Genotype-stratified treatment for monogenic insulin resistance: a systematic review

ADA/EASD PMDI; Robert K. Semple; Kashyap A. Patel; Sungyoung Auh; Rebecca J. Brown

doi:10.1038/s43856-023-00368-9

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

ADA/EASD PMDI, Robert K. Semple, Kashyap A. Patel, Sungyoung Auh, Rebecca J. Brown^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	134
Journal	Communications Medicine
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s43856-023-00368-9
Publication status	Published - 5 Oct 2023

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@article{e26535e7bbaf4ea1814a2974c3481029,

title = "Genotype-stratified treatment for monogenic insulin resistance: a systematic review",

abstract = "BackgroundMonogenic 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.MethodsSystematic 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.Results10 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.ConclusionsThe 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.",

author = "{ADA/EASD PMDI} and Semple, {Robert K.} and Patel, {Kashyap A.} and Sungyoung Auh and Tobias, {Deirdre K.} and Jordi Merino and Abrar Ahmad and Catherine Aiken and Benham, {Jamie L.} and Dhanasekaran Bodhini and Clark, {Amy L.} and Kevin Colclough and Rosa Corcoy and Cromer, {Sara J.} and Daisy Duan and Felton, {Jamie L.} and Francis, {Ellen C.} and Pieter Gillard and V{\'e}ronique Gingras and Romy Gaillard and Eram Haider and Alice Hughes and Ikle, {Jennifer M.} and Jacobsen, {Laura M.} and Kahkoska, {Anna R.} and Kettunen, {Jarno L. T.} and Kreienkamp, {Raymond J.} and Lee-Ling Lim and M{\"a}nnist{\"o}, {Jonna M. E.} and Robert Massey and Niamh-Maire Mclennan and Miller, {Rachel G.} and Morieri, {Mario Luca} and Jasper Most and Naylor, {Rochelle N.} and Bige Ozkan and Patel, {Kashyap Amratlal} and Pilla, {Scott J.} and Katsiaryna Prystupa and Sridaran Raghaven and Rooney, {Mary R.} and Martin Sch{\"o}n and Zhila Semnani-Azad and Magdalena Sevilla-Gonzalez and Pernille Svalastoga and Takele, {Wubet Worku} and Tam, {Claudia Ha-Ting} and Thuesen, {Anne Cathrine B.} and Mustafa Tosur and Wallace, {Amelia S.} and Wang, {Caroline C.} and Wong, {Jessie J.} and Yamamoto, {Jennifer M.} and Katherine Young and Chlo{\'e} Amouyal and Andersen, {Mette K.} and Bonham, {Maxine P.} and Mingling Chen and Feifei Cheng and Tinashe Chikowore and Chivers, {Sian C.} and Christoffer Clemmensen and Dana Dabelea and Dawed, {Adem Y.} and Deutsch, {Aaron J.} and Dickens, {Laura T.} and Dimeglio, {Linda A.} and Monika Dudenh{\"o}ffer-Pfeifer and Carmella Evans-Molina and Fern{\'a}ndez-Balsells, {Mar{\'i}a Merc{\`e}} and Hugo Fitipaldi and Fitzpatrick, {Stephanie L.} and Gitelman, {Stephen E.} and Goodarzi, {Mark O.} and Grieger, {Jessica A.} and Marta Guasch-Ferr{\'e} and Nahal Habibi and Torben Hansen and Chuiguo Huang and Arianna Harris-Kawano and Ismail, {Heba M.} and Benjamin Hoag and Johnson, {Randi K.} and Jones, {Angus G.} and Koivula, {Robert W.} and Aaron Leong and Leung, {Gloria K. W.} and Libman, {Ingrid M.} and Kai Liu and Long, {S. Alice} and Lowe, {William L.} and Morton, {Robert W.} and Motala, {Ayesha A.} and Suna Onengut-Gumuscu and Pankow, {James S.} and Maleesa Pathirana and Sofia Pazmino and Dianna Perez and Petrie, {John R.} and Powe, {Camille E.} and Alejandra Quinteros and Rashmi Jain and Debashree Ray and Mathias Ried-Larsen and Zeb Saeed and Vanessa Santhakumar and Sarah Kanbour and Sudipa Sarkar and Monaco, {Gabriela S. F.} and Scholtens, {Denise M.} and Elizabeth Selvin and Sheu, {Wayne huey-Herng} and Cate Speake and Stanislawski, {Maggie A.} and Nele Steenackers and Steck, {Andrea K.} and Norbert Stefan and Julie St{\o}y and Rachael Taylor and Tye, {Sok cin} and Ukke, {Gebresilasea gendisha} and Marzhan Urazbayeva and {Van der schueren}, Bart and Camille Vatier and Wentworth, {John m.} and Wesley Hannah and White, {Sara l.} and Gechang Yu and Yingchai Zhang and Zhou, {Shao j.} and Jacques Beltrand and Michel Polak and Ingvild Aukrust and {De franco}, Elisa and Flanagan, {Sarah e.} and Maloney, {Kristin a.} and Andrew Mcgovern and Janne Molnes and Mariam Nakabuye and Nj{\o}lstad, {P{\aa}l rasmus} and Hugo Pomares-Millan and Michele Provenzano and C{\'e}cile Saint-Martin and Cuilin Zhang and Yeyi Zhu and Sungyoung Auh and {De souza}, Russell and Fawcett, {Andrea j.} and Chandra Gruber and Mekonnen, {Eskedar getie} and Emily Mixter and Diana Sherifali and Eckel, {Robert h.} and Nolan, {John j.} and Philipson, {Louis h.} and Brown, {Rebecca j.} and Billings, {Liana k.} and Kristen Boyle and Tina Costacou and Dennis, {John m.} and Florez, {Jose c.} and Gloyn, {Anna l.} and Gomez, {Maria f.} and Gottlieb, {Peter a.} and Greeley, {Siri atma w.} and Kurt Griffin and Hattersley, {Andrew t.} and Hirsch, {Irl b.} and Marie-France Hivert and Hood, {Korey k.} and Josefson, {Jami l.} and Kwak, {Soo heon} and Laffel, {Lori m.} and Lim, {Siew s.} and Loos, {Ruth j. f.} and Ma, {Ronald c. w.} and Chantal Mathieu and Nestoras Mathioudakis and Meigs, {James b.} and Shivani Misra and Viswanathan Mohan and Rinki Murphy and Richard Oram and Owen, {Katharine r.} and Ozanne, {Susan e.} and Pearson, {Ewan R.} and Wei Perng and Pollin, {Toni i.} and Rodica Pop-Busui and Pratley, {Richard e.} and Redman, {Leanne m.} and Redondo, {Maria j.} and Reynolds, {Rebecca M.} and Sherr, {Jennifer l.} and Sims, {Emily k.} and Arianne Sweeting and Tiinamaija Tuomi and Udler, {Miriam s.} and Vesco, {Kimberly k.} and Tina Vilsb{\o}ll and Robert Wagner and Rich, {Stephen s.} and Franks, {Paul w.} and Brown, {Rebecca J.}",

year = "2023",

month = oct,

day = "5",

doi = "10.1038/s43856-023-00368-9",

language = "English",

volume = "3",

journal = "Communications Medicine",

issn = "2730-664X",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Genotype-stratified treatment for monogenic insulin resistance: a systematic review

AU - ADA/EASD PMDI

AU - Semple, Robert K.

AU - Patel, Kashyap A.

AU - Auh, Sungyoung

AU - Tobias, Deirdre K.

AU - Merino, Jordi

AU - Ahmad, Abrar

AU - Aiken, Catherine

AU - Benham, Jamie L.

AU - Bodhini, Dhanasekaran

AU - Clark, Amy L.

AU - Colclough, Kevin

AU - Corcoy, Rosa

AU - Cromer, Sara J.

AU - Duan, Daisy

AU - Felton, Jamie L.

AU - Francis, Ellen C.

AU - Gillard, Pieter

AU - Gingras, Véronique

AU - Gaillard, Romy

AU - Haider, Eram

AU - Hughes, Alice

AU - Ikle, Jennifer M.

AU - Jacobsen, Laura M.

AU - Kahkoska, Anna R.

AU - Kettunen, Jarno L. T.

AU - Kreienkamp, Raymond J.

AU - Lim, Lee-Ling

AU - Männistö, Jonna M. E.

AU - Massey, Robert

AU - Mclennan, Niamh-Maire

AU - Miller, Rachel G.

AU - Morieri, Mario Luca

AU - Most, Jasper

AU - Naylor, Rochelle N.

AU - Ozkan, Bige

AU - Patel, Kashyap Amratlal

AU - Pilla, Scott J.

AU - Prystupa, Katsiaryna

AU - Raghaven, Sridaran

AU - Rooney, Mary R.

AU - Schön, Martin

AU - Semnani-Azad, Zhila

AU - Sevilla-Gonzalez, Magdalena

AU - Svalastoga, Pernille

AU - Takele, Wubet Worku

AU - Tam, Claudia Ha-Ting

AU - Thuesen, Anne Cathrine B.

AU - Tosur, Mustafa

AU - Wallace, Amelia S.

AU - Wang, Caroline C.

AU - Wong, Jessie J.

AU - Yamamoto, Jennifer M.

AU - Young, Katherine

AU - Amouyal, Chloé

AU - Andersen, Mette K.

AU - Bonham, Maxine P.

AU - Chen, Mingling

AU - Cheng, Feifei

AU - Chikowore, Tinashe

AU - Chivers, Sian C.

AU - Clemmensen, Christoffer

AU - Dabelea, Dana

AU - Dawed, Adem Y.

AU - Deutsch, Aaron J.

AU - Dickens, Laura T.

AU - Dimeglio, Linda A.

AU - Dudenhöffer-Pfeifer, Monika

AU - Evans-Molina, Carmella

AU - Fernández-Balsells, María Mercè

AU - Fitipaldi, Hugo

AU - Fitzpatrick, Stephanie L.

AU - Gitelman, Stephen E.

AU - Goodarzi, Mark O.

AU - Grieger, Jessica A.

AU - Guasch-Ferré, Marta

AU - Habibi, Nahal

AU - Hansen, Torben

AU - Huang, Chuiguo

AU - Harris-Kawano, Arianna

AU - Ismail, Heba M.

AU - Hoag, Benjamin

AU - Johnson, Randi K.

AU - Jones, Angus G.

AU - Koivula, Robert W.

AU - Leong, Aaron

AU - Leung, Gloria K. W.

AU - Libman, Ingrid M.

AU - Liu, Kai

AU - Long, S. Alice

AU - Lowe, William L.

AU - Morton, Robert W.

AU - Motala, Ayesha A.

AU - Onengut-Gumuscu, Suna

AU - Pankow, James S.

AU - Pathirana, Maleesa

AU - Pazmino, Sofia

AU - Perez, Dianna

AU - Petrie, John R.

AU - Powe, Camille E.

AU - Quinteros, Alejandra

AU - Jain, Rashmi

AU - Ray, Debashree

AU - Ried-Larsen, Mathias

AU - Saeed, Zeb

AU - Santhakumar, Vanessa

AU - Kanbour, Sarah

AU - Sarkar, Sudipa

AU - Monaco, Gabriela S. F.

AU - Scholtens, Denise M.

AU - Selvin, Elizabeth

AU - Sheu, Wayne huey-Herng

AU - Speake, Cate

AU - Stanislawski, Maggie A.

AU - Steenackers, Nele

AU - Steck, Andrea K.

AU - Stefan, Norbert

AU - Støy, Julie

AU - Taylor, Rachael

AU - Tye, Sok cin

AU - Ukke, Gebresilasea gendisha

AU - Urazbayeva, Marzhan

AU - Van der schueren, Bart

AU - Vatier, Camille

AU - Wentworth, John m.

AU - Hannah, Wesley

AU - White, Sara l.

AU - Yu, Gechang

AU - Zhang, Yingchai

AU - Zhou, Shao j.

AU - Beltrand, Jacques

AU - Polak, Michel

AU - Aukrust, Ingvild

AU - De franco, Elisa

AU - Flanagan, Sarah e.

AU - Maloney, Kristin a.

AU - Mcgovern, Andrew

AU - Molnes, Janne

AU - Nakabuye, Mariam

AU - Njølstad, Pål rasmus

AU - Pomares-Millan, Hugo

AU - Provenzano, Michele

AU - Saint-Martin, Cécile

AU - Zhang, Cuilin

AU - Zhu, Yeyi

AU - Auh, Sungyoung

AU - De souza, Russell

AU - Fawcett, Andrea j.

AU - Gruber, Chandra

AU - Mekonnen, Eskedar getie

AU - Mixter, Emily

AU - Sherifali, Diana

AU - Eckel, Robert h.

AU - Nolan, John j.

AU - Philipson, Louis h.

AU - Brown, Rebecca j.

AU - Billings, Liana k.

AU - Boyle, Kristen

AU - Costacou, Tina

AU - Dennis, John m.

AU - Florez, Jose c.

AU - Gloyn, Anna l.

AU - Gomez, Maria f.

AU - Gottlieb, Peter a.

AU - Greeley, Siri atma w.

AU - Griffin, Kurt

AU - Hattersley, Andrew t.

AU - Hirsch, Irl b.

AU - Hivert, Marie-France

AU - Hood, Korey k.

AU - Josefson, Jami l.

AU - Kwak, Soo heon

AU - Laffel, Lori m.

AU - Lim, Siew s.

AU - Loos, Ruth j. f.

AU - Ma, Ronald c. w.

AU - Mathieu, Chantal

AU - Mathioudakis, Nestoras

AU - Meigs, James b.

AU - Misra, Shivani

AU - Mohan, Viswanathan

AU - Murphy, Rinki

AU - Oram, Richard

AU - Owen, Katharine r.

AU - Ozanne, Susan e.

AU - Pearson, Ewan R.

AU - Perng, Wei

AU - Pollin, Toni i.

AU - Pop-Busui, Rodica

AU - Pratley, Richard e.

AU - Redman, Leanne m.

AU - Redondo, Maria j.

AU - Reynolds, Rebecca M.

AU - Sherr, Jennifer l.

AU - Sims, Emily k.

AU - Sweeting, Arianne

AU - Tuomi, Tiinamaija

AU - Udler, Miriam s.

AU - Vesco, Kimberly k.

AU - Vilsbøll, Tina

AU - Wagner, Robert

AU - Rich, Stephen s.

AU - Franks, Paul w.

AU - Brown, Rebecca J.

PY - 2023/10/5

Y1 - 2023/10/5

N2 - BackgroundMonogenic 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.MethodsSystematic 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.Results10 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.ConclusionsThe 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.

AB - BackgroundMonogenic 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.MethodsSystematic 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.Results10 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.ConclusionsThe 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.

U2 - 10.1038/s43856-023-00368-9

DO - 10.1038/s43856-023-00368-9

M3 - Article

SN - 2730-664X

VL - 3

JO - Communications Medicine

JF - Communications Medicine

IS - 1

M1 - 134

ER -

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

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