Genotype-stratified treatment for monogenic insulin resistance: a systematic review
Authors: Semple Robert K. , Patel Kashyap A. , Auh Sungyoung ,   ADA/EASD PMDI, Tobias Deirdre K. , Merino Jordi , Ahmad Abrar , Aiken Catherine , Benham Jamie L. , Bodhini Dhanasekaran , Clark Amy L. , Colclough Kevin , Corcoy Rosa , Cromer Sara J. , Duan Daisy , Felton Jamie L. , Francis Ellen C. , Gillard Pieter , Gingras Véronique , Gaillard Romy , Haider Eram , Hughes Alice , Ikle Jennifer M. , Jacobsen Laura M. , Kahkoska Anna R. , Kettunen Jarno L. T. , Kreienkamp Raymond J. , Lim Lee-Ling , Männistö Jonna M. E. , Massey Robert , Mclennan Niamh-Maire , Miller Rachel G. , Morieri Mario Luca , Most Jasper , Naylor Rochelle N. , Ozkan Bige , Patel Kashyap Amratlal , Pilla Scott J. , Prystupa Katsiaryna , Raghaven Sridaran , Rooney Mary R. , Schön Martin , Semnani-Azad Zhila , Sevilla-Gonzalez Magdalena , Svalastoga Pernille , Takele Wubet Worku , Tam Claudia Ha-ting , Thuesen Anne Cathrine B. , Tosur Mustafa , Wallace Amelia S. , Wang Caroline C. , Wong Jessie J. , Yamamoto Jennifer M. , Young Katherine , Amouyal Chloé , Andersen Mette K. , Bonham Maxine P. , Chen Mingling , Cheng Feifei , Chikowore Tinashe , Chivers Sian C. , Clemmensen Christoffer , Dabelea Dana , Dawed Adem Y. , Deutsch Aaron J. , Dickens Laura T. , DiMeglio Linda A. , Dudenhöffer-Pfeifer Monika , Evans-Molina Carmella , Fernández-Balsells María Mercè , Fitipaldi Hugo , Fitzpatrick Stephanie L. , Gitelman Stephen E. , Goodarzi Mark O. , Grieger Jessica A. , Guasch-Ferré Marta , Habibi Nahal , Hansen Torben , Huang Chuiguo , Harris-Kawano Arianna , Ismail Heba M. , Hoag Benjamin , Johnson Randi K. , Jones Angus G. , Koivula Robert W. , Leong Aaron , Leung Gloria K. W. , Libman Ingrid M. , Liu Kai , Long S. Alice , Lowe William L. , Morton Robert W. , Motala Ayesha A. , Onengut-Gumuscu Suna , Pankow James S. , Pathirana Maleesa , Pazmino Sofia , Perez Dianna , Petrie John R. , Powe Camille E. , Quinteros Alejandra , Jain Rashmi , Ray Debashree , Ried-Larsen Mathias , Saeed Zeb , Santhakumar Vanessa , Kanbour Sarah , Sarkar Sudipa , Monaco Gabriela S. F. , Scholtens Denise M. , Selvin Elizabeth , Sheu Wayne Huey-Herng , Speake Cate , Stanislawski Maggie A. , Steenackers Nele , Steck Andrea K. , Stefan Norbert , Støy Julie , Taylor Rachael , Tye Sok Cin , Ukke Gebresilasea Gendisha , Urazbayeva Marzhan , Van der Schueren Bart , Vatier Camille , Wentworth John M. , Hannah Wesley , White Sara L. , Yu Gechang , Zhang Yingchai , Zhou Shao J. , Beltrand Jacques , Polak Michel , Aukrust Ingvild , de Franco Elisa , Flanagan Sarah E. , Maloney Kristin A. , McGovern Andrew , Molnes Janne , Nakabuye Mariam , Njølstad Pål Rasmus , Pomares-Millan Hugo , Provenzano Michele , Saint-Martin Cécile , Zhang Cuilin , Zhu Yeyi , Auh Sungyoung , de Souza Russell , Fawcett Andrea J. , Gruber Chandra , Mekonnen Eskedar Getie , Mixter Emily , Sherifali Diana , Eckel Robert H. , Nolan John J. , Philipson Louis H. , Brown Rebecca J. , Billings Liana K. , Boyle Kristen , Costacou Tina , Dennis John M. , Florez Jose C. , Gloyn Anna L. , Gomez Maria F. , Gottlieb Peter A. , Greeley Siri Atma W. , Griffin Kurt , Hattersley Andrew T. , Hirsch Irl B. , Hivert Marie-France , Hood Korey K. , Josefson Jami L. , Kwak Soo Heon , Laffel Lori M. , Lim Siew S. , Loos Ruth J. F. , Ma Ronald C. W. , Mathieu Chantal , Mathioudakis Nestoras , Meigs James B. , Misra Shivani , Mohan Viswanathan , Murphy Rinki , Oram Richard , Owen Katharine R. , Ozanne Susan E. , Pearson Ewan R. , Perng Wei , Pollin Toni I. , Pop-Busui Rodica , Pratley Richard E. , Redman Leanne M. , Redondo Maria J. , Reynolds Rebecca M. , Sherr Jennifer L. , Sims Emily K. , Sweeting Arianne , Tuomi Tiinamaija , Udler Miriam S. , Vesco Kimberly K. , Vilsbøll Tina , Wagner Robert , Rich Stephen S. , Franks Paul W. , Brown Rebecca J. 
Published: October 2023

Abstract
Background
Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.

Methods
Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.

Results
10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.

Conclusions
The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.