Changes in Glycogen Structure over Feeding Cycle Sheds New Light on Blood-Glucose Control

Abstract

Liver glycogen, a highly branched polymer of glucose, is important for maintaining blood-glucose homeostasis. It was recently shown that db/db mice, a model for Type 2 diabetes, are unable to form the large composite glycogen α particles present in normal, healthy mice. In this study, the structure of healthy mouse-liver glycogen over the diurnal cycle was characterized using size exclusion chromatography and transmission electron microscopy. Glycogen was found to be formed as smaller β particles, and then only assembled into large α particles, with a broad size distribution, significantly after the time when glycogen content had reached a maximum. This pathway, missing in diabetic animals, is likely to give optimal blood-glucose control during the daily feeding cycle. Lack of this control may contribute to, or result from, diabetes. This discovery suggests novel approaches to diabetes management.

The Molecular Size Distribution of Glycogen and its Relevance to Diabetes

“…An in vitro study [56] with rabbit-liver glycogen supports this hypothesis, with glycogen phosphorylase having a higher activity for smaller molecules in the direction of glycogen synthesis. In 1971 Geddes [16] also found that Replotted from data in Sullivan et al [50] glucose tended to be incorporated more into lower-weight material, which is consistent with smaller molecules being synthesised more rapidly. The second major insight resulting from the structural study of glycogen across a diurnal cycle is that towards the end of glycogen degradation, there is a much greater proportion of large a-particles remaining.…”

“…[45,49] This striking difference between non-diabetic and diabetic glycogen has highlighted the importance of understanding glycogen metabolism in terms of structure. A recent study [50] has used SEC to analyse the structure of mouse-liver glycogen at various time points in the feeding cycle, exploiting the natural diurnal rhythm of liver glycogen metabolism in mice. [47,[51][52][53][54] As has been previously reported, [47,55] liver glycogen was synthesised in the dark hours and subsequently degraded in the hours of light (see Fig.…”

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

“…Differently from skeletal muscle glycogen, these larger particles with a proportionally lower protein content [9] would be in line with a slower mobilization of glucosyl units for hepatic glucose output during progressive fasting. Interestingly, the formation of aparticles in the liver appears to occur during net glycogen degradation, providing a mechanism to control glucose release [12,13].…”

Implications for biological function of lobe dependence of the molecular structure of liver glycogen

“…Those in Group 1 were sacrificed in the morning, between 9 and 10 am, and those in Group 2 were sacrificed in the afternoon between 2 to 3 pm. These two times are respectively at the beginning and end of the degradation phase in glycogen synthesis [14]. Rats were anaesthetized with sodium pentobarbitone (150 mg/kg intraperitoneal) and their livers were rapidly excised and divided into six parts according to the lobe sections given in Fig.…”

“…The liver-glycogen content was analyzed using a method reported elsewhere [14,16]. Liver homogenates from Group 1 (sacrificed in the morning) were used for glycogen content assay.…”