Insulin Action in the Brain regulates both Central and Peripheral Functions

2021 ◽  
Author(s):  
Rahul Agrawal ◽  
Candace M Reno ◽  
Sunny Sharma ◽  
Camille Christensen ◽  
Yiqing Huang ◽  
...  
Keyword(s):  
Insulin Action ◽  
Therapeutic Option ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Neuronal Population ◽  
Brain Insulin ◽  
Increased Risk ◽  
Cognitive Diseases ◽  
Brain Insulin Resistance ◽  
The Brain

The brain has traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin sensitive tissues such as muscle, liver and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression and cognitive behavior. Additionally, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.

scholarly journals Role of hepatic STAT3 in brain-insulin action on hepatic glucose production

2006 ◽  
Vol 3 (4) ◽  
pp. 267-275 ◽  
Author(s):  
Hiroshi Inoue ◽  
Wataru Ogawa ◽  
Akihiro Asakawa ◽  
Yasuo Okamoto ◽  
Akihiko Nishizawa ◽  
...  
Keyword(s):  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Brain Insulin ◽  
Hepatic Glucose

scholarly journals Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans

2016 ◽  
Vol 96 (4) ◽  
pp. 1169-1209 ◽  
Author(s):  
Stephanie Kullmann ◽  
Martin Heni ◽  
Manfred Hallschmid ◽  
Andreas Fritsche ◽  
Hubert Preissl ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Eating Behavior ◽  
Insulin Action ◽  
Cognitive Disorders ◽  
Metabolic Effects ◽  
Pathological Feature ◽  
Brain Insulin ◽  
Maternal Metabolism ◽  
Brain Insulin Resistance ◽  
The Brain

Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

scholarly journals Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 394-404 ◽  
Author(s):  
Jonathan P. German ◽  
Joshua P. Thaler ◽  
Brent E. Wisse ◽  
Shinsuke Oh-I ◽  
David A. Sarruf ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Underlying Mechanism ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Uncontrolled Diabetes ◽  
Urinary Glucose ◽  
Hepatic Glucose ◽  
Glucose Excretion ◽  
The Brain

Abstract The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

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.

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

1989 ◽  
Vol 120 (3) ◽  
pp. 257-265 ◽  
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.

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

Diabetes ◽  
2013 ◽  
Vol 62 (7) ◽  
pp. 2266-2277 ◽  
Author(s):  
K. Kimura ◽  
Y. Nakamura ◽  
Y. Inaba ◽  
M. Matsumoto ◽  
Y. Kido ◽  
...  
Keyword(s):  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose

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

1988 ◽  
Vol 117 (4) ◽  
pp. 457-462 ◽  
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.

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

2007 ◽  
Vol 293 (4) ◽  
pp. E1103-E1111 ◽  
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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