Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct 5;3(1):134.
doi: 10.1038/s43856-023-00368-9.

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

Collaborators, Affiliations

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

Robert K Semple et al. Commun Med (Lond). .

Erratum in

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.

Plain language summary

The hormone insulin stimulates nutrient uptake from the bloodstream into tissues. In insulin resistance (IR), this action is blunted. Some rare gene alterations cause severe IR, diabetes that is difficult to control, and early complications. Many treatments have been suggested, but reliable evidence of their risks and benefits is sparse. We analysed all available reports describing treatment outcomes in severe IR. We found that the evidence is of low to very low quality overall. Injections of leptin, a hormone from fat tissue, or thiazolidinedione tablets that increase fat tissue both appear to improve diabetes control in people with reduced ability to make fat tissue. Injections of another treatment, insulin-like growth factor, appear to improve diabetes control in people with direct blockage of insulin action. There is a pressing need to improve evidence for treatment in these rare and severe conditions.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing interests: R.K.S. has received speaker fees from Eli Lilly, Novo Nordisk, and Amryt. R. J. B. has received research support from Amryt, Third Rock Ventures, Ionis, and Regeneron. K.A.P. and S.A. report no conflicts of interest.

Figures

Fig. 1
Fig. 1. PRISMA diagram.
PRISMA flow diagram of publications evaluated based on the search strategy.
Fig. 2
Fig. 2. Effects of metreleptin in monogenic forms of lipodystrophy.
Least square mean change in (a) Hemoglobin A1c (A1c), (b) Log10 serum triglyceride concentration and (c) Body Mass Index (BMI) in patients with partial lipodystrophy, generalized lipodystrophy, all forms of lipodystrophy, and subgroups with PPARG, LMNA, BSCL2, and AGPAT2 mutations. Error bars represent 95% confidence intervals. N = 64, 38, 102, 12, 52, 17, and 20 for change in A1c in partial lipodystrophy, generalized lipodystrophy, all lipodystrophy, PPARG, LMNA, BSCL2, and AGPAT2-associated lipodystrophy, respectively. N = 66, 40, 106, 12, 54, 19, and 20 for change in log10 triglycerides in partial lipodystrophy, generalized lipodystrophy, all lipodystrophy, PPARG, LMNA, BSCL2, and AGPAT2-associated lipodystrophy, respectively. N = 47, 14, 61, 10, 35, 8, and 7 for change in BMI in partial lipodystrophy, generalized lipodystrophy, all lipodystrophy, PPARG, LMNA, BSCL2, and AGPAT2-associated lipodystrophy, respectively.
Fig. 3
Fig. 3. Effects of thiazolidinediones in monogenic forms of lipodystrophy.
Least square mean change in (a) Hemoglobin A1c (A1c), (b) Log10 serum triglyceride concentration and (c) Body Mass Index (BMI) in patients with partial lipodystrophy, generalized lipodystrophy, all forms of lipodystrophy, and subgroups with PPARG, and LMNA mutations. Error bars represent 95% confidence intervals. N = 5, 5, and 10 for change in A1c and change in log10 triglycerides in PPARG, LMNA, and all lipodystrophy, respectively. N = 1, 5, and 6 for change in BMI in PPARG, LMNA, and all lipodystrophy, respectively.
Fig. 4
Fig. 4. Effects of recombinant human Insulin-like Growth Factor-1 (rhIGF) alone or in combination with Insulin-like Growth Factor Binding Protein-3 (IGFBP3) in patients with INSR mutations.
Least square mean change in hemoglobin A1c (A1c), in all patients with INSR mutations, and in subgroups with biallelic and monoallelic mutations. Error bars represent 95% confidence intervals. N = 7, 6, and 13 for biallelic, monoallelic, and all INSR mutations.

Update of

References

    1. Bonnefond A, Semple RK. Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes. Diabetologia. 2022;65:1782–1795. doi: 10.1007/s00125-022-05720-7. - DOI - PMC - PubMed
    1. Lim K, Haider A, Adams C, Sleigh A, Savage DB. Lipodistrophy: a paradigm for understanding the consequences of “overloading” adipose tissue. Physiol. Rev. 2021;101:907–993. - PubMed
    1. Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr. Rev. 2011;32:498–514. doi: 10.1210/er.2010-0020. - DOI - PubMed
    1. Gonzaga-Jauregui C, et al. Clinical and molecular prevalence of lipodystrophy in an unascertained large clinical care cohort. Diabetes. 2020;69:249–258. doi: 10.2337/db19-0447. - DOI - PubMed
    1. Brown RJ, et al. The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J. Clin. Endocrinol. Metab. 2016;101:4500–4511. doi: 10.1210/jc.2016-2466. - DOI - PMC - PubMed