Higher Insulin Concentrations Are Required to Suppress Gluconeogenesis Than Glycogenolysis in Nondiabetic Humans

Adkins, Aron; Basu, Rita; Persson, Mai; Dicke, Betty A.; Shah, Pankaj; Vella, Adrian; Schwenk, W.; Rizza, Robert A.

doi:10.2337/diabetes.52.9.2213

Cited by 66 publications

(52 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Either the factors determining flux through the cycle changed or the glycosyl units released were increasingly labelled. The increase in portal insulin relative to glucagon activities [44,45] would favour an increase in glycogen synthesis and a decrease in the activity of phosphorylase, hence the breakdown of glycogen [46][47][48]. The glycosyl units deposited are assumed not to be those released [1].…”

Section: Discussionmentioning

confidence: 99%

Changes in hepatic glycogen cycling during a glucose load in healthy humans

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested 2 H 2 O (5 ml/kg body water) and were infused with [5-3 H] glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of 2 H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the 3 H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results: Glucose infusion rates increased (p<0.01) to ∼50 μmol kg −1 min −1 . Plasma insulin and the insulin : glucagon ratio rose ∼3.6-and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2-4 h, 54±6%; 4-6 h, 59±5%; 6-8 h, 63±4%) and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2-4 h) to 4±3% (4-6 h) and 1±3% (6-8 h). Conclusions/interpretation: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.

show abstract

Section: Discussionmentioning

confidence: 99%

Changes in hepatic glycogen cycling during a glucose load in healthy humans

et al. 2005

View full text Add to dashboard Cite

show abstract

“…We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects using the C5 glucose-to-2 H 2 O ratio (7). However, in those as well as other glucose clamp experiments (4,6,7,11,12,18), gluconeogenesis calculated using the C5 glucose-to-2 H 2 O ratio commonly exceeded total endogenous glucose production. Since endogenous glucose production equals the sum of glucose derived via gluconeogenesis and glycogenolysis, this result was biologically implausible.…”

Section: Results-plasma C2 Glucose and Plasmamentioning

confidence: 99%

“…Since 2 H 2 O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose-to-2 H 2 O ratio to calculate gluconeogenesis after an overnight fast (4 -7,9 -12,18). The C5 glucose-to-2 H 2 O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

et al. 2008

Self Cite

View full text Add to dashboard Cite

OBJECTIVE-Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose-to-2 H 2 O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown. RESEARCH DESIGN AND METHODS-Ten nondiabetic and 10 diabetic subjects ingested2 H 2 O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU ⅐ kg Ϫ1⅐ min Ϫ1 and glucose was clamped at ϳ5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and 2 H 2 O enrichments were measured hourly from 2 h onward. RESULTS-Plasma C2 glucose and plasma2 H 2 O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma 2 H 2 O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose-to-2 H 2 O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose-to-2 H 2 O ratio overestimated (P Ͻ 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.CONCLUSIONS-Plasma C5 glucose-to-2 H 2 O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2-3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated. Diabetes 57:1800-1804, 2008 M easurement of gluconeogenesis in humans is difficult. The deuterated water method is widely used for this purpose (1-17). This method relies on the fact that the fifth carbon of glucose is labeled during gluconeogenesis, whereas the second carbon of glucose is labeled with deuterium during equilibration of glucose-6-phosphate and fructose-6-phoshate (1,2). Therefore, at steady state, the ratio of plasma glucose with deuterium on the fifth carbon (C5 glucose) to plasma glucose labeled on the second carbon (C2 glucose) equals the percentage of plasma glucose derived from gluconeogenesis (1,2). Measurement of C2 glucose enrichment is cumbersome. Since 2 H 2 O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose-to-2 H 2 O ratio to calculate gluconeogenesis after an overnight fast (4 -7,9 -12,18). The C5 glucose-to-2 H 2 O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain. We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects us...

show abstract

“…The rate of gluconeogenesis was calculated by multiplying the plasma ratio of C5 and C2 glucose enrichments times the rate of EGP (32,33). Glycogenolysis was calculated by subtracting the rate of gluconeogenesis from EGP (26,36,37). Statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose

et al. 2007

Self Cite

View full text Add to dashboard Cite

OBJECTIVE-To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG).RESEARCH DESIGN AND METHODS-Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (ϳ80 pmol/l, "preprandial") or within 30 min of eating (ϳ300 pmol/l, "prandial").RESULTS-Despite higher (P Ͻ 0.001) insulin and C-peptide concentrations and visceral fat (P Ͻ 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P Ͻ 0.05) and EGP higher (P Ͻ 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P Ͻ 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P Ͻ 0.01) in IFG than in NFG subjects.CONCLUSIONS-Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia. Diabetes

show abstract

Higher Insulin Concentrations Are Required to Suppress Gluconeogenesis Than Glycogenolysis in Nondiabetic Humans

Cited by 66 publications

References 41 publications

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose

Contact Info

Product

Resources

About