The inability of insulin to suppress hepatic glucose production (HGP) is a key defect found in type 2 diabetes. Insulin inhibits HGP through both direct and indirect means, the latter of which include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid level, decrease in the load of gluconeogenic substrates reaching the liver, and change in neural signaling to the liver. Two studies in this issue of the JCI demonstrate that selective changes in the expression of insulin receptors in mouse liver do not have a detectable effect on the ability of insulin to inhibit HGP (see the related articles beginning on pages 1306 and 1314). These provocative data suggest that the indirect effects of insulin on the liver are the primary determinant of HGP in mice.
Alan D. Cherrington
Title and authors | Publication | Year |
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Therapeutic Potential of Myricitrin in a db/db Mouse Model of Type 2 Diabetes
Kim SR, Kim YJ, Kim H, Park S, Jung UJ |
Molecules | 2025 |
Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver
Justin A. Fletcher, Stanislaw Deja, Santhosh Satapati, Xiaorong Fu, Shawn C. Burgess, Jeffrey D. Browning |
JCI Insight | 2019 |
The integrative biology of type 2 diabetes
M Roden, GI Shulman |
Nature | 2019 |
Honokiol Improves Insulin Resistance, Hepatic Steatosis, and Inflammation in Type 2 Diabetic db/db Mice
YJ Kim, UJ Jung |
International journal of molecular sciences | 2019 |
Non-islet Cell Hypoglycemia: Case Series and Review of the Literature
V Garla, H Sonani, V Palabindala, C Gomez-Sanchez, J Subauste, LF Lien |
Frontiers in Endocrinology | 2019 |
Sex Dependent Dysregulation of Hepatic Glucose Production in Lean Type 2 Diabetic Rats
CS Blesson, A Schutt, S Chacko, JC Marini, PR Mathew, D Tanchico, M Balakrishnan, C Yallampalli |
Frontiers in Endocrinology | 2019 |
Mechanisms of Insulin Action and Insulin Resistance
MC Petersen, GI Shulman |
Physiological reviews | 2018 |
Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice
VR Muñoz, RC Gaspar, BM Crisol, GP Formigari, MR SantAna, JD Botezelli, RS Gaspar, AS da Silva, DE Cintra, LP de Moura, ER Ropelle, JR Pauli |
The Journal of Physiological Sciences | 2017 |
FoxO integration of insulin signaling with glucose and lipid metabolism
S Lee, HH Dong |
Journal of Endocrinology | 2017 |
The new biology of diabetes
UB Pajvani, D Accili |
Diabetologia | 2015 |
Intradermal insulin infusion achieves faster insulin action than subcutaneous infusion for 3-day wear.
Rini CJ, McVey E, Sutter D, Keith S, Kurth HJ, Nosek L, Kapitza C, Rebrin K, Hirsch L, Pettis RJ |
Drug Delivery and Translational Research | 2015 |
Control of hepatic glucose metabolism by islet and brain
JM Rojas, MW Schwartz |
Diabetes Obesity and Metabolism | 2014 |
Role for the TRPV1 channel in insulin secretion from pancreatic beta cells.
Diaz-Garcia CM, Morales-Lázaro SL, Sánchez-Soto C, Velasco M, Rosenbaum T, Hiriart M |
The Journal of Membrane Biology | 2014 |
Central nervous system control of metabolism
MG Myers, DP Olson |
Nature | 2012 |
Central Endocannabinoid Signaling Regulates Hepatic Glucose Production and Systemic Lipolysis
JD O'Hare, E Zielinski, B Cheng, T Scherer, C Buettner |
Diabetes | 2011 |
FoxOs Function Synergistically to Promote Glucose Production*
RA Haeusler, KH Kaestner, D Accili |
The Journal of biological chemistry | 2010 |
Brain insulin infusion does not augment the counterregulatory response to hypoglycemia or glucoprivation
KK Ishihara, SC Haywood, D Daphna-Iken, EC Puente, SJ Fisher |
Metabolism | 2009 |
Inducible gene silencing defines CNS insulin action as a major determinant of peripheral glucose and fat metabolism
Linda Koch1, F. Thomas Wunderlich1, Jost Seibler2, A. Christine Könner1, Brigitte Hampel1, Sigrid Irlenbusch1, Georg Brabant3, C. Ronald Kahn4, Frieder Schwenk2,5, Jens C. Brüning1 |
Journal of Clinical Investigation | 2008 |
An explorative study of in vivo digestive starch characteristics and postprandial glucose kinetics of wholemeal wheat bread
MG Priebe, RE Wachters-Hagedoorn, JA Heimweg, A Small, T Preston, H Elzinga, F Stellaard, RJ Vonk |
European Journal of Nutrition | 2008 |
Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum
CM Kusminski, PG McTernan, T Schraw, K Kos, JP OHare, R Ahima, S Kumar, PE Scherer |
Diabetologia | 2007 |
Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice
M Simmgen, C Knauf, M Lopez, AI Choudhury, M Charalambous, J Cantley, DC Bedford, M Claret, MA Iglesias, H Heffron, PD Cani, A Vidal-Puig, R Burcelin, DJ Withers |
Diabetologia | 2006 |
Central nervous system and control of endogenous glucose production
G Demuro, S Obici |
Current Diabetes Reports | 2006 |
Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN
CM Taniguchi, TT Tran, T Kondo, J Luo, K Ueki, LC Cantley, CR Kahn |
Proceedings of the National Academy of Sciences | 2006 |
Insulin’s effect on the liver: “Direct or indirect?” continues to be the question
J Girard |
Journal of Clinical Investigation | 2006 |