Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response.

The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer.

Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics.

Tirabrutinib is a highly selective Bruton's tyrosine kinase (BTK) inhibitor used to treat hematological malignancies. We analyzed the anti-tumor mechanism of tirabrutinib using phosphoproteomic and transcriptomic methods. It is important to check the drug's selectivity against off-target proteins to understand the anti-tumor mechanism based on the on-target drug effect. Tirabrutinib's selectivity was evaluated by biochemical kinase profiling assays, peripheral blood mononuclear cell stimulation assays, and the BioMAP system. Next, in vitro and in vivo analyses of the anti-tumor mechanisms were conducted in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells followed by phosphoproteomic and transcriptomic analyses. In vitro kinase assays showed that, compared with ibrutinib, tirabrutinib and other second-generation BTK inhibitors demonstrated a highly selective kinase profile. Data from in vitro cellular systems showed that tirabrutinib selectively affected B-cells. Tirabrutinib inhibited the cell growth of both TMD8 and U-2932 cells in correlation with the inhibition of BTK autophosphorylation. Phosphoproteomic analysis revealed the downregulation of ERK and AKT pathways in TMD8. In the TMD8 subcutaneous xenograft model, tirabrutinib showed a dose-dependent anti-tumor effect. Transcriptomic analysis indicated that IRF4 gene expression signatures had decreased in the tirabrutinib groups. In conclusion, tirabrutinib exerted an anti-tumor effect by regulating multiple BTK downstream signaling proteins, such as NF-κB, AKT, and ERK, in ABC-DLBCL.

Investigating the effect of computer-mediated feedback via an LMS integration in a large-scale Japanese speaking class.

In second or foreign language (SFL) education, oral corrective feedback (OCF) is widely used to individually correct students' erroneous utterances during classroom hours. However, students cannot have sufficient opportunities for oral production and personalized feedback during classroom hours if a class is large-scale with many students. This paper addresses the lack of OCF opportunities in a large-scale class, assuming the causes to be the severe time constraints and the teachers' labor intensiveness in examining students' utterances and generating OCF. This research proposes using computer-mediated feedback (CMF) outside classroom hours to complement OCF in an online, semiautomated, and scalable fashion. This paper implements Oral Repetition Practice (ORP) Gym to provide students with sufficient opportunities for speaking practice through two types of CMFs; Hybrid Recast to enhance the recognition of errors and Explicit Error Correction to make errors detectable and correctable. Online External Assistant (OEA) is a mechanism used to increase the amount and quality of feedback by distributing the workload for scoring and generating CMF. The evaluation was conducted as a classroom observational study by introducing ORP Gym to a spoken Japanese SFL basics course with 55 students at an Indian university. Compared with the students who did not utilize ORP Gym, those who utilized ORP Gym performed more ORP and exhibited significant score improvement in the posttest. This research contributes to enabling CMF in large-scale SFL classes and empirically and statistically proving the improvement of the learning effect, including uptake and repair, by CMF using ORP Gym and an OEA. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-022-11262-7.

Correction to: Non-autoimmune acute-onset type 1 diabetes mellitus newly developed in an elderly patient presenting elevation of serum pancreatic exocrine enzymes.

[This corrects the article DOI: 10.1007/s13340-021-00535-0.].

Non-autoimmune acute-onset type 1 diabetes mellitus newly developed in an elderly patient presenting elevation of serum pancreatic exocrine enzymes.

An 82 year-old female patient not suffering from diabetes was transported to our hospital with hyperglycemia (HbA1c 8.2%, blood glucose 584 mg/dL) and mildly increased levels of pancreatic exocrine enzymes (amylase 543 IU/L, lipase 59 U/L, elastase-1 479 ng/dL), while there were no findings indicating pancreatitis. Under a diagnosis of new-onset diabetes, she was discharged with oral hypoglycemic agents, as retention of insulin secretion function [blood glucose 117 mg/dL, serum connecting peptide immunoreactivity (CPR) 1.63 ng/mL] with normalization of the enzymes was confirmed following administration. However, at 73 days after the hospitalization, she returned with diabetic ketoacidosis (blood glucose 910 mg/dL, pH in blood gas analysis 7.15, total blood ketone bodies > 7000 µmol/L) with a transient repeated increase of the enzymes (amylase 382 IU/L, lipase 82 U/L, elastase-1 569 ng/dL) and without pancreatitis. Notably, depletion of insulin secretion (6.1 µg/day in urine, 0.36 ng/mL in serum CPR with no response in glucagon-loading test) was revealed, and serum CPR level remained low after discharge. Together with negative findings for islet-related autoantibodies, the patient was diagnosed with acute-onset type 1B diabetes (T1BD). In the present patient with acute-onset T1BD, a mild increase in pancreatic exocrine enzymes was repeatedly observed, which may mimic fulminant type and raise questions for us about the commonly accepted pathophysiology of T1D. These findings may help to clarify issues related to newly developed T1D in elderly individuals.

Identification and Clinical Associations of 3 Forms of Circulating T-cadherin in Human Serum.

CONTEXT: T-cadherin (T-cad) is a glycosylphosphatidylinositol (GPI)-anchored cadherin that mediates adiponectin to induce exosome biogenesis and secretion, protect cardiovascular tissues, promote muscle regeneration, and stimulate therapeutic heart protection by transplanted mesenchymal stem cells. CDH13, the gene locus of T-cad, affects plasma adiponectin levels most strongly, in addition to affecting cardiovascular disease risk and glucose homeostasis. Recently, it has been suggested that T-cad exists in human serum, although the details are still unclear. OBJECTIVE: To validate the existence of T-cad forms in human serum and investigate the association with clinical parameters of type 2 diabetes patients. METHODS: Using newly developed monoclonal antibodies against T-cad, pooled human serum was analyzed, and novel T-cad enzyme-linked immunosorbent assays (ELISAs) were developed. The serum T-cad concentrations of 183 Japanese type 2 diabetes patients were measured in a cross-sectional observational study. The main outcome measure was the existence of soluble T-cad in human serum. RESULTS: There were 3 forms of soluble T-cad: a 130-kDa form with a prodomain, a 100-kDa mature form, and a 30-kDa prodomain in human serum. Using newly developed ELISAs to measure them simultaneously, we found that the 130-kDa form of T-cad positively correlated with plasma adiponectin (r = 0.28, P < .001), although a physiological interaction with adiponectin was not observed in serum. The unique 30-kDa prodomain was associated with several clinical parameters in diabetes patients. CONCLUSION: We identified 3 novel forms of soluble T-cad. Their importance as disease markers and/or biomarkers of adiponectin function and the possible bioactivity of the respective molecules require further investigation.

Low muscle quality in Japanese type 2 diabetic patients with visceral fat accumulation.

BACKGROUND: Although obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated. METHODS: We enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation. RESULTS: The prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (-) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (-) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018). CONCLUSIONS: T2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.

Association of Epicardial, Visceral, and Subcutaneous Fat With Cardiometabolic Diseases.

BACKGROUND: Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat.Methods and Results:Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm2) and was also reduced in the high EFV group (EFV ≥80 cm3). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis. CONCLUSIONS: Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.

Degree of discrepancy between HbA1c and glycemia in variant hemoglobin is smaller when HbA1c is measured by new-type Arkray HPLC compared with old-type HPLC.

OBJECTIVES: Although variant hemoglobin mainly demonstrates inappropriate HbA1c values measured by high-performance liquid chromatography (HPLC), these values differ depending on the HPLC model. In the 1990s, old-type HPLC models were replaced with new-type HPLC models which could separate stable HbA1c from labile HbA1c and modified hemoglobin. This study compared HbA1c values in subjects with variant hemoglobin measured using old-type Arkray HPLC (HA-8150) and new-type Arkray HPLC (HA-8160 or HA-8180). DESIGN AND METHODS: This study included non-diabetic subjects with apparently low HbA1c values who had variant hemoglobins due to a ß-chain heterozygous mutation. HbA1c was measured by old-type HPLC in 28 subjects with 12 variant hemoglobins (group 1) and new-type HPLC in six subjects with four variant hemoglobins (group 2). When HbA1c was measured by HPLC (HPLC-HbA1c), HbA1c measured by immunoassay (IA-HbA1c) and glycated albumin (GA) were also measured. RESULTS: IA-HbA1c and GA did not significantly differ between both groups. However, HPLC-HbA1c in group 2 was significantly higher than that in group 1 (group 1: 2.9 ± 0.7% vs. group 2: 3.7 ± 0.2%, P = 0.006). CONCLUSIONS: When HbA1c in subjects with variant hemoglobin is measured by new-type Arkray HPLC, the degree of discrepancy between HbA1c and glycemia is smaller compared with that measured by old-type HPLC.

Study on the mechanism causing elevation of serum CA19-9 levels in diabetic patients.

Serum CA19-9 levels are often elevated in diabetic patients. To elucidate this mechanism, we investigated the metabolism of CA19-9 in diabetic patients without obvious cancer. Study 1 included 119 patients in whom HbA1c, glycated albumin (GA) and CA19-9 were measured at the time of hospital admission. Study 2 examined 6 patients with markedly elevated CA19-9 levels (≥100 U/mL). Their half-lives for HbA1c, GA, and serum CA19-9 were calculated using the data before and after diabetes treatment. Three diabetic patients with pancreatic cancer were also examined as controls. In Study 1, serum CA19-9 (logarithmically transformed value) was significantly correlated with fasting plasma glucose (FPG), HbA1c and GA. On multivariate analysis, GA and FPG, but not HbA1c, were significant explanatory variables for serum CA19-9. In Study 2, serum CA19-9 decreased together with HbA1c and GA after diabetes treatment. The calculated half-lives for HbA1c, GA, and serum CA19-9 were 33.8 days, 16.1 days, and 10.9 days, respectively. The half-life of serum CA19-9 was longer in the study patients than that reported in patients with malignant tumors. By contrast, in the diabetic patients with pancreatic cancer serum CA19-9 showed a marginal decrease after diabetes treatment. Taken all together, prolonged half-life of serum CA19-9 may contribute to the increase in serum CA19-9 levels in diabetic patients without obvious cancer.

The glycated albumin to HbA1c ratio is elevated in patients with fulminant type 1 diabetes mellitus with onset during pregnancy.

Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic ß cell. The most common form of type 1 diabetes mellitus with onset during pregnancy has been shown to be FT1DM at least in Japan. We previously reported that the ratio of glycated albumin (GA) to HbA1c (GA/HbA1c ratio) is elevated in FT1DM patients at the diagnosis. In the present study, we investigated whether the GA/HbA1c ratio is also elevated in FT1DM with onset during pregnancy (P-FT1DM). The study subjects consisted of 7 patients with P-FT1DM. Ten patients with untreated type 2 diabetes mellitus (T2DM) discovered during pregnancy (P-T2DM) and 9 non-pregnant women with untreated T2DM (NP-T2DM) were used as controls. All study patients satisfied HbA1c < 8.7%, the diagnostic criteria for FT1DM. The GA/HbA1c ratio in the P-FT1DM patients at the diagnosis was significantly higher than that in the P-T2DM patients and the NP-T2DM patients. The GA/HbA1c ratio was ≥ 3.0 in all P-FT1DM patients, whereas it was < 3.0 in 8 of 10 P-T2DM patients and all NP-T2DM patients. The GA/HbA1c ratio was also elevated in P-FT1DM patients at the diagnosis compared with T2DM with or without pregnancy.

Comparison of annual variability in HbA1c and glycated albumin in patients with type 1 vs. type 2 diabetes mellitus.

OBJECTIVE: It has been suggested that plasma glucose (PG) levels per se and long-term variations in PG levels are associated with diabetic vascular complications. Glycated albumin (GA) reflects shorter-term glycemic control, as well as postprandial PG levels, as compared to HbA1c. In this study, we hypothesized that GA more strongly reflects long-term variations in PG levels than HbA1c, and compared the variability of HbA1c and that of GA in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHODS: This study included 8 T1DM patients and 48 T2DM patients. Over a 1-year period, HbA1c and GA were measured every month and the mean values and coefficients of variation (CV) for each patient were calculated. RESULTS: In both T1DM and T2DM patients, the CV of GA was significantly higher than the CV of HbA1c. Both the CV of HbA1c and the CV of GA were significantly higher in the T1DM patients than in the T2DM patients. CONCLUSION: The annual variability in GA was greater than that in HbA1c. In addition, the annual variability in HbA1c and that in GA in the T1DM patients were greater than in the T2DM patients. Our findings suggest that GA more accurately reflects long-term variations in PG levels than HbA1c.

Usefulness of glycated albumin for early detection of deterioration of glycemic control state after discharge from educational admission.

Glycated albumin (GA) reflects shorter term glycemic control state than HbA1c. This study evaluated whether GA is useful for early detection of deterioration of glycemic control state after discharge from educational admission. Among the patients with educational admission, this study included 21 diabetic patients who were followed for at least 10 weeks after discharge from educational admission. Deterioration was defined that GA after discharge increased by ≥0.6% compared to the previous GA. Thirteen patients without deterioration up to 10 weeks after discharge were used as controls. In 8 patients with deterioration within 10 weeks after discharge, their HbA1c and GA at the time of admission and the decrease in HbA1c and GA during hospitalization were not significantly different from the control patients. At the time of deterioration, GA in the patients with deterioration increased significantly from 18.7 ± 2.7% to 21.0 ± 2.5%, whereas HbA1c decreased significantly from 9.1 ± 0.7% to 8.3 ± 0.6%. Subsequently, HbA1c increased significantly to 9.0 ± 0.8% together with GA. Thus, GA is useful for early detection of deterioration of glycemic control state after discharge from educational admission.

Estimation of HbA1c response to sitagliptin by change in glycated albumin level for 2 weeks.

UNLABELLED: Aims/Introduction: Since glycated albumin (GA) reflects shorter-term (about 2 weeks) control of plasma glucose levels compared with HbA1c, GA is thought to be a useful glycemic control indicator for the early period following commencement of the treatment of diabetes. In this study, we attempted to estimate HbA1c using the change in GA level before and after the first 2 weeks (ΔGA2w) of administration of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: The study included 28 patients with type 2 diabetes who were administered sitagliptin at a dose of 50 mg/day for 12 weeks. RESULTS: At 2 weeks after administration of sitagliptin, GA markedly decreased, while HbA1c had only slightly decreased. A significant positive correlation was observed between the ΔGA2w and the change in HbA1c before and after the first 12 weeks of administration of sitagliptin (ΔHbA1c12w) (R = 0.793, P < 0.0001). The latter was about 0.6 times the former. The estimated HbA1c after 12 weeks of therapy was calculated by adding ΔGA2w × 0.6 to the baseline HbA1c. A significant positive correlation was observed between the estimated HbA1c and the measured HbA1c after 12 weeks (R = 0.735, P < 0.0001) and both were similar levels. CONCLUSIONS: HbA1c in the first 12 weeks after administration of sitagliptin could be estimated from the formula using the ΔGA2w. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00167.x, 2011).

Estimation of Duration of Symptoms in Fulminant Type 1 Diabetes Mellitus Using HbA1c or Glycated Albumin.

Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic ß cells. Because of an abrupt increase in plasma glucose, HbA1c and glycated albumin (GA) might increase along with duration of symptoms in FT1DM patients. We attempted to devise a formula to estimate duration of symptoms based on the increased levels in HbA1c or GA. Four patients who developed FT1DM during the course of type 2 diabetes mellitus and in whom HbA1c was measured before onset were investigated in this study. The percents of the estimated duration of symptoms calculated from HbA1c (four patients) and GA (two patients) to the actual duration were 137 ± 88% and 122%, respectively. In FT1DM patients in whom HbA1c and/or GA before onset and at the time of ketoacidosis are measured, duration of symptoms might be estimated with using the increased levels in HbA1c or GA.

Glycated albumin levels are higher relative to HbA1c levels in people with autoimmune acute-onset type 1 diabetes mellitus than in people with type 2 diabetes mellitus at the time of diagnosis.

Glycated albumin (GA) is a new glycemic control indicator. GA/HbA1c ratio in autoimmune acute-onset type 1 diabetes mellitus patients was significantly higher than in type 2 diabetes mellitus patients at the time of diagnosis. This difference might reflect speed of increase in plasma glucose after the onset of diabetes.

Profiles of atherosclerotic risk factors in gastrectomized men.

Postprandial hyperglycemia is an established risk factor for atherosclerotic vascular diseases, and it is frequently observed in gastrectomized subjects. This study sought to examine whether other atherosclerotic risk factors are also common among gastrectomized subjects. The study population comprised of 44 non-diabetic men who previously underwent gastrectomy. The age- and body mass index-matched control population comprised of 278 non-diabetic men without gastrectomy. In addition to traditional atherosclerotic risk factors for atherosclerosis, high sensitivity C-reactive protein (hsCRP) and brachial-ankle pulse wave velocity (baPWV) were also compared between the groups. Fasting plasma glucose was not different between both groups, while glycated hemoglobin (HbA1c) was significantly higher in the gastrectomized men than in the control men. Systolic and diastolic blood pressures and high density lipoprotein cholesterol (HDL-C) were significantly higher, whereas low density lipoprotein cholesterol (LDL-C) was lower in the gastrectomized men than in the control men. baPWV, hsCRP, triglycerides and insulin resistance (as per the homeostasis model assessment) were not different between groups. While levels of certain atherosclerotic risk factors, including HbA1c and blood pressure are higher among gastrectomized men, HDL-C and LDL-C were actually favorable. Additionally, levels of more emerging risk factors, such as hsCRP and baPWV were not altered among gastrectomized men.

Genetic basis for the hierarchical interaction between Tobamovirus spp. and L resistance gene alleles from different pepper species.

The pepper L gene conditions the plant's resistance to Tobamovirus spp. Alleles L(1), L(2), L(3), and L(4) confer a broadening spectra of resistance to different virus pathotypes. In this study, we report the genetic basis for the hierarchical interaction between L genes and Tobamovirus pathotypes. We cloned L(3) using map-based methods, and L(1), L(1a), L(1c), L(2), L(2b), and L(4) using a homology-based method. L gene alleles encode coiled-coil, nucleotide-binding, leucine-rich repeat (LRR)-type resistance proteins with the ability to induce resistance response to the viral coat protein (CP) avirulence effectors by themselves. Their different recognition spectra in original pepper species were reproduced in an Agrobacterium tumefaciens-mediated transient expression system in Nicotiana benthamiana. Chimera analysis with L(1), which showed the narrowest recognition spectrum, indicates that the broader recognition spectra conferred by L(2), L(2b), L(3), and L(4) require different subregions of the LRR domain. We identified a critical amino acid residue for the determination of recognition spectra but other regions also influenced the L genes' resistance spectra. The results suggest that the hierarchical interactions between L genes and Tobamovirus spp. are determined by the interaction of multiple subregions of the LRR domain of L proteins with different viral CP themselves or some protein complexes including them.

Usefulness of glycated albumin as an indicator of glycemic control status in patients with hemolytic anemia.

BACKGROUND: In patients with hemolytic anemia (HA), glycated hemoglobin (HbA(1C)) presents lower values in relation to glycemia because the lifespan of erythrocytes is shortened, whereas glycated albumin (GA) is not affected. In the present study, we examined the usefulness of GA as an indicator of glycemic control status in patients with HA. METHODS: We enrolled 21 patients with HA. A total of 202 patients with type 2 diabetes mellitus (T2DM) without complications were used as controls. RESULTS: We identified a significant correlation between GA and HbA(1C) in the patients with HA. However, in a comparison between the patients with HA and those with T2DM, the regression line showed a leftward shift in the former group. There was a significant positive correlation between hemoglobin (Hb) and HbA(1C) in the patients with HA (R=0.541, p=0.025), although there was no significant correlation between Hb and GA. There was an inverse correlation between Hb levels and GA/HbA(1C) ratio (R=-0.710, p=0.001). The measured HbA(1C) levels were lower than the HbA(1C) levels estimated from mean plasma glucose levels, whereas the GA/3 levels were close to the estimated HbA(1C) levels. CONCLUSIONS: GA is a useful indicator of glycemic control status in patients with HA.