Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

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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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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The synthetic human growth hormone fragment (32–38) increases glucose uptake in the conscious dog

Acta Endocrinologica ◽

10.1530/acta.0.1170457 ◽

1988 ◽

Vol 117 (4) ◽

pp. 457-462 ◽

Cited By ~ 7

Author(s):

Ralph W. Stevenson ◽

Nowell Stebbing ◽

Theodore Jones ◽

Keith Carr ◽

Peter M. Jones ◽

...

Keyword(s):

Glucose Uptake ◽

Plasma Glucose ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Control Period ◽

Human Growth ◽

Glucose Production ◽

Independent Action ◽

Conscious Dog ◽

Hepatic Glucose

Abstract. hGH32-38 was tested to determine if the peptide could affect hepatic glucose production in the conscious dog under basal conditions (euglycemia) or if it could enhance glucose uptake when hyperglycemia was induced. hGH32-38 (1.6 nmol · kg−1 · min−1) or vehicle was infused in a cross-over design study into each of 4 conscious 16 h-fasted dogs for 3 h (0–180 min) following a 40 min control period. At 90 min, plasma glucose was raised to and maintained at 9.4 mmol/l by glucose infusion for 3 h (until 270 min). Neither hGH32-38 nor vehicle infusion had a significant effect on insulin and glucagon levels or on tracer determined ([3-3H]glucose) glucose production. As a result, neither treatment changed plasma glucose (5.72 ± 0.17 to 5.78 ± 0.17 mmol/l with hGH32-38; 5.50 ± 0.22 to 5.50 ± 0.17 mmol/l with vehicle). Induction of hyperglycemia (9.4 mmol/l) caused glucagon concentrations to fall similarly to about 50 ng/l with and without hGH32-38. Insulin rose to similar levels in both protocols, yet more glucose was required to maintain the same hyperglycemia with hGH32-38 (135– 180 min) (74.9 ± 12.7 vs 43.7 ± 7.1 μmol · kg−1 · min−1, P < 0.05). In summary, hGH32-38 significantly increased glucose disposition during hyperglycemia and this effect may be attributed to enhanced insulin action or to an insulin independent action of the peptide.

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Effects of fasting on insulin action and glucose kinetics in lean and obese men and women

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00613.2006 ◽

2007 ◽

Vol 293 (4) ◽

pp. E1103-E1111 ◽

Cited By ~ 51

Author(s):

Bryan C. Bergman ◽

Marc-Andre Cornier ◽

Tracy J. Horton ◽

Daniel H. Bessesen

Keyword(s):

Insulin Action ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Obese Individual ◽

Glucose Kinetics ◽

Men And Women ◽

Hepatic Glucose ◽

Marked Decline ◽

Obese Subjects ◽

Fast Insulin

The development of insulin resistance in the obese individual could impair the ability to appropriately adjust metabolism to perturbations in energy balance. We investigated a 12- vs. 48-h fast on hepatic glucose production (Ra), peripheral glucose uptake (Rd), and skeletal muscle insulin signaling in lean and obese subjects. Healthy lean [ n = 14; age = 28.0 ± 1.4 yr; body mass index (BMI) = 22.8 ± 0.42] and nondiabetic obese ( n = 11; age = 34.6 ± 2.3 yr; BMI = 36.1 ± 1.5) subjects were studied following a 12- and 48-h fast during 2 h of rest and a 3-h 40 mU·m−2·min−1hyperinsulinemic-euglycemic clamp (HEC). Basal glucose Radecreased significantly from the 12- to 48-h fast (lean 1.96 ± 0.23 to 1.63 ± 0.15; obese 1.23 ± 0.07 to 1.07 ± 0.07 mg·kg−1·min−1; P = 0.004) and was equally suppressed during the HEC after both fasts. The increase in glucose Rdduring the HEC after the 12-h fast was significantly decreased in lean and obese subjects after the 48-h fast (lean 9.03 ± 1.17 to 4.16 ± 0.34, obese 6.10 ± 0.77 to 3.56 ± 0.30 mg·kg FFM−1·min−1; P < 0.001). After the 12- but not the 48-h fast, insulin-stimulated AKT Ser473phosphorylation was greater in lean than obese subjects. We conclude that 1) 48 h of fasting produces a marked decline in peripheral insulin action, while suppression of hepatic glucose production is maintained in lean and obese men and women; and 2) the magnitude of this decline is greater in lean vs. obese subjects.

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Insulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production

Cell Metabolism ◽

10.1016/j.cmet.2007.05.004 ◽

2007 ◽

Vol 5 (6) ◽

pp. 438-449 ◽

Cited By ~ 416

Author(s):

A. Christine Könner ◽

Ruth Janoschek ◽

Leona Plum ◽

Sabine D. Jordan ◽

Eva Rother ◽

...

Keyword(s):

Insulin Action ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glucose

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-1371 ◽

2015 ◽

Vol 100 (7) ◽

pp. 2525-2531 ◽

Cited By ~ 13

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.

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Insulin action on the liver in vivo

Biochemical Society Transactions ◽

10.1042/bst0351171 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1171-1174 ◽

Cited By ~ 25

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.

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Effect of timing of energy and carbohydrate replacement on post-exercise insulin action

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-126 ◽

2007 ◽

Vol 32 (6) ◽

pp. 1139-1147 ◽

Cited By ~ 12

Author(s):

Brooke R. Stephens ◽

Jeffrey M. Sautter ◽

Kaila A. Holtz ◽

Carrie G. Sharoff ◽

Stuart R. Chipkin ◽

...

Keyword(s):

Insulin Action ◽

Hepatic Glucose Production ◽

Exercise Bout ◽

Glucose Production ◽

Baseline Sensitivity ◽

Post Exercise ◽

Carbohydrate Consumption ◽

Stable Isotope Dilution ◽

Hepatic Glucose ◽

Nutritional Environment

The nutritional environment surrounding an exercise bout modulates post-exercise insulin action. The purpose of this study was to determine how timing energy and carbohydrate replacement proximate to an exercise bout influences exercise-enhanced insulin action. To create an appropriate baseline, sensitivity to insulin was reduced in 9 healthy young men (n = 6) and women (n = 3) by 2 days of energy surplus and detraining. Then, insulin action (glucose uptake per unit plasma insulin) was assessed by stable isotope dilution during a continuous glucose infusion 12 h after a standardized meal under 4 conditions. In 3 conditions, the meal replaced the energy and carbohydrate expended during an exercise bout (62.9 ± 2.8 min cycle ergometry at 65% VO2 peak followed by ten 30 s sprints). The meal was given before (Pre), immediately after (ImmPost), or 3 h after exercise (Delay). The 4th condition was a no-exercise control (Control). Data were analyzed using linear mixed-effects models with planned contrasts. Relative to Control, insulin action increased by 22% in Pre (p = 0.05), 44% in ImmPost (p < 0.01), and 19% in Delay (p = 0.09). Non-oxidative disposal was higher, and oxidative disposal was lower in ImmPost relative to Control and Pre (p < 0.05). Hepatic glucose production was suppressed by the infusion to a greater extent in Pre and Delay (76.9% ± 8.8% and 81.2% ± 4.7%) compared with ImmPost (64.7% ± 10.0%). A bout of exercise enhances insulin action even when expended energy and carbohydrate are replaced. Further, timing of energy and carbohydrate consumption subtly modulates the effectiveness of exercise to enhance insulin action.

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Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.4.e576 ◽

1993 ◽

Vol 264 (4) ◽

pp. E576-E582 ◽

Cited By ~ 6

Author(s):

M. Gilbert ◽

S. Basile ◽

A. Baudelin ◽

M. C. Pere

Keyword(s):

Insulin Resistance ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Late Pregnancy ◽

Plasma Free Fatty Acid ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Total Glucose ◽

Control Study

Acute elevation in plasma free fatty acid (FFA) levels in nonpregnant rabbits simulates some aspects of insulin resistance observed in late pregnancy. The aim of this study was therefore to evaluate whether lowered FFA induced by nicotinic acid (NA) infusion can improve insulin action in pregnant rabbits. To assess insulin sensitivity we applied euglycemic hyperinsulinemic clamp without (control study) or with concomitant NA infusion (NA study; infusion started 150 min before the glucose clamp) in conscious virgin and pregnant rabbits after an 18-h fast. A primed constant infusion of [3-3H]glucose was used to measure total glucose disposal and hepatic glucose production. Hyperinsulinemia, in association with NA infusion (NA study) brings about a significantly greater stimulation of total glucose disposal in both pregnant (approximately 30%) and nonpregnant (approximately 35%) rabbits compared with the control study. A more pronounced inhibition of hepatic glucose production occurred in NA study in pregnant rabbits (approximately 30 vs. approximately 10%) but it did not reach a statistical significance, whereas there was a total inhibition in nonpregnant rabbits. We conclude that acute decrease in plasma FFA levels mainly improves insulin action at the site of glucose utilization. These results therefore suggest that elevated FFA would contribute to the peripheral insulin resistance in late pregnancy.

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