Insulin action on the liver in vivo

Insulin has a potent inhibitory effect on hepatic glucose production by direct action at hepatic receptors. The hormone also inhibits glucose production by suppressing both lipolysis in the fat cell and secretion of glucagon by the α-cell. Neural sensing of insulin levels appears to participate in control of hepatic glucose production in rodents, but a role for brain insulin sensing has not been documented in dogs or humans. The primary effect of insulin on the liver is its direct action.

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Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922370117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6733-6740 ◽

Cited By ~ 2

Author(s):

Thiago M. Batista ◽

Sezin Dagdeviren ◽

Shannon H. Carroll ◽

Weikang Cai ◽

Veronika Y. Melnik ◽

...

Keyword(s):

Messenger Rna ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Glucose Production ◽

Hepatic Glycogen ◽

Glycogen Accumulation ◽

Hepatic Glucose ◽

Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

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Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels

Diabetes Obesity and Metabolism ◽

10.1111/dom.13615 ◽

2019 ◽

Vol 21 (4) ◽

pp. 993-1000

Author(s):

Peter Plomgaard ◽

Jakob S. Hansen ◽

Bodil Ingerslev ◽

Jens O. Clemmesen ◽

Niels H. Secher ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Fasting Insulin ◽

Insulin Administration ◽

Insulin Levels ◽

Hepatic Glucose

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Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

Endocrine Reviews ◽

10.1210/edrv.31.4.9983 ◽

2010 ◽

Vol 31 (4) ◽

pp. 606-606

Author(s):

Aidan S. Hancock ◽

Aiping Du ◽

Jingxuan Liu ◽

Mayumi Miller ◽

Catherine L. May

Keyword(s):

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Postprandial Glucose ◽

Glucagon Receptor ◽

Glucose Levels ◽

Adult Mice ◽

Hepatic Glucose ◽

Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

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In vivo insulin sensitivity in the rat determined by euglycemic clamp

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.1.e1 ◽

1983 ◽

Vol 245 (1) ◽

pp. E1-E7 ◽

Cited By ~ 21

Author(s):

E. W. Kraegen ◽

D. E. James ◽

S. P. Bennett ◽

D. J. Chisholm

Keyword(s):

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Porcine Insulin ◽

Metabolic Clearance ◽

Conscious Rat ◽

Insulin Levels ◽

In Vivo Measurement ◽

Plasma Insulin Levels

Our aim was to develop the glucose clamp (GC) technique in the conscious rat for assessment of in vivo insulin sensitivity. A 2-h euglycemic GC could be performed in chronically cannulated rats using 625 microliter blood. Overnight-fasted rats were infused with porcine insulin (1.67 mU . kg-1 . h-1). Insulin levels of 41 +/- 2 (SE) mU/liter were produced in rats aged 91 +/- 4 days with a 60- to 120-min glucose infusion rate (GIR60-120) of 10.6 +/- 0.6 mg . kg-1 . min-1 (n = 9) during euglycemia. GIR60-120 was significantly (P less than 0.025) reduced in rats aged greater than 130 days (mean, 169 +/- 16 days) to 7.7 +/- 1.2 mg . kg-1 . min-1 (n = 7). Metabolic clearance rate of porcine insulin (46 +/- 3 ml . kg-1 . min-1) and GIR60-120 compared with plateau plasma insulin levels are higher than values reported in humans. The latter may be due to suppression of a higher basal hepatic glucose production or increased potency of porcine compared with native insulin. We conclude that the GC can be accomplished in the rat. When combined with tracer administration and subsequent killing, it should provide a quantitative in vivo measurement of insulin sensitivity in individual tissues.

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Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00158.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E1137-E1146 ◽

Cited By ~ 49

Author(s):

Maziyar Saberi ◽

David Bjelica ◽

Simon Schenk ◽

Takeshi Imamura ◽

Gautam Bandyopadhyay ◽

...

Keyword(s):

Type 2 Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Primary Mouse Hepatocytes ◽

Primary Mouse ◽

Hepatic Glucose ◽

Zdf Rats ◽

Mouse Hepatocytes

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phospho enolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

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Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Acta Endocrinologica ◽

10.1530/acta.0.1200257 ◽

1989 ◽

Vol 120 (3) ◽

pp. 257-265 ◽

Cited By ~ 71

Author(s):

Ole Hother-Nielsen ◽

Ole Schmitz ◽

Per H. Andersen ◽

Henning Beck-Nielsen ◽

Oluf Pedersen

Keyword(s):

Type Ii Diabetes ◽

Insulin Action ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Metformin Treatment ◽

Obese Patients ◽

Type Ii ◽

Plasma Lactate ◽

Hepatic Glucose

Abstract. Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 ± 1.2 vs 11.4 ± 1.2 mmol/l, P< 0.01) without enhancing mean day-time plasma insulin (43 ± 4 vs 50 ± 7 mU/l, NS) or C-peptide levels (1.26 ± 0.12 vs 1.38 ± 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 ± 0.16 vs 1.44 ± 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 ± 0.11 vs 1.38 ± 0.11 mmol/l, P< 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 ± 38 vs 313 ± 33 mg · m−2 · min−1, P< 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 ± 5.8 vs 50.6 ± 2.8 ml · n−2 · min−1,, P< 0.05), whereas basal hepatic glucose production was unchanged (81 ± 6 vs 77 ± 4 mg · m−2 · min−1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion. 2) The improved glycemic control during metformin treatment was associated with an enhanced insulin-mediated glucose utilization, presumably in skeletal muscle, whereas no effect could be demonstrated on hepatic glucose production.

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Autoregulation of hepatic glucose production

Acta Endocrinologica ◽

10.1530/eje.0.1380240 ◽

1998 ◽

pp. 240-248 ◽

Cited By ~ 77

Author(s):

MC Moore ◽

CC Connolly ◽

AD Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glycogen ◽

Neural Pathways ◽

Hepatic Glucose Output ◽

Counterregulatory Hormones ◽

Hepatic Glucose ◽

Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

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AICAR response element binding protein (AREBP), a key modulator of hepatic glucose production regulated by AMPK in vivo

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2011.08.120 ◽

2011 ◽

Vol 414 (2) ◽

pp. 287-291 ◽

Cited By ~ 10

Author(s):

Tomomi Shirai ◽

Erina Inoue ◽

Yoshiko Ishimi ◽

Jun Yamauchi

Keyword(s):

Binding Protein ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Response Element ◽

Hepatic Glucose ◽

Element Binding Protein

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Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00126.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. E536-E543 ◽

Cited By ~ 21

Author(s):

Chaodong Wu ◽

Salmaan A. Khan ◽

Li-Jen Peng ◽

Honggui Li ◽

Steven G. Carmella ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Flux ◽

Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

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