The glucose homeostasis system maintains normoglycaemia by adapting the mass and function of betacells that counter insulin resistance, a lowered betacell mass or an excess nutrient intake. It is often assumed that hyperglycaemia is the stimulatory force for beta-cell adaptation through the well-known regulatory effects of glucose on insulin secretion, proinsulin synthesis and beta-cell proliferation [1±4]. However, healthy subjects with obesity-associated insulin resistance have higher insulin secretion compared with non-obese control subjects when glycaemia is identical in the two groups [5]. We made the same observation in two rat models of beta-cell adaptation: Diabetologia (2001 Increased islet DNA synthesis and glucose-derived lipid and amino acid production in association with beta-cell hyperproliferation in normoglycaemic 60 % pancreatectomy rats Abstract Aims/hypothesis. Glycaemia does not change following a 60 % pancreatectomy in rats because of enhanced beta-cell function and proliferation (so-called beta-cell adaptation). We previously studied these rats 4 weeks after surgery and showed hypersensitization of glucose-induced insulin secretion because of increased glucokinase activity. In this study of 60 % pancreatectomy rats 5 days after surgery, when betacell proliferation increased threefold, we investigated whether increases in glucose metabolism enhance the production of glucose-derived lipid, amino acids and DNA.Methods. Isolated islets from 60 % pancreatectomy and sham-operated control rats 5 days or 4 weeks after surgery were studied.Results. Five days after 60 % pancreatectomy surgery, islet glucose phosphorylation increased threefold, but overall glucose usage increased only twofold. The glucose-6-phosphate (G6P) concentration thus doubled, resulting in a sixfold increase in G6P metabolism through the pentose phosphate shunt (PPS). The pentose phosphate shunt generates ribose-5-phosphate for nucleotide synthesis, and DNA synthesis doubled in the partial pancreatectomy islets. In contrast, partial pancreatectomy rats 4 weeks after surgery had a smaller increase in glucokinase activity and their islet glucose-6-phosphate concentration and pentose phosphate shunt activity were equal to that of the control rats. DNA synthesis and beta-cell proliferation, based on BrdU incorporation were close to normal. Another consequence of the heightened glucose metabolism in the 5-day partial pancreatectomy islets was twofold increase in production of glucose-derived lipid and the amino acids, alanine and glutamate. Conclusions/interpretation. The enhanced glucokinase activity in 60 % pancreatectomy rats supports the compensatory beta-cell hyperproliferation by increasing production of glucose-derived DNA, lipids and amino acids. [Diabetologia (2001

. Enhanced rat ␤-cell proliferation in 60% pancreatectomized islets by increased glucose metabolic flux through pyruvate carboxylase pathway.