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Free Fatty Acid as a Link in the Regulation of Hepatic Glucose Output by Peripheral Insulin

Published on Sep 1, 1995in Diabetes 7.20
· DOI :10.2337/diab.44.9.1038
Kerstin Rebrin21
Estimated H-index: 21
(SC: University of Southern California),
Garry M. Steil40
Estimated H-index: 40
(SC: University of Southern California)
+ 1 AuthorsRichard N. Bergman103
Estimated H-index: 103
(SC: University of Southern California)
Overproduction of glucose by the liver in the face of insulin resistance is a primary cause of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, mechanisms involved in control of hepatic glucose output (HGO) remain less than clear, even in normal individuals. Recent results have supported an indirect extrahepatic effect of insulin as the primary locus of insulin action to restrain HGO. One suggested extrahepatic site is the pancreatic ɑ-cell. To examine whether insulin9s extrahepatic site is independent of the ɑ-cells, HGO suppression was examined independent of changes in glucagon secretion or insulin antagonism of glucagon action. Euglycemic glucose clamps ( n = 40) with somatostatin infusion were performed in conscious dogs ( n = 5). Paired experiments were conducted in which insulin was infused either portally (1.2, 3.0, 6.0 pmol · min −1 · kg −1 ) or peripherally at half the portal infusion rate (0.6, 1.5, 3.0 pmol · min −1 · kg −1 ). Additional zero and saturating portal-dose experiments (100 pmol · min −1 · kg −1 ) were also performed. For the paired experiments, portal insulin infusion resulted in portal insulin concentrations approximately two to three times higher than in the corresponding peripheral insulin infusion experiments, while at the same time peripheral insulin concentrations were approximately matched. Equal peripheral insulin concentration resulted in equivalent HGO suppression irrespective of the portal concentrations. Thus, insulin affects a signal at a peripheral site, other than ɑ-cell, that in turn suppresses hepatic glucose production. To investigate the nature of this signal, we measured alanine, lactate, and free fatty acids (FFAs). There was no clear relationship between alanine or lactate and HGO suppression; however, there was an extremely strong relationship between plasma FFAs and HGO both at steady state and during dynamic changes in insulin. These data suggest, but do not prove, that insulin acts to suppress HGO as follows: Insulin slowly traverses the capillary endothelium in adipose tissue; elevated insulin in adipose tissue interstdtium inhibits lipolysis, thus decreasing FFA levels; and decreased FFAs act as a signal to the liver to suppress endogenous glucose production.
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Cited By246
Published on Mar 23, 2019in Naunyn-schmiedebergs Archives of Pharmacology 2.06
Olufunto O. Badmus (College of Health Sciences, Bahrain), Lawrence A. Olatunji9
Estimated H-index: 9
(College of Health Sciences, Bahrain)
Postpartum contraception is an important step for preventing closely spaced pregnancy. Combined oral contraceptive (COC) has been linked to cardiometabolic disturbances. We therefore hypothesized that postpartum oral estrogen-progestin use induces hepatic lipid accumulation that is associated with glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation via adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA)-dependent pathway. Female Wistar rats weighing 130–150 g w...
Dominic Santoleri (UPenn: University of Pennsylvania), Paul M. Titchenell8
Estimated H-index: 8
(UPenn: University of Pennsylvania)
Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathwa...
Published on Jan 1, 2019
Jothydev Kesavadev8
Estimated H-index: 8
Fatema Jawad7
Estimated H-index: 7
(Sindh Institute of Urology and Transplantation)
+ 5 AuthorsSanjay Kalra12
Estimated H-index: 12
While in the earlier times type 2 diabetes (T2D) was only considered as a disease related to a disturbance in the functioning of the pancreas, lots of evidences accumulated during the past few decades revealed a plethora of additional factors that contribute to this devastating disease. The understanding of T2D has evolved from recognizing the duo of pancreatic β-cell failure with defective insulin secretion and insulin resistance (IR), to the triumvirate with the addition of hepatic gluconeogen...
Published on Sep 1, 2018in Journal of Functional Foods 3.20
Pan Zhou3
Estimated H-index: 3
(Sichuan Agricultural University),
Yongsheng Wang (Sichuan Agricultural University)+ 12 AuthorsJian Li6
Estimated H-index: 6
(Sichuan Agricultural University)
Abstract The effects of adding inulin to low- or high-fat diet on the metabolic status and nutrient digestibility in gestating sows and the neonatal traits of their offspring were examined. Sixty sows were allocated to a 2 × 2 factorial treatment design with levels of inulin (0% or 1.5%) and fat (0% or 5%) addition as the fixed factors during gestation. Inulin supplementation resulted in the following: improved serum lipid profiles, insulin resistance, and glucose tolerance, which were adversely...
Published on Sep 1, 2018in Obesity Reviews 8.19
Kimber L. Stanhope39
Estimated H-index: 39
(UC Davis: University of California, Davis),
Michael I. Goran85
Estimated H-index: 85
(SC: University of Southern California)
+ 19 AuthorsGeorge A. Bray114
Estimated H-index: 114
(LSU: Louisiana State University)
Author(s): Stanhope, KL; Goran, MI; Bosy-Westphal, A; King, JC; Schmidt, LA; Schwarz, JM; Stice, E; Sylvetsky, AC; Turnbaugh, PJ; Bray, GA; Gardner, CD; Havel, PJ; Malik, V; Mason, AE; Ravussin, E; Rosenbaum, M; Welsh, JA; Allister-Price, C; Sigala, DM; Greenwood, MRC; Astrup, A; Krauss, RM | Abstract: © 2018 The Authors. Obesity Reviews published by John Wiley a Sons Ltd on behalf of World Obesity Federation Calories from any food have the potential to increase risk for obesity and cardiometabo...
Published on Mar 1, 2018in Physiological Genomics 2.58
Silvia V. Conde14
Estimated H-index: 14
(NOVA: Universidade Nova de Lisboa),
Joana F. Sacramento8
Estimated H-index: 8
(NOVA: Universidade Nova de Lisboa),
Maria P. Guarino13
Estimated H-index: 13
(NOVA: Universidade Nova de Lisboa)
The carotid body is currently looked at as a multipurpose sensor for blood gases, blood pH and several hormones. The matter of glucose sensing by the carotid body has been debated for several years in the literature, and nowadays there is a consensus that carotid body activity is modified by metabolic factors that contribute to glucose homeostasis. However, the sensing ability for glucose is still being pondered: are the carotid bodies low glucose sensors or, in contrast, are they overresponsive...
Published on Jan 1, 2018in Current Topics in Developmental Biology
Terry G. Unterman53
Estimated H-index: 53
(UIC: University of Illinois at Chicago)
Abstract FoxO proteins are ancient targets of insulin action and play an important role in mediating effects of insulin on gene expression and metabolism. Regulation of FoxO function in the liver is critical for the ability of insulin to maintain glucose homeostasis and suppress hepatic glucose production (HGP), and dysregulation of FoxO function is thought to contribute to the pathogenesis of diabetes mellitus. Signaling by the insulin/PI3 kinase/Akt pathway suppresses FoxO function, and FoxO p...
Published on Dec 1, 2017in Scientific Reports 4.01
Anna M. van Opstal5
Estimated H-index: 5
(LEI: Leiden University),
Abimbola A. Akintola9
Estimated H-index: 9
(LEI: Leiden University)
+ 4 AuthorsJeroen van der Grond11
Estimated H-index: 11
(LEI: Leiden University)
The hypothalamus is a crucial structure in the brain that responds to metabolic cues and regulates energy homeostasis. Patients with type 2 diabetes demonstrate a lack of hypothalamic neuronal response after glucose ingestion, which is suggested to be an underlying cause of the disease. In this study, we assessed whether intranasal insulin can be used to enhance neuronal hypothalamic responses to glucose ingestion. In a randomized, double-blinded, placebo-controlled 4-double cross-over experimen...
Published on Sep 1, 2017in Transplantation direct
Gerald Klaassen3
Estimated H-index: 3
E va Corpeleijn28
Estimated H-index: 28
+ 3 AuthorsDorien M. Zelle12
Estimated H-index: 12
BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is common in renal transplant recipients (RTR), increasing the risk of graft failure, cardiovascular disease, and mortality. Early detection of a high risk for PTDM is warranted. Because liver function and liver fat are involved, we investigated whether serum liver markers are associated with future PTDM in RTR. METHODS: Between 2001 and 2003, 606 RTR with a functioning allograft beyond the first year after transplantation were included of...
Published on Jul 1, 2017in Trends in Endocrinology and Metabolism 9.78
Paul M. Titchenell8
Estimated H-index: 8
(UPenn: University of Pennsylvania),
Mitchell A. Lazar113
Estimated H-index: 113
(UPenn: University of Pennsylvania),
Morris J. Birnbaum89
Estimated H-index: 89
(UPenn: University of Pennsylvania)
During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechan...