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

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
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.

scholarly journals Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

2015 ◽  
Vol 100 (7) ◽  
pp. 2525-2531 ◽  
Author(s):  
Satya Dash ◽  
Changting Xiao ◽  
Cecilia Morgantini ◽  
Khajag Koulajian ◽  
Gary F. Lewis
Keyword(s):  
Plasma Glucose ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Physiological Role ◽  
Glucose Production ◽  
Insulin Concentration ◽  
Hepatic Glycogen ◽  
Hepatic Glucose ◽  
Glucose Output

Purpose: In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Methods and Results: Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. Conclusions: The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

scholarly journals Autoregulation of hepatic glucose production

1998 ◽  
pp. 240-248 ◽  
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.

The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo

2009 ◽  
Vol 05 (01) ◽  
pp. 34 ◽  
Author(s):  
Christopher J Ramnanan ◽  
Dale S Edgerton ◽  
Alan D Cherrington ◽  
◽  
◽  
...  
Keyword(s):  
Messenger Rna ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Regulatory Control ◽  
Glycolytic Flux ◽  
Large Animals

The regulation of gluconeogenesis by insulin is complex and can involve insulin-mediated events in the liver, as well as in several non-hepatic tissues. Given the complexity of this regulation, it is no surprise that there is considerable debate regarding insulin’s ability to regulate the rate of gluconeogenic formation of glucose-6-phosphate (GNG flux to G6P)in vivo. Conventional ‘textbook’ teaching (based onin vitrostudies of rat liver) depicts that insulin can inhibit this pathway by suppressing the transcription of the enzyme phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is widely considered to be a ‘rate-limiting’ enzyme with high control strength. Additionally, recent data in rodents have led to the conclusion that hyperinsulinemia in the brain can inhibit GNG flux to G6P, likely through transcriptional regulation of PEPCK. Recent data from the authors’ lab have confirmed that the molecular regulation of PEPCK messenger RNA (mRNA) and protein by insulin is conserved in large animals. Acute physiological hyperinsulinemia does not alter gluconeogenic formation of G6P, however, despite substantial reductions in PEPCK protein. This indicates that PEPCK has poor regulatory control over the pathwayin vivo. A physiological rise in insulin suppresses hepatic glucose production by inhibiting glycogenolysis and promoting glycogen synthesis, stimulating glycolytic flux, and redirecting gluconeogenically derived carbon to glycogen. This review documents the relevant ways in which insulin can regulate GNG flux to G6Pin vivo.

Effects of fructose on hepatic glucose metabolism in humans

2000 ◽  
Vol 279 (4) ◽  
pp. E907-E911 ◽  
Author(s):  
Mirjam Dirlewanger ◽  
Philippe Schneiter ◽  
Eric Jéquier ◽  
Luc Tappy
Keyword(s):  
Glycogen Synthesis ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Healthy Humans ◽  
Hepatic Glucose Metabolism ◽  
Insulin Requirements ◽  
Hepatic Glucose ◽  
Total Glucose ◽  
Glucose Output

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 μmol · kg−1 · min−1fructose. Glucose rate of disappearance (GRd), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-2H2]- and [2-2H1]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-13C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GRd under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 μmol · kg−1 · min−1increase in TGO, a 7.8 μmol · kg−1 · min−1increase in NEGP, a 2.2 μmol · kg−1 · min−1increase in GC, and a 7.2 μmol · kg−1 · min−1decrease in GRd ( P < 0.05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

Accelerated glycogenolysis in uremia and under sucrose feeding: role of phosphorylase alpha regulators

1997 ◽  
Vol 273 (1) ◽  
pp. E17-E27
Author(s):  
Z. Bakkour ◽  
D. Laouari ◽  
S. Dautrey ◽  
J. P. Yvert ◽  
C. Kleinknecht
Keyword(s):  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Storage ◽  
Hepatic Insulin Resistance ◽  
Hepatic Glycogen ◽  
Glycogen Depletion ◽  
Sucrose Feeding

To understand the mechanism of hepatic glycogen depletion found in uremia and under sucrose feeding, we examined net hepatic glycogenolysis-associated active enzymes and metabolites during fasting. Liver was taken 2, 7, and 18 h after food removal in uremic and pair-fed control rats fed either a sucrose or cornstarch diet for 21 days. Other uremic and control rats fasted for 18 h were refed a sucrose meal to measure glycogen increment. Glycogen storage in uremia was normal, suggesting effective glycogen synthesis. During a short fast, sucrose feeding and uremia enhanced net glycogenolysis through different but additive mechanisms. Under sucrose feeding, there were high phosphorylase alpha levels associated with hepatic insulin resistance. In uremia, phosphorylase alpha levels were low, but the enzyme was probably activated in vivo by a fall of inhibitors (ATP, alpha-glycerophosphate, fructose-1,6-diphosphate, and glucose) and a rise of Pi, as verified in vitro. Enhanced gluconeogenesis was also suggested, but excessive hepatic glucose production was unlikely in uremia. During fasting, hypoglycemia occurred in uremia due to reduced glycogenolysis, inefficient hepatic gluconeogenesis, and impaired renal gluconeogenesis. This may be relevant to poor fasting tolerance in uremia, which could be aggravated under excessive sucrose intake.

Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice

1995 ◽  
Vol 269 (6) ◽  
pp. E1037-E1043 ◽  
Author(s):  
D. Massillon ◽  
W. Chen ◽  
M. Hawkins ◽  
R. Liu ◽  
N. Barzilai ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Direct Pathway ◽  
Hyperglycemic Clamp ◽  
Hepatic Glucose ◽  
Glycogen Formation

Mice were studied with the euglycemic hyperinsulinemic and the hyperglycemic clamp techniques after a 6-h fast: 1) euglycemic (6.7 +/- 0.2 mM) hyperinsulinemia (approximately 800 microU/ml); 2) hyperglycemic (15.3 +/- 0.4 mM) hyperinsulinemia (approximately 800 microU/ml). All mice received an infusion of [3-3H]glucose and [U-14C]lactate. Basal hepatic glucose production (HGP) averaged approximately 170 mumol.kg-1.min-1 in both groups. During euglycemic and hyperglycemic hyperinsulinemia, HGP decreased by 53% (to 76.7 +/- 11.1 mumol.kg-1.min-1; P < 0.01) and 74% (to 43.3 +/- 7.2 mumol.kg-1.min-1; P < 0.01), respectively. Hyperglycemia increased glucose cycling (by 2.1-fold; P < 0.01) and the contribution of gluconeogenesis to HGP (88 vs. 43%; P < 0.01) while decreasing that of glycogenolysis (12 vs. 57%; P < 0.01). The percentage of neosynthetized hepatic glycogen formed via the direct pathway was markedly increased during hyperglycemia (53 +/- 2% vs. 23 +/- 3%; P < 0.01): These data indicate that the assessment of hepatic glucose fluxes can be accomplished in conscious unrestrained mice and that, in the presence of hyperinsulinemia, hyperglycemia causes 1) a further inhibition of HGP mainly via inhibition of glycogenolysis and increase in hepatic glucose cycling; and 2) about a fivefold stimulation in the direct pathway of hepatic glycogen formation.

Insulin action on the liver in vivo

2007 ◽  
Vol 35 (5) ◽  
pp. 1171-1174 ◽  
Author(s):  
A.D. Cherrington ◽  
M.C. Moore ◽  
D.K. Sindelar ◽  
D.S. Edgerton
Keyword(s):  
Insulin Action ◽  
Direct Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Inhibitory Effect ◽  
Fat Cell ◽  
Insulin Levels ◽  
Hepatic Glucose ◽  
Potent Inhibitory Effect

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.

Insulin action during late pregnancy in the conscious dog

2004 ◽  
Vol 286 (6) ◽  
pp. E909-E915 ◽  
Author(s):  
Cynthia C. Connolly ◽  
Lisa N. Aglione ◽  
Marta S. Smith ◽  
D. Brooks Lacy ◽  
Mary Courtney Moore
Keyword(s):  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Pregnancy ◽  
Amino Acid Uptake ◽  
Canine Model ◽  
Acid Uptake ◽  
Nonesterified Fatty Acids ◽  
Hepatic Glucose ◽  
Glucose Output

Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU·kg−1·min−1) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n = 6) and nonpregnant (NP; n = 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted ∼17 days before experimentation. Arterial plasma insulin rose from 11 ± 2 to 192 ± 24 and 4 ± 2 to 178 ± 5 μU/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 ± 0.1 vs. 2.4 ± 0.2 mg·kg−1·min−1, P < 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (−0.4 ± 0.2 and −0.1 ± 0.2 mg·kg−1·min−1 in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 ± 1.3 vs. 11.5 ± 1.1 mg·kg−1·min−1, P < 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels.

Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes

2015 ◽  
Vol 129 (10) ◽  
pp. 839-850 ◽  
Author(s):  
Tong-Yan Liu ◽  
Chang-Xiang Shi ◽  
Run Gao ◽  
Hai-Jian Sun ◽  
Xiao-Qing Xiong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Therapeutic Strategy ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Hepatic Glucose ◽  
Effective Therapeutic Strategy ◽  
Type 2 Diabetic

This study provide evidence that irisin reduces hepatic glucose production and the blood glucose level, increases hepatic glycogen synthesis and improves insulin resistance in type 2 diabetes. Irisin may be regarded as an effective therapeutic strategy for type 2 diabetes.

scholarly journals Glycogen synthesis in the perfused liver of adrenalectomized rats

1976 ◽  
Vol 156 (3) ◽  
pp. 585-592 ◽  
Author(s):  
P D Whitton ◽  
D A Hems
Keyword(s):  
Intact Animal ◽  
Glycogen Synthesis ◽  
Hepatic Metabolism ◽  
Hepatic Glycogen ◽  
Perfused Liver ◽  
Short Term ◽  
Glycogen Accumulation ◽  
Glycogen Deposition ◽  
Adrenalectomized Rats

1. A total loss of capacity for net glycogen synthesis was observed in experiments with the perfused liver of starved adrenalectomized rats. 2. This lesion was corrected by insulin or cortisol in vivo (over 2-5h), but not by any agent tested in perfusion. 3. The activity of glycogen synthetase a, and its increase during perfusion, in the presence of glucose plus glucogenic substrates, were proportional to the rate of net glycogen accumulation. 4. This complete inherent loss of capacity for glycogen synthesis after adrenalectomy is greater than any defect in hepatic metabolism yet reported in this situation, and is not explicable by a decrease in the rate of gluconegenesis (which supports glycogen synthesis in the liver of starved rats). The short-term (2-5h) stimulatory effect of glucocorticoids in the intact animal, on hepatic glycogen deposition, may be mediated partly through insulin action, although neither insulin or cortisol appear to act directly on the liver to stimulate glycogen synthesis.

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