The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro
Abstract
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.
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PNPLA3 p.I148M is associated with a distinct pathogenesis, and may predict response to some therapeutic approaches and side effects of drugs, such as liver damage related to long-acting insulin-induced lipid accumulation.
“PNPLA3 p.I148M is associated with a distinct pathogenesis, and may predict response to some therapeutic approaches and side effects of drugs, e.g. liver damage related to long-acting insulin-induced lipid accumulation, 213”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [213]
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- Authors
- Pillai, S., Duvvuru, S., Bhatnagar, P., Foster, W., Farmen, M., Shankar, S., Harris, C., Bastyr, E., Hoogwerf, B., & Haupt, A.
- Affiliations
- Eli Lilly (United States) (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Pillai, S
- Venue
- The Pharmacogenomics Journal
- Published
- 2017-11-21
- Volume
- 18
- Issue
- 3
- Pages
- 487-493
- ISSN
- 1470-269X (ISSN-L)
- 1473-1150
- OpenAlex
- W2768431995
- Cited by
- 19
- References
- 48
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 1 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- The Pharmacogenomics Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- PNPLA3 I148M variant, type 2 diabetes, transaminase elevation, alanine aminotransferase, aspartate aminotransferase, liver fat, insulin glargine, non-alcoholic fatty liver disease, triglycerides, cholesterol, lipid metabolism, pharmacogenomics
- MeSH terms
- Acyltransferases, Adult, Alanine Transaminase, Aspartate Aminotransferases, Blood Glucose, Diabetes Mellitus, Type 2, Female, Genotype, Humans, Hypoglycemic Agents, Lipase, Cholesterol, LDL, Liver, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Polyethylene Glycols, Triglycerides, Polymorphism, Single Nucleotide, Lipid Metabolism, Phospholipases A2, Calcium-Independent, Insulin Lispro
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