Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

S. Kehlenbrink, S. Koppaka, M. Martin, R. Relwani, M. H. Cui, J. H. Hwang, Y. Li, R. Basu, M. Hawkins, P. Kishore

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP. Methods We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-2H 2] glucose) and hepatic glycogen concentrations (13C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA). Results EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ̃14% with prolonged fasting during euglycaemia and increased by ̃12% with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ̃23% reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA. Conclusions/interpretation Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.

Original languageEnglish (US)
Pages (from-to)3021-3028
Number of pages8
JournalDiabetologia
Volume55
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Glycogenolysis
Nonesterified Fatty Acids
Hyperglycemia
Glucose
Liver
Liver Glycogen
Aptitude
Type 2 Diabetes Mellitus
Fasting
Gluconeogenesis
Somatostatin
Glucagon
Growth Hormone
Magnetic Resonance Spectroscopy
Insulin

Keywords

  • Diabetes mellitus
  • Glucose production
  • Glycogen
  • Hyperglycaemia
  • NEFA
  • Non-esterified fatty acids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Kehlenbrink, S., Koppaka, S., Martin, M., Relwani, R., Cui, M. H., Hwang, J. H., ... Kishore, P. (2012). Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis. Diabetologia, 55(11), 3021-3028. https://doi.org/10.1007/s00125-012-2662-6

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis. / Kehlenbrink, S.; Koppaka, S.; Martin, M.; Relwani, R.; Cui, M. H.; Hwang, J. H.; Li, Y.; Basu, R.; Hawkins, M.; Kishore, P.

In: Diabetologia, Vol. 55, No. 11, 11.2012, p. 3021-3028.

Research output: Contribution to journalArticle

Kehlenbrink, S, Koppaka, S, Martin, M, Relwani, R, Cui, MH, Hwang, JH, Li, Y, Basu, R, Hawkins, M & Kishore, P 2012, 'Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis', Diabetologia, vol. 55, no. 11, pp. 3021-3028. https://doi.org/10.1007/s00125-012-2662-6
Kehlenbrink S, Koppaka S, Martin M, Relwani R, Cui MH, Hwang JH et al. Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis. Diabetologia. 2012 Nov;55(11):3021-3028. https://doi.org/10.1007/s00125-012-2662-6
Kehlenbrink, S. ; Koppaka, S. ; Martin, M. ; Relwani, R. ; Cui, M. H. ; Hwang, J. H. ; Li, Y. ; Basu, R. ; Hawkins, M. ; Kishore, P. / Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis. In: Diabetologia. 2012 ; Vol. 55, No. 11. pp. 3021-3028.
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abstract = "Aims/hypothesis Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP. Methods We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-2H 2] glucose) and hepatic glycogen concentrations (13C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA). Results EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ̃14{\%} with prolonged fasting during euglycaemia and increased by ̃12{\%} with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ̃23{\%} reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA. Conclusions/interpretation Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.",
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