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The Connection between Liver Disease and Diabetes Mellitus
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The Connection between Liver Disease and Diabetes Mellitus

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (20 June 2022) | Viewed by 25051

Special Issue Editors

Prof. Dr. Dirk Raddatz

E-Mail Website
Guest Editor
Universität Göttingen, Gottingen, Germany
Interests: obesity; bariatric surgery; metabolic endoscopy; diabetes; metabolic syndrome; NAFLD
Dr. Katja Gollisch

E-Mail Website
Guest Editor
Division of Endocrinology, Clinic for Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany
Interests: Diabetes; Metabolic Syndrome; NAFLD; Bones; Osteoporosis

Special Issue Information

Dear Colleagues,

Liver disease in the context of the metabolic syndrome is part of the daily business in every GP practice, and the co-occurrence of fatty liver and type 2 diabetes mellitus (T2DM) is a frequent phenomenon. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western nations, and the association of T2DM and fatty liver disease has led to immense costs in health care systems worldwide.

The liver, in its function as a central metabolic hub, plays a major role in maintaining glucose homeostasis. The relationship between liver disease and diabetes has been known for more than 100 years. At the end of the 19th century, the German physician Naunyn described the so-called “hepatogenic diabetes”. At that time, mainly alcohol and viral hepatitis were understood to cause liver cirrhosis with consecutive diabetes. Today the situation is regarded as much more complex. We know that metabolic pathologies like diabetes may lead to liver disease. Recently, the term metabolic-dysfunction-associated fatty liver disease (MAFLD) has been suggested to complement or replace the term NAFLD in order to emphasize the reciprocal relationship of metabolic disorders and liver disease.

Both T2DM and MAFLD are heterogeneous disorders that exhibit a wide range of different phenotypes. These phenotypes are most likely determined by different genetic and environmental factors as well as other as-yet unknown variables.   

The aim of the planned Special Issue on Liver Disease and Diabetes Mellitus is to come one step closer to a personalized management for patients with MAFLD and T2DM. The more detailed the knowledge of underlying pathomechanisms, epidemiology, genetics, environmental factors, biomarkers, diagnostic procedures, and interventions, the more successful this will be.

We would like to invite you to help illuminate the way with your contribution. Original research papers, reviews, and case reports are welcome.

Prof. Dr. Dirk Raddatz
Dr. Katja Gollisch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bariatric surgery
  • MAFLD (metabolic dysfunction-associated fatty liver disease)
  • NAFLD (non-alcoholic fatty liver disease)
  • T2DM (type 2 diabetes mellitus)
  • Insulin resistance
  • Drug therapy
  • Nutrition
  • Inflammation
  • Ultrasound elastography
  • Metabolic endoscopy

Published Papers (7 papers)

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Research

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11 pages, 1502 KiB  
Article
Non-Invasive Detection of Fibrotic NASH in NAFLD Patients with Low or Intermediate FIB-4
by Katharina John, Martin Franck, Sherin Al Aoua, Monika Rau, Yvonne Huber, Joern M. Schattenberg, Andreas Geier, Matthias J. Bahr, Heiner Wedemeyer, Klaus Schulze-Osthoff and Heike Bantel
J. Clin. Med. 2022, 11(15), 4394; https://doi.org/10.3390/jcm11154394 - 28 Jul 2022
Cited by 3 | Viewed by 1566
Abstract
Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier [...] Read more.
Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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12 pages, 978 KiB  
Article
Metformin Improves the Hepatic Steatosis Index in Non-Obese Patients with Polycystic Ovary Syndrome
by Annika Riemann, Martina Blaschke, Annukka Jauho-Ghadimi, Heide Siggelkow and Katja Susanne Claudia Gollisch
J. Clin. Med. 2022, 11(15), 4294; https://doi.org/10.3390/jcm11154294 - 24 Jul 2022
Cited by 3 | Viewed by 6576
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common yet little recognized health problem in women with polycystic ovary syndrome (PCOS). In a retrospective setting, we investigated the effects of metformin treatment on the hepatic steatosis index (HSI) as a readily available biomarker panel [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a common yet little recognized health problem in women with polycystic ovary syndrome (PCOS). In a retrospective setting, we investigated the effects of metformin treatment on the hepatic steatosis index (HSI) as a readily available biomarker panel for NAFLD. HSI values of >36 are considered to be highly suggestive for NAFLD. In our cohort, HSI values indicating NAFLD were found in 60/81 (74.1%) women at baseline. The mean HSI improved significantly after the metformin treatment from 43.2 ± 1.0 to 41.0 ± 1.1. Subgroup analyses of non-obese (body mass index (BMI) < 30 kg/m2), obese (BMI 30–35 kg/m2) and very obese (BMI > 35 kg/m2) women yielded mean baseline HSI values of 35.5 ± 4.5, 41.2 ± 2.7 and 51.2 ± 4.7, respectively. A significant improvement in the HSI of 1.5 ± 2.1 was observed after metformin treatment in non-obese women but not in the obese subgroups. The data suggest a new aspect of metformin treatment in non-obese PCOS patients, namely, a possible improvement in NAFLD. This study highlighted hepatic steatosis as a common comorbidity in PCOS patients that can severely affect their long-term health, and therefore, deserves more attention in the management of PCOS patients. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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19 pages, 2701 KiB  
Article
Improvement of Type 2 Diabetes Mellitus and Attenuation of NAFLD Are Associated with the Success of Obesity Therapy
by Andreas Schmid, Miriam Arians, Thomas Karrasch, Jörn Pons-Kühnemann, Andreas Schäffler, Martin Roderfeld and Elke Roeb
J. Clin. Med. 2022, 11(7), 1756; https://doi.org/10.3390/jcm11071756 - 22 Mar 2022
Cited by 6 | Viewed by 1735
Abstract
Obesity and type 2 diabetes mellitus (T2D) represent important comorbidities of the metabolic syndrome, which are associated with non-alcoholic fatty liver disease (NAFLD)-related hepatic fibrosis. In total, 160 morbidly obese patients—81 following a low-calorie formula diet (LCD) program and 79 undergoing bariatric surgery [...] Read more.
Obesity and type 2 diabetes mellitus (T2D) represent important comorbidities of the metabolic syndrome, which are associated with non-alcoholic fatty liver disease (NAFLD)-related hepatic fibrosis. In total, 160 morbidly obese patients—81 following a low-calorie formula diet (LCD) program and 79 undergoing bariatric surgery (Roux-en-Y gastric bypass, RYGB)—were examined for anthropometric and metabolic parameters at base-line and during 12 months of weight loss, focusing on a putative co-regulation of T2D parameters and liver fibrosis risk. High NAFLD fibrosis scores (NFS) before intervention were associated with elevated HbA1c levels and T2D. Loss of weight and body fat percentage (BFL) were associated with improved glucose and lipid metabolism and reduced risk of NAFLD-related fibrosis, with particularly beneficial effects by RYGB. Both T2D improvement and NFS decrease were positively associated with high BFL. A highly significant correlation of NFS reduction with BFL was restricted to male patients while being absent in females, accompanied by generally higher BFL in men. Overall, the data display the relation of BFL, T2D improvement, and reduced NAFLD-related fibrosis risk during weight loss in morbidly obese individuals induced by diet or RYGB. Furthermore, our data suggest a considerable sexual dimorphism concerning the correlation of fat loss and improved risk of liver fibrosis. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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14 pages, 2544 KiB  
Article
Liraglutide + PYY3-36 Combination Therapy Mimics Effects of Roux-en-Y Bypass on Early NAFLD Whilst Lacking-Behind in Metabolic Improvements
by Valentin Metzner, Gloria Herzog, Tobias Heckel, Thorsten Bischler, Julia Hasinger, Christoph Otto, Martin Fassnacht, Andreas Geier, Florian Seyfried and Ulrich Dischinger
J. Clin. Med. 2022, 11(3), 753; https://doi.org/10.3390/jcm11030753 - 30 Jan 2022
Cited by 4 | Viewed by 3186
Abstract
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects [...] Read more.
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY3-36) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY3-36 (0.1 mg/kg/day), liraglutide+PYY3-36, and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY3-36 induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY3-36- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY3-36 partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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10 pages, 261 KiB  
Article
HCV Genotype Has No Influence on the Incidence of Diabetes—EpiTer Multicentre Study
by Paweł Rajewski, Dorota Zarębska-Michaluk, Ewa Janczewska, Andrzej Gietka, Włodzimierz Mazur, Magdalena Tudrujek-Zdunek, Krzysztof Tomasiewicz, Teresa Belica-Wdowik, Barbara Baka-Ćwierz, Dorota Dybowska, Waldemar Halota, Beata Lorenc, Marek Sitko, Aleksander Garlicki, Hanna Berak, Andrzej Horban, Iwona Orłowska, Krzysztof Simon, Łukasz Socha, Marta Wawrzynowicz-Syczewska, Jerzy Jaroszewicz, Zbigniew Deroń, Agnieszka Czauż-Andrzejuk, Jolanta Citko, Rafał Krygier, Anna Piekarska, Łukasz Laurans, Witold Dobracki, Jolanta Białkowska, Olga Tronina, Magdalena Wietlicka-Piszcz, Małgorzata Pawłowska and Robert Flisiakadd Show full author list remove Hide full author list
J. Clin. Med. 2022, 11(2), 379; https://doi.org/10.3390/jcm11020379 - 13 Jan 2022
Cited by 4 | Viewed by 1299
Abstract
HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the [...] Read more.
HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)

Review

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12 pages, 931 KiB  
Review
Role of Ultrasound Methods for the Assessment of NAFLD
by Golo Petzold
J. Clin. Med. 2022, 11(15), 4581; https://doi.org/10.3390/jcm11154581 - 05 Aug 2022
Cited by 12 | Viewed by 4635
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The prevalence in patients with type 2 diabetes mellitus is between 55–80%. The spectrum of NALFD ranges from simple steatosis to aggressive steatohepatitis with potentially progressive liver fibrosis up to cirrhosis [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The prevalence in patients with type 2 diabetes mellitus is between 55–80%. The spectrum of NALFD ranges from simple steatosis to aggressive steatohepatitis with potentially progressive liver fibrosis up to cirrhosis and hepatocellular carcinoma. In clinical practice, there are two important aims: First to make the diagnosis of NAFLD, and second, to identify patients with advanced fibrosis, because extent of fibrosis is strongly associated with overall mortality, cardiovascular disease, hepatocellular carcinoma, and extrahepatic malignancy. Histology by liver biopsy can deliver this information, but it is an invasive procedure with rare, but potentially severe, complications. Therefore, non-invasive techniques were developed to stage fibrosis. Ultrasound is the primary imaging modality in the assessment of patients with confirmed or suspected NAFLD. This narrative review focus on different ultrasound methods to detect and graduate hepatic steatosis and to determine grade of fibrosis using elastography-methods, such as transient elastography and 2-dimensional shear wave elastography in patients with NAFLD. Particular attention is paid to the application and limitations in overweight patients in clinical practice. Finally, the role of B-mode ultrasound in NAFLD patients to screen for hepatocellular carcinoma is outlined. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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30 pages, 20527 KiB  
Review
Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases
by Gerhard Paul Püschel, Julia Klauder and Janin Henkel
J. Clin. Med. 2022, 11(15), 4358; https://doi.org/10.3390/jcm11154358 - 27 Jul 2022
Cited by 29 | Viewed by 4678
Abstract
Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the [...] Read more.
Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver. Full article
(This article belongs to the Special Issue The Connection between Liver Disease and Diabetes Mellitus)
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