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Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-hACE2 transgenic(hACE2Tg)mice with a leptin receptor deficiency(hACE2-Lepr-/-)and high-fat diet(hACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5x105 median tissue culture infectious dose(TCID50)of SARS-CoV-2,with serum and lung tissue samples collected at 3 days post-infection.The hACE2-Lepr-/-mice were then administered a combination of low-molecular-weight heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with 1×104 TCID50 of SARS-CoV-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-CoV-2 susceptibility in hACE2Tg mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the hACE2-Lepr+/+mice,hACE2-Lepr-/-mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1a(HIF-1a),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.