Stimulation of Phosphoenolpyruvate Carboxykinase Gene Expression by Fatty Acids

Antras-Ferry, Jocelyne; Lebigot, G.; Robin, Pierre; Robin, D.; Forest, Claude

doi:10.1006/bbrc.1994.2194

Cited by 49 publications

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“…Plasma glucose, insulin, C-peptide, glucagon, NEFA, glycerol and lactate concentrations were measured as previously described [7,16]. For the D-[6,6-2 H 2 ]glucose determinations, GC/electron-impact MS analysis was performed in the CTSA Analytic Core Laboratory [17].…”

Section: Analytical Proceduresmentioning

confidence: 99%

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

et al. 2012

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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-[6,6-2 H 2 ] glucose) and hepatic glycogen concentrations ( 13 C 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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Section: Analytical Proceduresmentioning

confidence: 99%

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

et al. 2012

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“…Increased FFAs are known to potently stimulate gluconeogenesis (16,17). Additionally, increased FFA availability has been shown to affect the relative flux through the key hepatic enzymes, glucokinase and glucose-6-phosphatase, by altering both gene expression and enzyme activity (18 -23).…”

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confidence: 99%

Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes

et al. 2006

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Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-3 H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t ‫؍‬ 0 -240 min), and hyperglycemia (10 mmol/l, t ‫؍‬ 240 -360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA 1c 10.9 ؎ 0.4%, age 50 ؎ 3 years, BMI 30 ؎ 2 kg/m 2 ) on at least two occasions with saline (NA؊ group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h ‫؍‬ 31 ؎ 6% suppression of EGP with hyperglycemia vs. NA؊ ‫؍‬ 8 ؎ 7%; P < 0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h ‫؍‬ 41 ؎ 8% suppression of EGP; P ‫؍‬ NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.

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“…The experimental pancreatic clamp protocols lasted 6 h and consisted of an initial 4-h euglycemic period (ϳ90 mg/dl) followed by a 2-h hyperglycemic period (180 mg/dl), as described previously (2,21,23). All experiments consisted of 360-min insulin/somatostatin (250 g/h) infusions, with replacement of glucoregulatory hormones (glucagon 1.0 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 , growth hormone 3.0 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) to maintain fixed levels of these hormones throughout.…”

Section: Time-dependent Effects Of Ffa On Glucose Effectivenessmentioning

confidence: 99%

“…free fatty acids; hyperglycemia; diabetes mellitus FASTING HYPERGLYCEMIA IN TYPE 2 DIABETES MELLITUS (T2DM) is characterized by increased endogenous glucose production (EGP) (11,16) predominantly due to increased gluconeogenesis (GNG) (2,47). Considerable evidence has shown potent direct effects of glucose to suppress EGP in healthy individuals (6,17,31), with marked suppression even in the absence of an insulin response (48).…”

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Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production

Kehlenbrink¹,

Tonelli²,

Koppaka³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Kehlenbrink S, Tonelli J, Koppaka S, Chandramouli V, Hawkins M, Kishore P. Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production. Am J Physiol Endocrinol Metab 297: E165-E173, 2009. First published May 5, 2009 doi:10.1152/ajpendo.00001.2009.-Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for Ն3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by ϳ52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.free fatty acids; hyperglycemia; diabetes mellitus FASTING HYPERGLYCEMIA IN TYPE 2 DIABETES MELLITUS (T2DM) is characterized by increased endogenous glucose production (EGP) (11, 16) predominantly due to increased gluconeogenesis (GNG) (2, 47). Considerable evidence has shown potent direct effects of glucose to suppress EGP in healthy individuals (6,17,31), with marked suppression even in the absence of an insulin response (48). Loss of this "glucose effectiveness" contributes significantly to increased EGP (19,31,33). Elevated circulating free fatty acid (FFA) levels appear to play a pivotal role in the loss of glucose effectiveness in T2DM (2, 47), since FFAs increase EGP by stimulating GNG and by affecting key regulatory enzymes (1,24,25,30).Therefore, we wished to define 1) the time-dependent effects of raising FFA on glucose effectiveness in nondiabetic individuals, 2) the extent to which an increase in GNG is responsible for these defects, and 3) whether EGP can be inhibited in the presence of elevated plasma FFA by inhibiting GNG with ethanol. Our results confirm the striking effects of elevated plasma FFA to impair glucose effectiveness and suggest that increased GNG contributes importantly to this loss of regulation. RESEARCH DESIGN AND METHODS Subject CharacteristicsEighteen healthy subjects (13 men and 5 women) were recruited. Informed, written consent was obtained in accordance with the policies of the Institutional Committee on Clinical Investigations at the Al...

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Stimulation of Phosphoenolpyruvate Carboxykinase Gene Expression by Fatty Acids

Cited by 49 publications

References 0 publications

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes

Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production

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