RESUMEN
Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and act as a prediabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of glucagon resistance towards amino acid catabolism, resulting in a compensatory hyperglucagonemia. We investigated the presence of hyperglucagonemia in individuals with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD), and whether body mass index (BMI), T2D, hepatic steatosis and/or fibrosis contribute to this relationship. To dissect potential mechanisms, we determined hepatic gene expression related to amino acid transport and catabolism. Individuals with MASLD had hyperglucagonemia (controls (n=74) versus MASLD (n=106); median [Q1, Q3]; 4 [3, 7] versus 8 [6, 13] pM), p<.0001) and were glucagon resistant (assessed by the glucagon-alanine index) (1.3 [0.9, 2.1] versus 3.3 [2.1, 5.3] pM*mM, p<.0001). These changes associated with hepatic steatosis (p<.001, R2>.25) independently of BMI, sex, age, and T2D. Plasma levels of glucagon were similar in individuals with MASLD when stratified on T2D status (MASLD-T2D (n=52) versus MASLD+T2D (n=54); 8 [6, 11] versus 8 [6, 13] pM, p=.34) and hepatic fibrosis (MASLD+F0 (n=25) versus MASLD+F1-F3 (n=67); 8.4 [7.0, 13.3] versus 7.9 [5.2, 11.6] pM, p=.43). Obesity (BMI=30kg/m2) did not alter glucagon levels (p=.65) within groups (control/MASLD). The mRNA expression of proteins involved in amino acid transport and catabolism were downregulated in MASLD. Thus, prediabetogenic hyperglucagonemia is present in individuals with biopsy-verified MASLD, and hepatic steatosis partially drives hyperglucagonemia and glucagon resistance, irrespective of T2D, BMI, and hepatic fibrosis.
RESUMEN
Increased plasma levels of glucagon (hyperglucagonaemia) promote diabetes development but is also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance towards amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, consisting of two study days: a glucagon injection and measurements of plasma amino acids, and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The delta-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (p=0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (p<0.0001), but not T1D (p>0.99). In contrast, glucagon-induced glucose increments were similar in controls and MASLD (p=0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.
RESUMEN
Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.
Asunto(s)
Glucemia , Hepatitis Autoinmune , Resistencia a la Insulina , Insulina , Humanos , Femenino , Masculino , Persona de Mediana Edad , Glucemia/metabolismo , Estudios Transversales , Adulto , Insulina/sangre , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/metabolismo , Hepatitis Autoinmune/complicaciones , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/metabolismo , Hígado Graso/metabolismo , Hígado Graso/sangre , Polipéptido Inhibidor Gástrico/sangre , Polipéptido Inhibidor Gástrico/metabolismo , Anciano , Prueba de Tolerancia a la Glucosa , Colangitis Esclerosante/sangre , Colangitis Esclerosante/metabolismo , Colangitis Esclerosante/complicaciones , Glucagón/sangre , Glucagón/metabolismo , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Biliar/complicaciones , Péptido C/sangreRESUMEN
INTRODUCTION: Abdominal ultrasound (US) and CT are important tools for the initial evaluation of patients with liver disease. Our study aimed to determine the accuracy of these methods for diagnosing cirrhosis. METHODS: In all, 377 participants from 4 prospective cohort studies evaluating patients with various liver diseases were included. All patients were included between 2017 and 2022 and had undergone a liver biopsy as well as US and/or CT. Using the histological assessment as the gold standard, we calculated diagnostic accuracy for US and CT. Liver biopsies were evaluated by expert histopathologists and diagnostic scans by experienced radiologists. RESULTS: The mean age was 54 ± 14 years and 47% were female. Most patients had NAFLD (58.3%) or alcohol-associated liver disease (25.5%). The liver biopsy showed cirrhosis in 147 patients (39.0%). Eighty-three patients with cirrhosis had Child-Pugh A (56.4% of patients with cirrhosis) and 64 had Child-Pugh B/C (43.6%). Overall, the sensitivity for diagnosing cirrhosis by US was 0.71 (95% CI 0.62-0.79) and for CT 0.74 (95% CI 0.64-0.83). The specificity was high for US (0.94, 95% CI 0.90-0.97) and for CT (0.93, 95% CI 0.83-0.98). When evaluating patients with Child-Pugh A cirrhosis, sensitivity was only 0.62 (95% CI 0.49-0.74) for US and 0.60 (95% CI 0.43-0.75) for CT. For patients with Child-Pugh B/C, sensitivity was 0.83 (95% CI 0.70-0.92) for US and 0.87 (95% CI 0.74-0.95) for CT. When limiting our analysis to NAFLD (20% with cirrhosis), the sensitivity for US was 0.45 (95% CI 0.28-0.64) and specificity was 0.97 (95% CI 0.93-0.99). CONCLUSION: US and CT show moderate sensitivity and may potentially overlook compensated cirrhosis underlining the need for additional diagnostic testing.
Asunto(s)
Hepatopatías Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Estudios Prospectivos , Cirrosis Hepática/diagnóstico por imagen , Ultrasonografía , Tomografía Computarizada por Rayos XRESUMEN
Fatty liver disease has mainly been characterized under fasting conditions. However, as the liver is essential for postprandial homeostasis, identifying postprandial disturbances may be important. Here, we investigated postprandial changes in markers of metabolic dysfunction between healthy individuals, obese individuals with non-alcoholic fatty liver disease (NAFLD) and patients with cirrhosis. We included individuals with biopsy-proven NAFLD (n = 9, mean age 50 years, mean BMI 35 kg/m2 , no/mild fibrosis), cirrhosis with hepatic steatosis (n = 10, age 62 years, BMI 32 kg/m2 , CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2 ), randomized 1:1 to fasting or standardized mixed meal test (postprandial). None of the patients randomized to mixed meal test had type 2 diabetes (T2D). Peripheral blood was collected for 120 min. After 60 min, a transjugular liver biopsy and liver vein blood was taken. Plasma levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured. Postprandial peak glucose and C-peptide were significantly increased in NAFLD, and cirrhosis compared with healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia as a potential sign of glucagon resistance. FGF21 was increased in NAFLD and cirrhosis independent of sampling from the liver vein versus peripheral blood. Glucagon levels were higher in the liver vein compared with peripheral blood. Patients with NAFLD and cirrhosis without T2D showed impaired glucose tolerance, hyperinsulinemia, and hyperglucagonemia after a meal compared to healthy individual. Postprandial characterization of patients with NAFLD may be important to capture their metabolic health.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Persona de Mediana Edad , Adulto Joven , Adulto , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Glucagón , Diabetes Mellitus Tipo 2/metabolismo , Péptido C , Hígado/metabolismo , Glucosa/metabolismo , Cirrosis Hepática/metabolismoRESUMEN
A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥ 25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.
Asunto(s)
Glucagón , Enfermedad del Hígado Graso no Alcohólico , Humanos , Glucagón/metabolismo , Estudios Transversales , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , AminoácidosRESUMEN
AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1. METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured. RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change. CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study. CLINICALTRIALS: gov (NCT03893526).