Recent studies have shown that HCV infection may be an additional risk factor for the development of diabetes independently of chronic liver disease. Numerous studies have shown that patients with chronic HCV infection can lead to hyperinsulinemia and insulin resistance (IR) before they develop cirrhosis. It is currently believed that HCV causes IR mainly (Figure 2): 1) HCV core proteins induce the production of inhibitory factors of insulin, including the suppressor of cytokine signaling 7 (SOCS7), mammalian target of rapamycin (mTOR) and C-Jun amino-terminal kinase (JNK), which then promote the insulin receptor substrate (IRS) proteasome through its proteolytic effects (ii) increased secretion of serum tumor necrosis factor alpha (TNF-α) in HCV-infected patients, which then inhibits the activation of phosphatidylinositol 3-kinase (PI3K) and causes activated protein phosphatase 2A (PP2A) to inhibit the Akt signaling pathway, thereby interfering with the phosphorylation of IRS substrates, which may be (3) HCV can directly inhibit peroxisome proliferator-activated receptor (PPAR) to down-regulate IRS expression, while HCV inactivates Akt protein by down-regulating its phosphorylation, thus affecting insulin signaling and leading to IR; (4) extrahepatic replication of HCV and iron deposition may disrupt islet cell function and lead to IR. Note: (i): suppressor of cytokine signaling 7 (SOCS7); (ii): mammalian target of rapamycin protein (mTOR); (iii): C-Jun amino-terminal kinase (JNK); (iv): inhibition of phosphatidylinositol 3-kinase (PI3K) activity; (v): inhibition of Akt by protein phosphatase 2A (PP2A); (vi) inhibition of peroxisome proliferator-activated receptor (PPAR). (vii): inactivation of Akt protein Conversely, IR also affects CHC. IR activates hepatic stellate cells and initiates the development of hepatic fibrosis by promoting cytokine expression and glycosylation of serum proteins, and also promotes hepatocyte steatosis and accelerates the fibrosis process. Also, IR can affect the efficacy of anti-HCV therapy. Recent studies have shown that in patients with CHC receiving antiviral therapy, the presence or absence of IR is an independent predictor of whether patients will achieve a sustained virological response. In HCV antiviral therapy, relative contraindications to IFN therapy include uncontrolled diabetes. In patients with CHC combined with diabetes mellitus, glycemia should be controlled first, and if liver damage is significant, subcutaneous insulin may be given to control glycemia. After good blood glucose control, PEG IFN-α plus RBV treatment can be given. Fundus retinal, renal and microvascular complications of diabetes should be evaluated before treatment. The goal of treatment is HCV clearance, and the treatment endpoint is sustained virologic response (SVR), which is nearly equivalent to cure in more than 99% of those who achieve SVR. The specific regimen of antiviral therapy is the same as for other patients without diabetes. In principle, IFN should be contraindicated in patients with hepatitis C decompensated cirrhosis in combination with diabetes mellitus. in patients with hepatitis C compensated cirrhosis in combination with diabetes mellitus, treatment should be given to prevent complications if there is no contraindication. Adverse reactions, especially those associated with portal hypertension and hypersplenism, should be closely monitored and managed promptly. Adverse effects of treatment should be evaluated at weeks 2 and 4 of treatment and every 4 to 8 weeks thereafter, and possible adverse events in terms of blood glucose and retina should be closely monitored and promptly managed. Good glycemic control contributes to the successful antiviral therapy and to a higher SVR rate, which improves prognosis and reduces the potential for serious complications. Therefore, patients with combined diabetes mellitus and CHC should be given aggressive glycemic control and aggressive, standardized antiviral therapy to achieve SVR and thus improve or stop the progression of liver disease. Third, the treatment of CHC-related renal disease It is known that CHC is commonly autoimmune disease. Among them, the understanding of the relationship between HCV infection and glomerular disorders has gradually increased in recent years, and many studies have elucidated the relationship between HCV infection and glomerular diseases. The common renal diseases associated with HCV infection include: cold globulinemic membranoproliferative glomerulonephritis, membranoproliferative glomerulonephritis and membranous nephropathy. When HCV renal damage occurs, its treatment includes general and specific therapy. The general treatment is similar to the treatment of other glomerular diseases with proteinuria, including low salt diet and moderate amount of high quality protein diet; if hypertension is present, hypertension and hypercholesterolemia should be actively controlled, and nifedipine (cardiac pain relief) should be given 0.25-0.5mg/kg each time, divided into 3-4 times daily; if necessary, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist (ACEI) should be given to reduce proteinuria. If necessary, an angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist (ACEI) should be administered to reduce proteinuria, such as captopril (mercaptopropionic acid) 1 to 2 mg/kg per day, divided into 2 to 3 doses per day. Specific therapy includes IFNα and antiviral therapy for RBV. Because severe hemolysis can occur in patients with renal insufficiency, it should be used with caution when applying RBV combination therapy. The current efficacy of IFNα in the antiviral treatment of HCV-related renal diseases is variable: ① cold globulinemic glomerulonephritis: Studies have shown that HCV infection is one of the causes of cold globulinemic glomerulonephritis, and it has been reported that 80% to 100% of patients with cold globulinemia are positive for HCV RNA in the serum or in cold precipitation. The clinical features of cryoglobulinemic glomerulonephritis are hematuria and massive proteinuria with varying degrees of renal failure, and IFNα therapy has been shown to be effective in HCV-associated cryoglobulinemia. In a prospective study, 53 patients were randomized to either the conventional treatment group or the combined application of IFNα treatment group. The results were that in the interferon group (3 MU 3 times a week), the viremia disappeared in 60% of patients, whereas in the control group the viremia persisted. Patients with effective treatment showed clinically significant improvement in vasculitis symptoms, a decrease in serum creatinine and a decrease in urinary protein excretion, but the viremia and cold globulinemia recurred after discontinuation of interferon in all patients. Since IFNα 3 MU 3 times a week did not achieve satisfactory results, treatment with different doses of IFNα was proposed. In one report, IFNα 1 0 MU 3 times a week was used in patients who were not treated with conventional doses of IFNα. After 6 weeks of treatment, circulating HCV RNA and cryoglobulin were cleared, nephrotic syndrome was resolved, and urinary protein excretion was 1 g/ of at 18 months of follow-up, and HCV RNA was negative, but the patient could have recurrence of cryoglobulinemia. Another report of treatment with the same dose of IFNα yielded similar findings, where the patient’s viremia remained in remission for 1 year, but cold globulin was still measurable. The above studies suggest that HCV-associated cryoglobulinemia treated with IFNα has some efficacy, but the appropriate dose and duration of treatment are inconclusive and need to be further explored and studied. ②Membranoproliferative glomerulonephritis: Some patients with membranoproliferative glomerulonephritis may also have HCV infection as the etiology, therefore, all patients with histologically confirmed membranoproliferative glomerulonephritis need to be clarified for the presence of HCV infection in the serum even if the serum transaminases are normal. Studies have shown that treatment of HCV-associated membranoproliferative glomerulonephritis with IFNα has some efficacy. However, for HCV-associated membranoproliferative glomerulonephritis with thrombotic microangiopathy, IFNα should be avoided because IFNα itself can cause thrombotic microangiopathy. (iii) Membranous nephropathy: HCV may also be a cause of membranous nephropathy. Unlike HCV-associated membranoproliferative glomerulonephritis, patients with HCV-associated membranous nephropathy have normal complement levels and negative circulating rheumatoid factor and cryoglobulins. Reports on the efficacy of treatment with IFNα in HCV-associated membranous nephropathy are also inconsistent. HCV infection with some rare renal lesions, such as fibrofilamentous glomerulonephritis, is also seen clinically. The clinical presentation is a nephrotic syndrome with renal insufficiency and no cryoglobulinemia. Treatment with standard doses of IFNα resulted in disappearance of viremia, improvement of renal function and reduction of proteinuria. Currently, the treatment of HCV infection in combination with renal disease is a major challenge. the treatment with IFNα has not achieved satisfactory results. Since treatment with IFNα has resulted in improvement of hepatic histological lesions in some patients without any response in biochemical tests, further studies are needed to investigate whether this improvement is due to viral inhibition by IFNα or the direct effect of IFNα. The mechanism of adverse effects in IFNα therapy is also a hot topic of research, with the aim of enabling patients to tolerate long-term IFNα therapy. Notably, in an open, parallel, multi-dose pharmacokinetic study of HCV NS3 protease inhibitors in patients with renal impairment at the 2013 annual meeting of the American Academy of Liver Diseases (AASLD), the control group was 12 patients with normal renal function (creatinine clearance >90 ml/min) and the study group of 12 patients with end-stage renal disease who were on hemodialysis, i.e. glomerular filtration rate <15 ml/(min?1.73 m2), and all patients in the study group received the NS3 protease inhibitor Asunaprevir (ASV) 100 mg. The results showed no clinically significant alterations in ASV pharmacokinetics in patients with renal impairment. The results of the study suggest that no dose adjustment is required for future use of ASV in patients with renal impairment in combination with HCV infection, which offers new hope for the treatment of special populations with HCV infection in combination with renal disease.