Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked. This includes: (i) the inhibition of all glycogen synthesis, in vivo, when gluconeogenic flux is blocked by inhibitors; (ii) a dual relationship between glucose concentrations, lactate uptake by the liver and glycogen synthesis (by both pathways) which indicates that glucose sets the maximal rates of glycogen synthesis while lactate uptake determines the actual flux rate to glycogen; (iii) the decrease of both gluconeogenesis and glycogen synthesis by the biguanide, metformin; and (iv) correlations between increased gluconeogenesis and liver glycogen in obese patients and animal models. The degree to which the liver extracts portal glucose is not entirely agreed upon although a preponderance of evidence points to about a 5% extraction rate, following meals, which is dependent on a stimulation of glucokinase. This enzyme may be linked to the expression of other enzymes in the gluconeogenic pathway. Perivenous cells in the liver may induce additional gluconeogenesis in the periportal cells by increasing glycolytically produced lactate. A number of potential mechanisms therefore exist which could link glycogen synthesis from glucose and gluconeogenic substrate.

Aims/hypothesis: An increase in endogenous glucose production (EGP) is a major contributor to fasting morning hyperglycaemia in type 2 diabetes. This increase is dissipated with fasting, later in the day. To understand its origin, EGP, gluconeogenesis and hormones that regulate metabolism were measured over 24 h. We hypothesised that EGP, and therefore glycaemia, would demonstrate a centrally mediated circadian rhythm in type 2 diabetes. Subjects and methods: Seven subjects with type 2 diabetes and six age-and BMI-matched control subjects, fasting after breakfast (08

To directly assess the effects of the biguanide, metformin, on hepatic gluconeogenesis, it was added at high therapeutic levels (90 microg/ml) to the medium perfusing an isolated rat liver. Lactate (1 mg/min) was infused simultaneously along with [14C]lactate with or without [3H]lactate. [6-(3)H]glucose was added at the beginning of the perfusion in studies where [3H]lactate was not infused. Glucose levels decreased relative to control studies (metformin dose = 0) and lactate concentrations increased in this closed system. Quantitative analysis of the relationship between labeled glucose and lactate indicated that the flux of carbon from lactate to glucose and CO2 was halved, whereas reflux from glucose to lactate increased by approximately 80%. This was corroborated by measurement of labeled lactate extraction as well as glucose, CO2, and lactate production across the liver. Glycogen content of the liver fell by 60% relative to control and was greater for the gluconeogenic pathway. These data are consistent with an inhibitory action of metformin on gluconeogenesis, which is due to a primary inhibition of hepatic lactate uptake.