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It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4 . In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line , LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.

Purpose To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG). Methods We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). Results Changes in LECT2 were correlated with the percentage of total weight loss (ρ = − 0.499, P  = 0.024) and the decrease in total fat area (ρ = 0.559, P  = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P  = 0.043) and the insulinogenic index (ρ = 0.638, P  = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601). Conclusions SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications.

Blood circulates throughout the body via the peripheral tissues, contributes to host homeostasis and maintains normal physiological functions, in addition to responding to lesions. Previously, we revealed that gene expression analysis of peripheral blood cells is a useful approach for assessing diseases such as diabetes mellitus and cancer because the altered gene expression profiles of peripheral blood cells can reflect the presence and state of diseases. However, no chronological assessment of whole gene expression profiles has been conducted. In the present study, we collected whole blood RNA from 61 individuals (average age at registration, 50 years) every 4 years for 8 years and analyzed gene expression profiles using a complementary DNA microarray to examine whether these profiles were stable or changed over time. We found that the genes with very stable expression were related mostly to immune system pathways, including antigen cell presentation and interferon-related signaling. Genes whose expression was altered over the 8-year study period were principally involved in cellular machinery pathways, including development, signal transduction, cell cycle, apoptosis, and survival. Thus, this chronological examination study showed that the gene expression profiles of whole blood can reveal unmanifested physiological changes.

Aims/Introduction Leukocyte cell‐derived chemotaxin 2 (LECT2) is an obesity‐associated hepatokine that causes skeletal muscle insulin resistance. Since LECT2 is up‐regulated by the inactivation of the energy sensor AMPK in the liver, we hypothesized that LECT2 has potential as a biomarker for metabolic dysfunction‐associated steatotic liver disease (MASLD). Therefore, we investigated whether circulating LECT2 levels are associated with insulin sensitivity, liver enzymes, and MASLD. Materials and Methods This cross‐sectional study included 138 Japanese individuals. Plasma LECT2 levels were measured using fasting blood samples. B‐mode ultrasonography was used to assess hepatic steatosis. Results The mean age and body mass index (BMI) of participants were 63.5 ± 10.2 years and 23.0 ± 3.1 kg/m2, respectively. Higher LECT2 levels positively correlated with homeostatic model assessment for insulin resistance (HOMA‐IR) values and negatively correlated with the quantitative insulin sensitivity check index (QUICKI) among all participants (HOMA‐IR; non‐standardized β (B) = 6.38, P < 0.01: QUICKI; B = −161, P < 0.01). These correlations were stronger in the low BMI group (HOMA‐IR; B = 13.85, P < 0.01: QUICKI; B = −180, P < 0.01). LECT2 levels also positively correlated with gamma‐glutamyl transferase levels (B = 0.01, P = 0.01) and alanine aminotransferase levels (B = 0.33, P = 0.02). Higher LECT2 levels correlated with the prevalence of MASLD (odds ratio = 1.14, P = 0.02). Conclusions The present results suggest the potential of plasma LECT2 levels as a biomarker for insulin resistance in individuals who are not overweight and the prevalence of MASLD in the general population. Leukocyte cell‐derived chemotaxin 2 (LECT2) is an obesity‐associated hepatokine that causes skeletal muscle insulin resistance. We investigated whether circulating LECT2 levels are associated with insulin sensitivity, liver enzymes, and metabolic dysfunction‐associated steatotic liver disease (MASLD) in the general population. The results suggest the potential of plasma LECT2 levels as a biomarker for insulin resistance in individuals who are not overweight and the prevalence of MASLD.

Aims/Introduction Selenoprotein P (SeP; encoded by SEPP1 in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. Metformin downregulates SELENOP promoter activity through an adenosine monophosphate‐activated kinase–forkhead box protein O3a pathway in hepatocytes. This study aimed to test our hypothesis that circulating SeP levels are associated with the glucose‐lowering effect of metformin in humans. Materials and Methods A total of 84 participants with poorly controlled type 2 diabetes were randomly assigned to receive metformin (1,000 mg, twice daily) or a dipeptidyl peptidase‐4 inhibitor, alogliptin (25 mg, once daily) for 12 weeks. We tested metformin and alogliptin on SeP levels and factors associated therewith as a post‐hoc analysis. Results Both metformin and aloglipitin did not change the SeP levels. Although metformin significantly increased the insulin secretory index secretory units of islets in transplantation only in participants with higher baseline SeP (>3.87), both agents similarly reduced fasting plasma glucose and glycated hemoglobin. SeP levels at baseline were correlated negatively with changes in SeP (r = −0.484, P = 0.004) and fasting plasma glucose (r = −0.433, P = 0.011), and positively with changes in C‐peptide immunoreactivity (r = 0.420, P = 0.017) and secretory units of islets in transplantation (r = 0.388, P = 0.028) in the metformin, but not alogliptin, group. Conclusions Higher baseline levels of SeP significantly predicted metformin‐mediated, but not alogliptin‐mediated, glucose‐lowering and insulinotropic effects. Serum SeP levels might be a novel biomarker for predicting the outcomes of metformin therapy, which might be helpful in tailoring diabetes medication. Selenoprotein P (encoded by SELENOP in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. We found that higher baseline levels of selenoprotein P significantly predicted a hypoglycemic effect and recovery of insulin secretion under metformin therapy. Selenoprotein P might be a novel biomarker for predicting the effect of metformin therapy, and could potentially be the first “tailor‐made” diabetes treatment.

Background/Objectives: Blood flows through the body and reaches all tissues, contributing to homeostasis and physiological functions. Providing information and understanding on how the transcriptome of whole blood behaves in response to physiological or pathological stimuli is critical. Methods: We collected blood from four healthy individuals and performed long-read RNA sequencing (lrRNA-seq) for the precise identification and expression quantification of RNA variants. Moreover, we compared two genome references: the Genome Reference Consortium Human Build 38 (GRCh38) and the Telomere-to-Telomere (T2T) assembly of the CHM13 cell line (T2T-CHM13). Results: With GRCh38, we could identify an average of about 46,000 genes, 1.3-fold more genes than T2T-CHM13. Similarly, we identified about 185,000 isoforms with GRCh38 and 140,000 with T2T-CHM13, finding similar differences for full splice match (FSM) and incomplete splice match (ISM) transcript isoforms. There were about 90,000 novel isoforms for GRCh38 and 70,000 for T2T-CHM13, 47% and 50% of the total number of identified isoforms, respectively. Differences in isoform numbers between GRCh38 and T2T-CHM13 were identified for the subcategories “Genic Genomic”, “Intergenic”, and “Genic Intron”. Using GRCh38, we generally identified a higher number of non-coding isoforms, as well as a higher number of isoforms aligning within intron and intergenic regions. Nonetheless, GRCh38 might incur false positive results, and T2T-CHM13 is likely more accurate for genome sequences in the repetitive regions. Conclusions: LrRNA-seq is a valid method for the identification of novel isoforms in blood, and this study is a first step toward the creation of a comprehensive database of the structure and expression of transcript isoforms for optimized predictive medicine.

Aims/Introduction This study compares the effects of two different insulin regimens – basal versus bolus insulin – on metabolic and cardiovascular autonomic function in Japanese participants with type 2 diabetes. Materials and Methods Participants were randomly assigned to groups for therapy with insulin glulisine (IGlu) or insulin glargine (IGla). The primary efficacy end‐point was glycemic variability, including M‐values, mean of glucose levels, and a blood glucose profile of seven time points before and after the intervention. The secondary end‐points included pleiotropic effects, including endothelial and cardiac autonomic nerve functions. Results Blood glucose levels at all time points significantly decreased in both groups. Post‐lunch, post‐dinner, and bedtime blood glucose levels were significantly lower in the IGlu group than in the IGla group. Nadir fasting blood glucose levels at the end‐point were significantly lower in the IGla group than in the IGlu group. The M‐value and mean blood glucose levels were significantly decreased from baseline in both groups, although the former was significantly lower in the IGlu group than in the IGla group. IGla, but not IGlu, was found to elevate 24‐h parasympathetic tone, especially during night‐time, and it decreased 24‐h sympathetic nerve activity, especially at dawn. Conclusions Both IGlu and IGla regimens reduced glucose variability, with IGlu bringing a greater reduction in M‐value. IGla, but not IGlu, increased parasympathetic tone during night‐time and decreased sympathetic nerve activity at dawn. These findings shed light on the previously unrecognized role of night‐time basal insulin supplementation on sympathovagal activity in type 2 diabetes patients. Both insulin glulisine and insulin glargine regimens decrease glucose variability, with a greater decrease in M‐value by insulin glulisine in people with poorly controlled type 2 diabetes. Insulin glargine, but not insulin glulisine, elevated parasympathetic tone at night‐time, and reduced sympathetic nerve activity at dawn.

Aim Selenoprotein P (SeP, encoded by SELENOP in humans) is a hepatokine that causes insulin resistance in the liver and skeletal muscle. It was found that polyunsaturated fatty acid eicosapentaenoic acid (EPA) downregulates Selenop expression by inactivating SREBP‐1c. The present study aimed to examine the effect of EPA for 12 weeks on circulating SeP levels and insulin sensitivity in humans with type 2 diabetes. Methods A total of 20 participants with dyslipidemia and type 2 diabetes were randomly assigned to an EPA (900 mg, twice daily) group and a control group. The primary endpoint was a change in serum SeP levels. Organ‐specific insulin sensitivity in the liver (HGP and %HGP), skeletal muscle (Rd), and adipose tissue (FFA and %FFA) were assessed using a hyperinsulinemic‐euglycemic clamp study with stable isotope‐labeled glucose infusion. Results Serum SeP levels were not changed in either group at the end of the study. In the EPA group, the changes in SeP levels were positively correlated with the change in serum EPA levels (r = 0.709, P = 0.022). Treatment with EPA significantly enhanced %FFA but not %HGP and Rd. The change in serum EPA levels was significantly positively correlated with the change in %HGP, and negatively correlated with changes in Rd. Conclusions The change in serum EPA levels was positively correlated with serum SeP levels, hepatic insulin sensitivity, and negatively with skeletal muscle insulin sensitivity in humans with type 2 diabetes. The EPA‐induced enhancement of hepatic insulin sensitivity might be associated with a mechanism independent of serum SeP levels. The increase in serum EPA level was significantly correlated positively with an increase in the suppression of hepatic glucose production by insulin during a clamp study. The increase in serum EPA level tended to be negatively correlated with changes in insulin‐stimulated glucose disposal.

Aims/Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP‐1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose‐lowering effects of GLP‐1 receptor agonist liraglutide with and without prior glycemic control. Materials and Methods In an open‐label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once‐daily insulin therapy, degludec (Insulin–GLP‐1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP‐1 RA, liraglutide (GLP‐1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end‐points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c). Results The median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin–GLP‐1 RA relay group (P < 0.001) and GLP‐1 RA first group (P < 0.001) by week 24, although no intergroup differences were observed. The reduction of HbA1c in the Insulin–GLP‐1 RA relay group tended to be larger than that in the GLP‐1 RA first group in the lowest CPR (C‐peptide immunoreactivity) quartile (P = 0.072). The adverse events consisted of gastrointestinal problems, followed by hypoglycemia. Conclusions The GLP‐1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity‐induced GLP‐1 resistance. The glucagon‐like peptide‐1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity‐induced glucagon‐like peptide‐1 resistance.

Aims/Introduction The aim of the present study was to investigate the effects of metformin and a dipeptidyl peptidase‐4 inhibitor, alogliptin, on body composition in a 12‐week randomized add‐on trial in Japanese participants with type 2 diabetes. Materials and Methods A total of 84 participants with poorly controlled type 2 diabetes undergoing antidiabetic therapy were randomly assigned to receive alogliptin (25 mg, once daily) or metformin (1,000 mg, twice daily) for 12 weeks. The primary efficacy end‐point was body composition. The secondary end‐points included factors associated with decreased bodyweight. Results Compared with the baseline values, alogliptin significantly increased bodyweight (66.5 ± 19.2 to 67.6 ± 19.3 kg), body mass index (BMI; 25.4 ± 6.1 to 25.8 ± 6.3 kg/m2) and fat mass (20.3 ± 12.8 to 21.8 ± 14.5 kg), whereas metformin had no significant effect on body composition. Alogliptin was inferior to metformin in reducing bodyweight (0.84 ± 1.57 vs −0.35 ± 1.53 kg, P = 0.002), BMI (0.34 ± 0.69 to −0.15 ± 0.56 kg/m2, P = 0.002) and fat mass (1.49 ± 5.06 vs −0.04 ± 1.81 kg, P = 0.042). BMI at baseline was associated with changes in bodyweight negatively in the metformin group and positively in the alogliptin group. Conclusions Metformin and alogliptin exert opposite effects on bodyweight in type 2 diabetes patients who are overweight. The higher the BMI, the more metformin reduces bodyweight and alogliptin increases weight. The pleiotropic effects of DPP‐IV inhibitors and metformin have not been examined sufficiently. Our study is the first to investigate the pleiotropic effects of these drugs and identify clinical factors associated with reduced body weight and glucose levels after add‐on therapy. Compared with the baseline values, alogliptin significantly increased body weight, BMI, and fat mass, whereas metformin had no significant effect on body composition. Metformin and alogliptin exert opposite effects on body weight in type 2 diabetic patients with overweight. The higher the BMI, the more metformin reduces body weight and alogliptin increases weight.