The relationship between gluconeogenic substrate supply and glucose production in humans

Jahoor, F.; Peters, Edward J.; Wolfe, Robert R.

doi:10.1152/ajpendo.1990.258.2.e288

Cited by 93 publications

(90 citation statements)

References 27 publications

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“…The lack of increase in glucose production during the high-glycerol infusion is also consistent with previous reports in rats (57,58), mice (59), dogs (60), and humans (41,43) that glycerol increases gluconeogenesis but not glucose release. The increase in both total UDP-glucose flux and flux via the indirect pathway observed during the high-glycerol infusion adds to a growing body of evidence that increased flux through the glucose-6-phosphate pool in itself is not sufficient to increase hepatic glucose release.…”

Section: Discussionsupporting

confidence: 92%

“…Although the liver is generally assumed to be the source of the increased glucose release, this has yet to be established in humans because only the effects of FFAs on total-body (commonly referred to as endogenous) glucose production has been measured. Furthermore, although other substrates (e.g., glycerol) also increase gluconeogenesis, they do not increase glucose production because of socalled hepatic autoregulation (41)(42)(43). If elevated FFAs increase splanchnic glucose production, this implies that FFAs not only increase gluconeogenesis but also cause a greater proportion of the resultant glucose-6-phosphate to be dephosphorlyated and released into the systemic circulation.…”

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confidence: 99%

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Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

et al. 2002

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The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to ϳ1 mmol/l by an 8-h Intralipid/ heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n ‫؍‬ 5, low glycerol) or double (n ‫؍‬ 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at ϳ8.3 mmol/l, and insulin was increased to ϳ300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 ؎ 3.5 vs. 48.3 ؎ 9.3 and 57.8 ؎ 11.7 mol ⅐ kg ؊1 leg ⅐ min

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

et al. 2002

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“…Insulin influences hepatic GNG by powerfully regulating the transcription of important gluconeogenic enzymes [18,19], but the effect of enzyme expression on glucose production may not be immediate, since the mRNA half-life of many gluconeogenic enzymes is close to 1 h [20] and the enzyme itself takes several hours to degrade [21]. On the other hand, the supply of gluconeogenic substrates to the liver has an immediate impact on glucose homoeostasis by increasing GNG [22] and decreasing GLY [23]. Thus an indirect action of insulin on substrate supply from the periphery becomes a more appealing mechanism to explain changes in hepatic GNG [12].…”

Section: Introductionmentioning

confidence: 99%

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Hausler

Browning

Merritt

et al. 2006

Biochemical Journal

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A great deal is known about hepatic glucose production and its response to a variety of factors such as redox state, substrate supply and hormonal control, but the effects of these parameters on the flux through biochemical pathways which integrate to control glucose production are less clear. A combination of 13 C and [ 2 H]water tracers and NMR isotopomer analysis were used to investigate metabolic fluxes in response to altered cytosolic redox state and insulin. In livers isolated from fed mice and perfused with a mixture of substrates including lactate/pyruvate (10:1, w/w), hepatic glucose production had substantial contributions from glycogen, PEP (phosphoenolpyruvate) and glycerol. Inversion of the lactate/pyruvate ratio (1:10, w/w) resulted in a surprising decrease in the contribution from glycogen and an increase in that from PEP to glucose production. A change in the lactate/pyruvate ratio from 10:1 to 1:10 also stimulated flux through the tricarboxylic acid cycle (2-fold), while leaving oxygen consumption and overall glucose output unchanged. When lactate and pyruvate were eliminated from the perfusion medium, both gluconeogenesis and tricarboxylic-acid-cycle flux were dramatically lower. Insulin lowered glucose production by inhibiting glycogenolysis at both low and high doses, but only at high levels of insulin did gluconeogenesis or tricarboxylic-acid-cycle flux tend towards lower values (P < 0.1). Our data demonstrate that, in the isolated mouse liver, substrate availability and cellular redox state have a dramatic impact on liver metabolism in both the tricarboxylic acid cycle and gluconeogenesis. The tight correlation of these two pathways under multiple conditions suggest that interventions which increase or decrease hepatic tricarboxylic-acid-cycle flux will have a concomitant effect on gluconeogenesis and vice versa.

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“…Downstream effectors of hormonal inputs include transcription factors and coactivators that act as master regulators of metabolic transcriptional programs, such as PGC1␣, 3 CREB, TORC2, and Foxo1 (7)(8)(9)(10). Other mechanisms governing hepatic carbohydrate metabolism include changes in substrate availability (11), changes in mitochondrial respiration (12,13), and altered cellular redox state (14,15).…”

mentioning

confidence: 99%

Thioredoxin-interacting Protein (Txnip) Is a Critical Regulator of Hepatic Glucose Production

Chutkow¹,

Patwari²,

Yoshioka

et al. 2008

Journal of Biological Chemistry

174

158

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Thioredoxin-interacting protein (Txnip) has been recently described as a possible link between cellular redox state and metabolism; Txnip binds thioredoxin and inhibits its disulfide reductase activity in vitro, while a naturally occurring strain of Txnip-deficient mice has hyperlipidemia, hypoglycemia, and ketosis exacerbated by fasting. We generated Txnip-null mice to investigate the role of Txnip in glucose homeostasis. Txnip-null mice were hypoglycemic, hypoinsulinemic, and had blunted glucose production following a glucagon challenge, consistent with a central liver glucose-handling defect. Glucose release from isolated Txnip-null hepatocytes was 2-fold lower than wild-type hepatocytes, whereas ␤-hydroxybutyrate release was increased 2-fold, supporting an intrinsic defect in hepatocyte glucose metabolism. While hepatocyte-specific gene deletion of Txnip did not alter glucose clearance compared with littermate controls, Txnip expression in the liver was required for maintaining normal fasting glycemia and glucose production. In addition, hepatic overexpression of a Txnip transgene in wildtype mice resulted in elevated serum glucose levels and decreased ketone levels. Liver homogenates from Txnip-null mice had no significant differences in the glutathione oxidation state or in the amount of available thioredoxin. However, overexpression of wild-type Txnip in Txnip-null hepatocytes rescued cellular glucose production, whereas overexpression of a C247S mutant Txnip, which does not bind thioredoxin, had no effect. These data demonstrate that Txnip is required for normal glucose homeostasis in the liver. While available thioredoxin is not changed in Txnip-null mice, the effects of Txnip on glucose homeostasis are abolished by a single cysteine mutation that inhibits binding to thioredoxin.Tight regulation of glucose homeostasis is fundamental to all higher life forms, and dysregulated glucose metabolism is a significant medical problem (1, 2). The liver has a major role in determining glucose levels through its control of both hepatic glucose uptake and glucose release. During fasting states the liver is particularly important, as it is the primary organ for maintaining blood glucose levels by up-regulating gluconeogenesis and glycogenolysis to increase glucose release (3, 4). These processes are coordinated by hormonal control, primarily through the reciprocal actions of glucagon and insulin, as well as through glucocorticoid and adipokine cues (5, 6). Downstream effectors of hormonal inputs include transcription factors and coactivators that act as master regulators of metabolic transcriptional programs, such as PGC1␣, 3 CREB, TORC2, and Foxo1 (7-10). Other mechanisms governing hepatic carbohydrate metabolism include changes in substrate availability (11), changes in mitochondrial respiration (12, 13), and altered cellular redox state (14, 15).The thiol-disulfide redox state of the cell is emerging as an important regulator of diverse processes, including metabolism (16 -19). A key regulator is thioredoxin, a u...

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The relationship between gluconeogenic substrate supply and glucose production in humans

Cited by 93 publications

References 27 publications

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Thioredoxin-interacting Protein (Txnip) Is a Critical Regulator of Hepatic Glucose Production

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