Fig. 1.
The scheme of the functional patterns within the glycolytic pathway in beta cells in health and type 1 diabetes. (a) In health (without diabetes), glucokinase (GCK) limits and regulates glucose flux through glycolysis due to a Km of ~10 mmol/l. (b) Available RNA-Seq data from humans with type 1 diabetes indicates that, apart from GCK, HK1/2, with a Km of ~0.1 mmol/l, are upregulated, facilitating flux through glycolysis. Moreover, the rate-limiting subsequent step in glycolysis (conversion of fructose-6-phosphate to fructose-1,6-bisphosphate) is enhanced in type 1 diabetes by upregulation of PFKFB3, increasing pyruvate production. In type 1 diabetes, the extra pyruvate generated is directed to lactate rather than to the TCA cycle by upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase (LDHA). In health (a), pyruvate is metabolised to citrate (solid line) since pyruvate conversion to lactate is a disallowed pathway in adult beta cells (dotted line). In contrast, in type 1 diabetes (b), pyruvate is converted to lactate (solid line) rather than to citrate (dotted line). BP, bisphosphate; P, phosphate; PPP, pentose phosphate pathway.