ArticleAmerican journal of physiology. Endocrinology and metabolism2011
Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats.
Article in American journal of physiology. Endocrinology and metabolism, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 46 citations in OpenAlex.
- Effect of short-term intensive insulin therapy on α-cell function in patients with newly diagnosed type 2 diabetes.Medicine · 2020Trial
- Article
- Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells.Stem cell reports · 2025Article
- Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology.Current medicinal chemistry · 2025Review
- Laser Capture Microdissection Coupled Capillary Immunoassay to Study the Expression of PCK-2 on Spatially-Resolved Islets of Rat Langerhans.Pharmaceutics · 2021Article
- Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function.The Journal of clinical endocrinology and metabolism · 2021Article
- Glycemia Regulation: From Feedback Loops to Organizational Closure.Frontiers in physiology · 2020Article
- Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.The Journal of clinical endocrinology and metabolism · 2019Article
- Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production.Cell metabolism · 2019Article
- Glucose-Induced β-Cell Dysfunction In Vivo: Evidence for a Causal Role of C-jun N-terminal Kinase Pathway.Endocrinology · 2018Article
- Gs-DREADD Knock-In Mice for Tissue-Specific, Temporal Stimulation of Cyclic AMP Signaling.Molecular and cellular biology · 2017Article
- Genomics of Islet (Dys)function and Type 2 Diabetes.Trends in genetics : TIG · 2017Review
- Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells.Scientific reports · 2016Article
- There is Kisspeptin - And Then There is Kisspeptin.Trends in endocrinology and metabolism: TEM · 2015Review
- Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Article
- The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked?Biochimica et biophysica acta · 2014Review
- Glucagon regulates hepatic kisspeptin to impair insulin secretion.Cell metabolism · 2014Article
- A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis.The Journal of biological chemistry · 2014Article
- Current insights and new perspectives on the roles of hyperglucagonemia in non-insulin-dependent type 2 diabetes.Current hypertension reports · 2013Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 ± 0.7 vs. 6.1 ± 0.4 mg·kg(-1)·min(-1) on day 0, P < 0.001) but tripled between days 4 and 8 (9.9 ± 1.7 mg·kg(-1)·min(-1), P < 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ∼300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as α-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the β-cell to maintain glucose homeostasis.
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