hence, metformin treatment might be potentially harmful in these patients. Though, the precise cause of such profound and paradoxical worsening of glucose tolerance post metformin remains unknown, SHORT syndrome might prove to be an interesting model to study the mechanism(s) of metformin action.

Novel PIK3R1 mutation of SHORT syndrome: A case report with a 6‐month follow up

“…One study showed that metformin could exacerbate insulin resistance in a patient with SHORT syndrome. After 4 days of metformin treatment (850 mg twice a day), repeated OGTT showed dramatic worsening of glucose tolerance 9 . Therefore, the present report was limited to the short‐term follow up.…”

Transient Neonatal Diabetes Mellitus in SHORT Syndrome: A Case Report

“…The usefulness of an SGLT2 inhibitor and metformin in the management of IRDM in SHORT syndrome was reported ( 10 , 11 ). However, in a recent study, metformin treatment was shown to paradoxically lead to a potential deterioration of insulin resistance and development of glucose intolerance in SHORT syndrome patients ( 15 ). Further studies are warranted to confirm the clinical benefits of oral hypoglycemic agents for the treatment of genetic syndromes of insulin resistance.…”

Trends in insulin resistance: insights into mechanisms and therapeutic strategy

“… 486 , 487 Unfortunately, these agents have produced limited success due to reduced efficacy, low tolerability, and significant side effects including hypoglycemia, weight gain, bone fractures, and vomiting. 488 , 489 Thus, it is urgent to find new approaches to treat T2DM and modify insulin sensitivity.

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