Treatment with <scp>LY</scp>2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

Guzmán, Cristina B.; Zhang, Xiaotian M.; Liu, Rong; Regev, Arie; Shankar, Sudha; Garhyan, Parag; Pillai, Sreekumar; Kazda, C.; Chalasani, Naga; Hardy, Thomas

doi:10.1111/dom.12958

Cited by 133 publications

(126 citation statements)

References 18 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…For instance, it will be interesting to see whether changes in hepatic insulin and glucagon sensitivity (HOMA-IR and the glucagon-alanine index) move in parallel or follow distinct trajectories over time. Moreover, recent research has suggested that disruption of the glucagon-liver cycle (with glucagon receptor antagonists) may also lead to disturbances in lipid metabolism [49]. This has not been addressed in the present study, but needs to be investigated.…”

Section: Discussionmentioning

confidence: 82%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

View full text Add to dashboard Cite

Aims/hypothesis The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon. Methods To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance. Results Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. Conclusions/interpretation This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

show abstract

Section: Discussionmentioning

confidence: 82%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

View full text Add to dashboard Cite

show abstract

“…MRIs performed at baseline, 1, 3, 6, and 12 months from first treatment dose; at early discontinuation (if applicable); and at 4 months posttreatment were used to characterize the extent, time course, and reversibility of changes in HFF. More details about the MRI procedure are described in the original study manuscript . For this analysis, HFF was available at baseline, 1 month, 3 months, and at the time of the primary endpoint at 6 months.…”

Section: Methodsmentioning

confidence: 55%

“…As reported, LY2409021 treatment showed significant HbA1c reductions versus placebo (LSM difference, –0.77%; P < 0.001) but not versus sitagliptin (−0.20%; P = 0.383) at 6 months . A significant increase in HFF was seen with LY2409021 versus sitagliptin (LSM difference, 3.72%; P < 0.001) and placebo (4.44%; P < 0.001), accompanied by significant ALT elevations with LY2409021 versus sitagliptin (6.8 U/L; P = 0.039) and placebo (10.7 U/L; P < 0.001).…”

Section: Resultsmentioning

confidence: 99%

“…Adult patients with T2D who were on an optimally effective and stable dose of metformin and a sulfonylurea were recruited into the study. More details of the study are reported elsewhere and in http://onlinelibrary.wiley.com/doi/10.1002/hep4.1171/full. Patients were randomized in a 3:3:2 ratio and received double‐blinded LY2409021 (20 mg), placebo, or sitagliptin (100 mg), respectively, administered orally once daily.…”

Section: Methodsmentioning

confidence: 99%

“…LY2409021, administered orally once daily, is a novel agent with a long half‐life (approximately 60 hours) that competitively blocks the glucagon receptor. Recent results from an LY2409021 study have shown not only elevation of aminotransferases but also evidence of hepatic fat accumulation following treatment for 6 months in T2D …”

mentioning

confidence: 99%

See 2 more Smart Citations

Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

Guzmán

Duvvuru

Akkari³

et al. 2018

Hepatology Communications

Self Cite

View full text Add to dashboard Cite

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6‐week placebo‐controlled trial (I1R‐MC‐GLDI [GLDI], n = 246) and a 52‐week placebo‐ and active comparator‐controlled trial (I1R‐MC‐GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin‐like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin‐like growth factor 1 (IGF‐1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk‐allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10–5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561‐570)

show abstract

The 14‐3‐3 protein YWHAB inhibits glucagon‐induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1

Wang

Liu

et al. 2021

FEBS Letters

View full text Add to dashboard Cite

Glucagon antagonism has been reported as a new therapeutic approach to hyperglycaemia. As the 14‐3‐3 protein YWHAB has been identified as a regulator of the glucagon receptor (GCGR) by affinity purification and mass spectrometry, we examined the role of YWHAB in vivo. Ywhab knockout mice display impaired blood glucose homeostasis only under pyruvate stimulation. Deletion of Ywhab in mouse primary hepatocytes (MPHs) increases hepatocyte glucose production by magnifying the effect of glucagon. Mechanistic analysis indicates that YWHAB forms a phosphorylation‐dependent complex with GCGR and directly interacts with forkhead box O1 (FOXO1). Together, these results reveal the inhibitory role of YWHAB in glucagon‐mediated hepatic glucose production, which may be a potential target for the control of gluconeogenesis and associated metabolic diseases.

show abstract

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

Abstract: In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.

Cited by 133 publications

References 18 publications

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

The 14‐3‐3 protein YWHAB inhibits glucagon‐induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1

Contact Info

Product

Resources

About