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Prediabetes is characterised by impaired glucose tolerance and elevated glycated haemoglobin (HbA1c). Although metformin improves insulin sensitivity, adherence limitations to lifestyle interventions highlight the need for alternative drugs that can be effective even without dietary intervention. In our laboratory, we synthesised a novel ruthenium complex that exhibits elevated biological activity. Accordingly, this study investigated the metabolic effects of a novel ruthenium (II)\u2013uracil Schiff base complex in HFHC diet-induced prediabetic rats, with and without dietary intervention. Methods: Forty-eight male Sprague-Dawley rats (150\u2013180 g) were divided into two groups, the standard diet (n = 12) and HFHC diet groups (n = 36), for prediabetic induction. Prediabetic animals were randomly assigned to respective treatment groups. The ruthenium complex was administered to prediabetic rats once a day, every third day, for 12 weeks, while monitoring changes in blood glucose, caloric intake, and body weight. Results: Diet-induced prediabetes resulted in increased fasting blood glucose and elevated HbA1c. The administration of the ruthenium (II)\u2013uracil Schiff base complex reduced fasting blood glucose, improved insulin levels and ghrelin, enhanced GLUT4 expression, and significantly increased skeletal muscle glycogen, especially when combined with dietary intervention. Conclusions: The findings showed that the ruthenium complex exerts a pronounced effect on ameliorating glucose homeostasis, enhancing skeletal muscle glucose uptake, and improving overall metabolic function.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070811","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Evaluation of the Effects of the Ruthenium (II)\u2013Uracil Schiff Base Complex on Selected Markers of Glucose Homeostasis in Diet-Induced Prediabetic Male Rats"],"prefix":"10.3390","volume":"18","author":[{"given":"Zenele","family":"Chonco","sequence":"first","affiliation":[{"name":"Department of Human Physiology, School of Medicine, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2571-5112","authenticated-orcid":false,"given":"Nompumelelo Anna-Cletta","family":"Gumede","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, School of Medicine, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-0038","authenticated-orcid":false,"given":"Andile","family":"Khathi","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, School of Medicine, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-8505","authenticated-orcid":false,"given":"Lindokuhle","family":"Mabuza-Mashaba","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, School of Medicine, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","first-page":"37","article-title":"Type 2 diabetes as a prominent global health issue: A narrative review","volume":"5","author":"Ansaripour","year":"2022","journal-title":"J. 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