Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study

Isokuortti, Elina; Zhou, You; Peltonen, Markku; Bugianesi, Elisabetta; Clément, Karine; Bonnefont‐Rousselot, Dominique; Lacorte, Jean‐Marc; Gastaldelli, Amalia; Schuppan, Detlef; Schattenberg, Jörn M.; Hakkarainen, Antti; Lundbom, Nina; Jousilahti, Pekka; Männistö, Satu; Keinänen‐Kiukaanniemi, Sirkka; Saltevo, Juha; Anstee, Quentin M.; Yki‐Järvinen, Hannele

doi:10.1007/s00125-017-4340-1

Cited by 100 publications

(83 citation statements)

References 47 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…alanine) during an OGTT were affected by increasing HOMA-IR; the BCAAs were also affected but in the opposite direction, as previously reported [24][25][26]. These observations support our hypothesis that impaired hepatic glucagon signalling, potentially due to fat accumulation in the liver and resulting hepatic insulin resistance [14], impairs glucagon's ability to lower plasma levels of non-BCAAs. Taken together, the current findings support the proposed existence and importance of a liver-alpha cell axis in humans [8].…”

Section: Discussionsupporting

confidence: 90%

“…In addition, GGT, a liver-related enzyme that contributes to the transfer of γ-glutamyl groups to other amino acids and which has been suggested to be a potential surrogate marker of hepatic steatosis [47], was here coupled to changes in plasma glucagon and HOMA-IR, thereby supporting the suggestion that the increases in glucagon concentrations might be due to increased hepatic fat. HOMA-IR was recently demonstrated to be closely linked to hepatic steatosis [14].…”

Section: Discussionmentioning

confidence: 99%

“…As the model is based on glucose and insulin concentrations measured in the fasting state, HOMA-IR predominantly reflects hepatic insulin resistance [14,22]. The HOMA-IR values for the study population are presented as tertiles of HOMA-IR: lower tertile, 0.10-1.06; middle tertile, 1.07-1.84; upper tertile, 1.85-24.05.…”

Section: Study Populationmentioning

confidence: 99%

“…In order to address this hypothesis, we studied whether fasting plasma glucagon concentrations were associated with fasting plasma concentrations of branched-chain amino acids (BCAAs) as well as four non-BCAAs (alanine, histidine, tyrosine and glutamine) and phenylalanine in a cross-sectional study including 1408 individuals with progressive stages of risk of type 2 diabetes. Furthermore, we examined whether hepatic insulin resistance (reflected by an increased HOMA-IR [14]) would modify glucagon-induced amino acid turnover.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

“…Of note, in Wildman's study the cut off for HOMA-IR was 5.13, but this seems quite high. We therefore propose a lower cut-of as HOMA-IR >2.0 that corresponds to the upper 95th percentile for two population-based cohorts, the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; (n = 2849)] and (FINRISK 2007 (n = 5024) [81]). …”

Section: Adipose Tissue Remodeling: the Metabolically Healthy Vs Metmentioning

confidence: 99%

The color of fat and its central role in the development and progression of metabolic diseases

Gaggini

Carli

Gastaldelli

2017

Hormone Molecular Biology and Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Abstract:Excess caloric intake does not always translate to an expansion of the subcutaneous adipose tissue (SAT) and increase in fat mass. It is now recognized that adipocyte type (white, WAT, or brown, BAT), size (large vs. small) and metabolism are important factors for the development of cardiometabolic diseases. When the subcutaneous adipose tissue is not able to expand in response to increased energy intake the excess substrate is stored as visceral adipose tissue or as ectopic fat in tissues as muscle, liver and pancreas. Moreover, adipocytes become dysfunctional (adiposopathy, or sick fat), adipokines secretion is increased, fat accumulates in ectopic sites like muscle and liver and alters insulin signaling, increasing the demand for insulin secretion. Thus, there are some subjects that despite having normal weight have the metabolic characteristics of the obese (NWMO), while some obese expand their SAT and remain metabolically healthy (MHO). In this paper we have reviewed the recent findings that relate the metabolism of adipose tissue and its composition to metabolic diseases. In particular, we have discussed the possible role of dysfunctional adipocytes and adipose tissue resistance to the antilipolytic effect of insulin on the development of impaired glucose metabolism. Finally we have reviewed the possible role of BAT vs. WAT in the alteration of lipid and glucose metabolism and the recent studies that have tried to stimulate browning in human adipose tissue.

show abstract

A Pathophysiologic Approach Combining Genetics and Insulin Resistance to Predict the Severity of Nonalcoholic Fatty Liver Disease

et al. 2018

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin‐like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy‐proven NAFLD were enrolled in this cross‐sectional study. PNPLA3 I148M and TM6SF2 E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP‐IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP‐IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (P < 0.001 to 0.02) after adjustment for potential confounders. PNPLA3 148M and TM6SF2 E167K genotypes were significantly associated with steatosis (P = 0.003 and P = 0.02, respectively). A combination of the eLP‐IR and genetic score was able to predict the presence of NAS ≥3 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3‐4 liver fibrosis with an AUROC of 0.82. Conclusion: This proof‐of‐concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors.

show abstract

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study

Cited by 100 publications

References 47 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

The color of fat and its central role in the development and progression of metabolic diseases

A Pathophysiologic Approach Combining Genetics and Insulin Resistance to Predict the Severity of Nonalcoholic Fatty Liver Disease

Contact Info

Product

Resources

About