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OBJECTIVE -- Insulin resistance, associated with increased lipolysis, results in a high exposure of nonadipose tissue to lipids. Experimental data indicate that fatty infiltration of pancreatic islets may also contribute to β-cell dysfunction, but whether this occurs in humans in vivo is unknown. RESEARCH DESIGN AND METHODS -- Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of β-cell function in 12 insulin-naive type 2 diabetic and 24 age- and BMI-matched nondiabetic men. RESULTS -- Patients versus control subjects had higher A1C, fasting plasma glucose, and insulin and triglyceride levels and lower HDL cholesterol, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients and control subjects was 20.4% (13.4-43.6) and 9.7% (7.0-20.2), respectively (P = 0.032). Pancreatic fat correlated negatively with β-cell function parameters, including the insulinogenic index adjusted for insulin resistance, early glucose-stimulated insulin secretion, β-cell glucose sensitivity, and rate sensitivity (all P < 0.05), but not potentiation. However, these associations were significantly affected by the diabetic state, such that a significant association of pancreatic fat with β-cell dysfunction was only present m the nondiabetic group (all P < 0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat account for further β-cell function decline. In control subjects, the association of pancreatic fat and β-cell function remained significant after correction for BMI, fasting plasma glucose, and triglycerides (P = 0.006). CONCLUSIONS -- These findings indicate that pancreatic lipid content may contribute to β-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans. [ABSTRACT FROM AUTHOR]

In insulin resistant states, increased lipolysis in adipose tissue and unsuppressed hepatic VLDL-triglyceride output lead to a high exposure of non-adipose tissues to lipids. Experimental and autopsy data indicate that fatty infiltration of pancreatic islets may also contribute to β-cell dysfunction, but whether this phenomenon occurs in humans in vivo is unknown. Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of β-cell function in 12 insulin-naïve type 2 diabetic and 24 age- and BMI-matched non-diabetic males. Patients versus controls had higher HbA1c, fasting plasma glucose, insulin and triglyceride levels, lower HDL-C, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients was 20.4(13.4-43.6) and 9.7(7.0-20.2)% in controls (P=0.032). Pancreatic fat correlated negatively with β-cell function parameters, including insulinogenic index adjusted for insulin resistance, early phase insulin secretion, β-cell glucose sensitivity, rate sensitivity (all P<0.05), but not potentiation. The interaction of pancreatic fat with the diabetic state significantly affected the association. Separate analyses showed a significant association of pancreatic fat with β-cell dysfunction in the non-diabetic group only (all P<0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat may account for further β-cell function decline. In controls, the association of pancreatic fat and β-cell dysfunction remained significant after correction for BMI, fasting plasma glucose and triglycerides (P=0.006). These findings indicate that pancreatic lipid content may contribute to β-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (DM2) and the metabolic syndrome (MetS) are conditions associated with a high risk of coronary artery disease (CAD) and congestive heart failure (CHF). Although CAD contributes to diastolic dysfunction and left ventricular (LV) stiffness, the interaction between CAD, DM2 and the MetS, is largely unknown. We studied the impact of CAD, DM2 and the MetS on LV function and stiffness in patients who underwent a diagnostic coronary angiography. Sixty patients (n=22 with and n=21 without the MetS and n=17 with DM2; n=38 males were studied. Only subjects with LV ejection fraction >40% were included to avoid the confounding of post myocardial infarction remodeling. CAD severity was determined according to the number of the vessels with >50% stenosis. Thus, 26 patients had no CAD, 14 had 1, 9 had 2, 11 had 3 vessel disease. Hemodynamic and echocardiographic data were collected and combined to calculate percent LV wall thickening (LVWT%), a measure of systolic function, as well as LV end-diastolic wall thickness (LVWTed) and myocardial stiffness modulus, both variables of diastolic function. LVWT% did not differ among groups. DM2 subjects and those with the MetS had higher LVWTed than controls (P=0.019), but LV stiffness was not increased. Patients with vs those without CAD had higher LVWTed (P=0.022) and lower LVWT% (P=0.031). A trend for increased LV stiffness in CAD patients was observed (P=0.158). LV stiffness worsened according to the number of vessels involved (P=0.044). Multivariate analyses revealed CAD as an independent determinant of LV stiffness, after correction for age, gender and fasting glucose, in patients with MetS and DM2 (P=0.002), but not in controls (P=0.895). In conclusion, increased LVWTed was observed in subjects with the MetS and DM2, vs controls, and in patients with relative to those without CAD. We show that the contribution of CAD to LV stiffness depends on the presence of dysmetabolic conditions including the MetS and DM2. These findings implicate that strategies aiming early detection and treatment of CAD in people with MetS and DM2 may prevent future development of CHF. [ABSTRACT FROM AUTHOR]

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria., Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC., Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria ( p = 0.46 and p = 0.40, respectively) or from AIH ( p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs . 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043)., Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy., Impact and Implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome., (© 2024 The Author(s).)

Background and Aims: A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment., Methods: A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects., Results: Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events., Conclusions: CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed., Competing Interests: ME Tushuizen has been an editorial board member of Journal of Clinical and Translational Hepatology since 2021, and B van Hoek has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2022 Authors.)

Objective: Hepatic steatosis and obesity are components of the metabolic syndrome and risk factors for developing type 2 diabetes (T2DM). We studied how liver fat and body fat distribution relate to various aspects of beta-cell function., Methods: In 12 men with T2DM, 10 men with impaired glucose tolerance (IGT), and 14 age- and body mass index-matched controls, we measured body fat distribution and liver fat by magnetic resonance imaging and spectroscopy. An oral glucose tolerance test was performed to calculate insulin secretory rate (ISR) by C-peptide deconvolution, and beta-cell function using a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor., Results: Waist circumference and the various body fat compartments did not differ among groups. IGT had the highest total and late phase insulin secretion (P<0.001), whereas patients had the lowest insulinogenic index adjusted for insulin resistance (P=0.006). In spite of the hypersecretion, IGT had beta-cell glucose sensitivity, rate sensitivity, and potentiation similar to controls. Liver fat content was highest in diabetic patients (P=0.004) and showed the strongest association with total and late phase of insulin secretion in the IGT group (r=0.657, P=0.039 and r=0.732, P=0.016 respectively). Model beta-cell function variables showed no association with liver fat or body fat compartments., Conclusions: These data suggest that, in spite of the association of central adiposity and liver fat with T2DM risk, additional, hitherto unknown factors may contribute to beta-cell dysfunction in susceptible humans.