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Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss. We have identified that the hepatic Farnesol X Receptor (FXR) plays an important role in an anti-obesogenic effect of glucagon receptor (GcgR) agonism. Chronic administration of IUB288, a potent GcgR agonist, significantly reduced diet-induced obesity (DIO) in wild type (WT, 17%) mice compared to (FXR∆liver, 6%) liver-specific FXR knock-out mice. Weight loss was associated with increased energy expenditure (p Disclosure T. Kim: None. S. Nason: None. J.P. Antipenko: None. C.S. Vestri: None. K. Smith-Johnston: None. M.E. Pepin: None. A.R. Wende: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. D.R. Moellering: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from glucagon receptor (GCGR) activation, prompting us to search for additional pathways. Intriguingly, chronic GCGR agonism increases plasma bile acid levels. We hypothesized that GCGR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole-body and liver-specific FXR-knockout (Fxr∆liver) mice. Chronic GCGR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21, and Fxr whole-body or liver-specific knockout (∆liver) mice failed to reduce body weight when compared with wild-type (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not Fxr∆liver mice. GCGR agonism increased [14C]palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from Fxr∆liver mice. Our data clearly demonstrate that control of whole-body energy expenditure by GCGR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GCGR agonism in the therapy of metabolic disorders.

Cardiovascular disease is the leading cause of death in patients with diabetes. However, identifying mechanisms of disease progression has proven difficult as diabetes involves dysfunction of numerous pathways including cellular signaling and mitochondrial capacity. This results in the alteration of circulating hormones and nutrients that can lead to inflammation, oxidative stress, endoplasmic reticulum stress, lipotoxicity, and glucotoxicity (1). One hallmark of diabetes is the development of hyperglycemia and one goal of patient care is to control glycemia through the modification of lifestyle and drug therapy. However, the effectiveness of antihyperglycemia drugs on the development of heart failure in individuals with diabetes is not fully understood (2). Part of this challenge results from an incomplete understanding of how glucose regulates molecular function. Over 30 years ago, Torres and Hart (3) identified a unique posttranslational modification (PTM) by glycosylation of intracellular proteins via addition of an O -linked β- N -acetyl-d-glucosamine ( O- GlcNAc), termed O -GlcNAcylation. Owing to the input of multiple metabolic pathways to generate uridine diphosphate (UDP)-GlcNAc, the substrate of O- GlcNAcylation, this PTM gained attention as the link between metabolism and chronic disease (4). Increases in glucose associated with diabetes lead to excess O- GlcNAcylation and represent a crucial link between glucose and molecular regulation. Similar to protein phosphorylation, O- GlcNAcylation occurs at serine and threonine residues in proteins. It has been identified on ∼4,000 targets across most cellular pathways, as reviewed by Bond and Hanover (5). Unlike other PTMs that may have dozens if not …