Hepatic Glycogen Metabolism in Type 1 Diabetes After Long-Term Near Normoglycemia

Abstract

We tested the impact of long-term near normoglycemia (HbA 1c <7% for >1 year) on glycogen metabolism in seven type 1 diabetic and seven matched nondiabetic subjects after a mixed meal. Glycemic profiles (6.2 ؎ 0.10 vs. 5.9 ؎ 0.07 mmol/l; P < 0.05) of diabetic patients were approximated to that of nondiabetic subjects by variable insulin infusion. Rates of hepatic glycogen synthesis and breakdown were calculated from the glycogen concentration time curves between 7:30 P.M. and 8:00 A.M. using in vivo 13 C nuclear magnetic resonance spectroscopy. Glucose production was determined with D-[6,6-2 H 2 ]glucose, and the hepatic uridine-diphosphate glucose pool was sampled with acetaminophen. Glycogen synthesis and breakdown as well as glucose production were identical in diabetic and healthy subjects: 7.3 ؎ 0.9 vs. 7.1 ؎ 0.7, 4.2 ؎ 0.5 vs. 3.8 ؎ 0.3, and 8.7 ؎ 0.5 vs. 8.4 ؎ 0.7 mol ⅐ kg ؊1 ⅐ min ؊1 , respectively. Although portal vein insulin concentrations were doubled, the flux through the indirect pathway of glycogen synthesis remained higher in type 1 diabetic subjects: ϳ70 vs. ϳ50%; P < 0.05. In conclusion, combined longand short-term intensified insulin substitution normalizes rates of hepatic glycogen synthesis but not the contribution of gluconeogenesis to glycogen synthesis in type 1 diabetes. Diabetes 51:49 -54, 2002 E arly studies on glycogen metabolism in type 1 diabetic patients using liver biopsies revealed controversial results, reporting either increased or decreased liver glycogen concentrations (1-4). When liver glycogen was continuously measured with 13 C nuclear magnetic resonance (NMR) spectroscopy, it became clear that under physiologic conditions of mixed meal ingestion, poorly controlled type 1 diabetic patients indeed exhibit a defect of net liver glycogen synthesis that accumulates throughout the day and is most pronounced after dinner (5). Furthermore, these authors reported higher contribution of the indirect (carbon 3 compounds 3 glucose 3 glucose-6-phosphate 3 glucose-1-phosphate 3 UDP-glucose 3 glycogen) compared with the direct pathway of glycogen synthesis (glucose 3 glucose-6-phosphate 3 glucose-1-phosphate 3 UDP-glucose 3 glycogen) (5,6). We recently found that type 1 diabetic subjects with poor metabolic control, as evidenced by an HbA 1c of ϳ9%, also present with reduced glycogen breakdown during the night after mixed meal ingestion (7). Short-term intensified insulin treatment for 24 h, resulting in near-normal plasma glucose concentrations, improved both defects in glycogen synthesis and breakdown that, however, were still ϳ52 and ϳ26% lower, respectively, compared with nondiabetic subjects.At present, even advanced insulin substitution regimens do not resemble the physiologic insulin secretion pattern, since peripheral administration of insulin distorts the portal-to-peripheral insulin gradient and thereby affects hepatic glycogen turnover (8). Furthermore, the physiologic inhibition of glucagon secretion by insulin is impaired (9), giving rise to the portal vein glucagon-to-insu...

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

“…Patients with poorly controlled type 1 diabetes have impaired net hepatic glycogen synthesis following ingestion of a mixed meal and show an increase in hepatic gluconeogenesis [17]. However, these defects can be corrected after combined long-term and overnight control of glycaemia with intravenous insulin [40], and our results support this observation. Postprandial, pre-exercise liver glycogen concentration in type 1 diabetes was comparable to that in control subjects despite the relative lower estimated portal insulin concentration (∼150-200 pmol/l) when compared with controls (∼600 pmol/l).…”

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

“…In this regard, we need to emphasise that in the present study the patients were studied as they were in their everyday life (poor metabolic control), and therefore it is likely that these findings do not represent an intrinsic alteration but rather that they may be due to the poor therapeutic control. This view is supported by the fact that in type 1 diabetic patients with long-term near-normoglycaemia (HbA 1 c <7% for 1 year), hepatic glycogen synthesis was normalised after ingestion of a mixed meal in association with restoration of the glucagon/estimated hepatic insulin ratio [29]. Insulin and glucagon are considered to be of pivotal importance in the regulation of hepatic glycogen synthesis and turnover in humans [30].…”

Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study

“…HCL content was assessed from methylene and methyl resonance to that of water in localized breathhold STEAM 1 H spectra (VOI ϭ 3 ϫ 3 ϫ 3 cm 3 ; TMϭ 30 ms; TEϭ 15, 20, 30, 50, 70 ms; NA ϭ 1 for each TE) and following the individual spin-spin relaxation correction of water and methylene resonance expressed as percent of total tissue signal (water ϩ methylene ϩ methyl) (1). Gas chromatography-mass spectrometry was applied for determination of 2 H enrichment as previously described (5).…”