Canagliflozin Improves Glycemic Control and Beta-Cell Mass in the TallyHo Polygenic Model of Type 2 Diabetes

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

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Studies to develop a glucagon sensitivity test in humans: The GLUSENTIC study protocol

Kjeldsen

Richter

Jensen

et al. 2022

Preprint

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Introduction: Glucagon is secreted from pancreatic alpha cells in response to amino acid stimuli and during states of hypoglycemia. A physiological feedback system exists between hepatocytes and the alpha cells termed the liver-alpha cell axis and signifies the role between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) disrupts this feedback system, perhaps as a consequence of impaired glucagon receptor (GCGR) signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective is to develop and evaluate a test for measuring glucagon sensitivity in humans. Methods and analysis: The study protocol is based on several pilot studies presented in this paper. The study will include 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI equal to or above 25 kg/m2, but no higher than 40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6-40 kg/m2. For the subsequent analysis, participants will be grouped according to their percentage of hepatic steatosis in the whole liver measured using the magnetic resonance imaging (MRI) scan. The primary outcome measure will be differences in a novel glucagon sensitivity index between individuals with and without hepatic steatosis without diabetes. Secondary outcomes include between-group differences regarding the glucagon-alanine-index, incremental and decremental area under the curve (AUC) and association analyses between hepatic steatosis and glucagon sensitivity. This report describes the design of the cross-sectional study currently taking place at Bispebjerg University Hospital. Results: These data will be published in peer-reviewed scientific journals and presented at scientific conferences. Ethics and dissemination: The study was approved by the scientific-ethical committee of the Capital region of Denmark (H-20023717) and registered with Danish Data protection Agency (P-2021-39) and ClinicalTrials.gov (NCT04907721). Written and oral consent will be obtained from all participants, and the study will adhere to the principles of the Declaration of Helsinki.

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Canagliflozin Improves Glycemic Control and Beta-Cell Mass in the TallyHo Polygenic Model of Type 2 Diabetes

Cited by 4 publications

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Heterogeneity and altered β-cell identity in the TallyHo model of early-onset type 2 diabetes

Heterogeneity and altered β-cell identity in the TallyHo model of early-onset type 2 diabetes

PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

Studies to develop a glucagon sensitivity test in humans: The GLUSENTIC study protocol

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