A global health priority (1), type 1 diabetes (T1D) has witnessed a 3%–4% increase in prevalence over the past three decades (2). The risk of multiorgan complications, including acute complications [diabetic ketoacidosis, coma, etc. (3)] and chronic complications [ophthalmopathy, neurological, renal disease, etc. (4)], is increased by the imbalance in glycemic control triggered by insulin deficiency (5) brought on by pancreatic beta-cell autoimmunity. In recent years, we have witnessed an abundance of research on the liver, one of the organs related to type 1 diabetes (6).

A significant worldwide health issue is liver fibrosis induced by either viral or metabolic liver disease (7). Cirrhosis with structural loss, ensuing functional failure, and the emergence of life-threatening consequences have been defined as advanced chronic fibrosis (8). Liver fibrosis is a potentially reversible pathophysiological event (9, 10). Consequently, preventing the development of liver fibrosis to the point of cirrhosis is a potential way to prevent liver-related deaths (7). T2D boosts the risk of cirrhosis and liver-related mortality, particularly in people with NAFLD (11). Nevertheless, the link between liver fibrosis and the less prevalent type of diabetes, T1D, is rather uncommon and has generated debate. According to certain research, it results in little to no progression of liver fibrosis (12, 13), and according to two mate analysis studies, NAFLD patients with T1D experienced little to no progression of liver fibrosis (14, 15). According to certain observational studies, it may result in liver fibrosis (16, 17), which heightens liver stiffness (18, 19). One study revealed that 1 in 20 T1D patients had increased liver stiffness (12) or a 2.0% frequency of advanced fibrosis (15), whereas a Brazilian cross-sectional investigation indicated that 8.4% of T1D people had liver fibrosis (20). The most current MATE observational study (21) comprised just three investigations of T1D patients. However, virtually nothing has been established regarding the association between type 1 diabetes complications and the risk of liver fibrosis in the general population. Possible explanations include the low proportion of T1D patients recruited compared with T2D patients, the rarity of patients with comorbidities, and the length of certain studies, which makes it more challenging to perform research since patients are more likely to drop out. On the other hand, conclusions regarding the causal relationship between T1D, comorbid multisystem complications, and the degree of risk of liver fibrosis progression are hindered by the residual confounding of observational studies and the inherent difficulties of potential reverse causality, a challenge that may be overcome using MR methods.

Similar to RCT research, Mendelian randomization is an efficient statistical technique for determining causation based on whole-genome sequencing data (22). Public big data analysis is more effective and possesses a greater degree of proof as opposed to randomized controlled research, and it is capable of preventing bias and reverse causality. Previous MR research has investigated the risk factors for liver fibrosis and even cirrhosis, and MR studies have also discovered an association between the comorbidity of type 1 diabetes and NAFLD (23). However, neither of these two has previously been the subject of Mendelian randomization experiments.

In this study, we performed the first MR analysis of type 1 diabetes, its acute and chronic complications, liver fibrosis, and cirrhosis. Additionally, we investigated the possible causal relationship between these, as well as offered new suggestions for the early prevention and treatment of liver fibrosis progression and cirrhosis in patients with type 1 diabetes, especially in combination with acute and chronic complications.

SNPs with large outliers and those that departed from the symmetric midline utilizing scatter plots and funnel plots were initially omitted since they might be confounding factors in liver fibrosis and cirrhosis. We obtained eight separate sets of IVs without linkage disequilibrium ( Supplementary Material ). The bias of weak IVs was eliminated by the F statistics of these eight groups of IVs, which were all more than 1,000. Finally, for these eight groups, we created scatter plots ( Figure 2 ) and leave-one-out plots ( Figure 3 ).

The results of the forest plot ( Figure 4 ) presented a positive causal relationship between both type 1 diabetes and its complications and liver fibrosis and cirrhosis. Firstly, we performed IVW analysis, type 1 diabetes (exclude DM2): OR = 1.13, 95% CI: 1.04–1.23, ^** P = 3.42 × 10⁻³. Type 1 diabetes without complications: OR = 1.12, 95% CI: 1.03–1.23, ^* P = 1.26 × 10⁻². Type 1 diabetes with coma: OR = 1.09, 95% CI: 1–1.18, ^* P = 4.74 × 10⁻². Type 1 diabetes with ketoacidosis: OR = 1.07, 95% CI: 1.01–1.13, ^* P = 1.3 × 10⁻². Type 1 diabetes with neurological complications: OR = 1.18, 95% CI: 1.11–1.26, ^*** P = 4.05 × 10⁻⁷. Type 1 diabetes with ophthalmic complications: OR = 1.16, 95% CI: 1.05–1.28, ^** P = 3.06 × 10⁻³. Type 1 diabetes with renal complications: OR = 1.07, 95% CI: 1–1.13, ^* P = 3.45 × 10⁻². Type 1 diabetes with other specified/multiple/unspecified complications: OR = 1.12, 95% CI: 1.02–1.23, ^* P = 1.41 × 10⁻². In addition, MR-Egger’ analysis portrayed that type 1 diabetes with ophthalmic complications: OR = 1.3, 95% CI: 1.04–1.62, ^* P = 4.43 × 10⁻². Type 1 diabetes with neurological complications: OR = 1.19, 95% CI: 1.04–1.36, ^* P = 2.68 × 10⁻². Weighted median analysis shows that type 1 diabetes (exclude DM2): OR = 1.14, 95% CI: 1.05–1.24, ^** P = 1.86 × 10⁻³. Type 1 diabetes with neurological complications: OR = 1.18, 95% CI: 1.08–1.28, ^*** P = 1.48 × 10⁻⁴. Type 1 diabetes with other specified/multiple/unspecified complications: OR = 1.1, 95% CI: 1.01–1.2, ^* P = 2.37 × 10⁻². Weighted mode analysis shows that type 1 diabetes (exclude DM2): OR = 1.15, 95% CI: 1.06–1.25, ^* P = 1.03 × 10⁻². Type 1 diabetes with neurological complications: OR = 1.17, 95% CI: 1.07–1.28, ^** P = 5.07 × 10⁻³. Simple median analysis showed that type 1 diabetes with neurological complications: OR = 1.15, 95% CI: 1.03–1.28, ^* P = 1.26 × 10⁻². The scatter plot ( Figure 2 ) demonstrated that the five lines of “inverse variance weighted,” “MR-Egger,” “weighed median,” “weighed mode,” and “simple mode” all had consistent slope beta values and P values. Taking these findings together, we concluded that type 1 diabetes and complications had significant differences in liver fibrosis and cirrhosis and that they all satisfied the positive relationship, i.e., the higher the risk of having type 1 diabetes and complications. Cochran’s IVWQ test results revealed that there was no discernible heterogeneity in these IVs ( Table 1 ). According to the outcomes of the MR-Egger regression intercept analysis, there was also no discernible directional horizontal pleiotropy ( Table 1 ). However additional MR-PRESSO analysis likewise failed to detect any appreciable horizontal pleiotropy ( Table 1 ).

To determine the causal link between type 1 diabetes, complications, and liver fibrosis and cirrhosis, we conducted the first thorough bivariate multivariate MR analysis of type 1 diabetes, its acute and chronic consequences (exposure), and liver fibrosis and cirrhosis (outcome). According to our research, there is a causal association between type 1 diabetes, its acute and chronic consequences, and liver fibrosis and cirrhosis, implying that these conditions raise the likelihood of liver fibrosis advancement.

As a result, we surmised that T1D might hasten the development of liver fibrosis. Millions of people throughout the world suffer from type 1 diabetes (30), an inflammatory illness, and one of its complications is liver alterations (18, 31). We are aware that the long-term exposure of hepatocytes to glucose levels above the physiological range is a factor in the development of fibrosis (32), looking back at earlier investigations into type 1 diabetes and liver fibrosis. Patients with advanced fibrosis are more likely to suffer from metabolic syndrome, particularly if they have unfavorable lipid profiles, or are less sensitive to insulin compared with people without progressive fibrosis (15). Recent research reveals that sedentary lifestyles and high-calorie consumption are contributing factors in a rising proportion of T1D patients becoming overweight and developing insulin resistance (IR) features (33). Adipose tissue that is metabolically harmful is produced by insulin resistance in the liver and the periphery, which is increasingly thought to be associated with T1D (34). Adipose tissue inflammation is one of the factors contributing to steatohepatitis and fibrosis, especially in NAFLD (35), when type 1 diabetes is more severe or combined with complications manifested by elevated liver enzymes, which are typically linked to increased liver fat (6, 36). A similar relevance to glycogen deposition in hepatocytes has also been demonstrated in other studies (37). Hyperglycemia or insulin resistance, increased glycogen synthesis, stimulation of immunological cells, fibrogenic-programmed cells in the vasculature, or organ-specific parenchymal cells are all effects of inadequately managed T1D hyperglycemia (17). Therefore, we hypothesize that variations in insulinemia and hyperglycemia could possess a significant role in T1D-related liver fibrosis.

In addition, this study also discovered that patients with type 1 diabetes who experienced neurological and ophthalmic complications possessed ORs that were higher than the mean OR value for people with type 1 diabetes, whereas patients who experienced ketoacidosis and coma, renal complications, and other specified/multiple/unspecified complications experienced ORs that were lower than the mean OR value for people with type 1 diabetes, which is more in line with observational studies. The first observational study discovered an association between ALT and GGT activity and type 1 diabetes along with joint restriction and neuropathy, and GGT activity was also discovered to be associated with the severity of retinopathy (38). Another Dutch cross-sectional study revealed that concomitant neuropathy and ophthalmopathy were considerably more prevalent in the 150 patients with type 1 diabetes than coexisting renal and cardiovascular illness, but unfortunately, the number of participants was insufficient to draw any conclusions. Unfortunately, a correlation factor analysis (15) was not possible due to the small number of patients with type 1 diabetes and its comorbidities. Recent studies (39, 40) have additionally demonstrated that people with severe insulin-deficient diabetes are more likely to develop retinopathy and neuropathy. In this context, we hypothesize that type 1 diabetes with neurological and ocular problems is more likely to encourage the development of liver inflammation and fibrosis in comparison with type 1 diabetes with other comorbidities. Meanwhile, the OR of type 1 diabetes with chronic complications was slightly greater than the OR of type 1 diabetes without complications and acute complications. However, despite the fact that the data were high and the ORs and 95% CI of type 1 diabetes patients without complications could not significantly differ from those of patients with combined complications, it is possible that this is because the patients included in the study did not have enough combined multisystem complications to be separated, the complications were not identified, or the lesions were mild but not to the point where other complications could be diagnosed, etc., or the difference between the progression of liver fibrosis solely and the presence or absence of combination problems in type 1 diabetes was not significant.

Unquestionably, this study discovered that type 1 diabetes and its consequences, to a greater or lesser extent, speed up the progression of liver fibrosis, which has ramifications for both current and future generations’ clinical and public health. In this regard, our recommendation is to make an effort to manage blood glucose in type 1 diabetes patients in order to lessen the progression of multiple diseases such as liver fibrosis and to slow down oscillations in glucose and insulinemia. Future research is required in order to better comprehend the mechanisms behind the association between type 1 diabetes, its concomitant conditions, and the risk of cirrhosis and liver fibrosis.

According to our MR investigation, type 1 diabetes and both its acute and chronic consequences might increase the likelihood that liver fibrosis could develop. The development of liver inflammation and fibrosis is more likely to be promoted by type 1 diabetes with neurological and ocular problems, which offers fresh insights into the genetic and clinical research of liver fibrosis and cirrhosis. Future research is required to clarify the probable processes underlying how type 1 diabetes, as well as its acute and chronic consequences, contribute to liver fibrosis.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

This research has been conducted using published studies and consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent. In addition, no individual-level data were utilized in this study. Therefore, no new ethical review board approval was required. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

GH: Writing – original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. YG: Writing – review & editing, Supervision, Project administration, Funding acquisition.