ReviewThe Journal of physiology2003
A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex.
Review in The Journal of physiology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 53 citations in OpenAlex.
- Logistic model of glucose-regulated C-peptide secretion: hysteresis pathway disruption in impaired fasting glycemia.American journal of physiology. Endocrinology and metabolism · 2012Trial
- Glucose-Responsive Materials for Smart Insulin Delivery: From Protein-Based to Protein-Free Design.ACS materials Au · 2025Review
- The impact of weight loss in early pregnancy on the incidence of late gestational diabetes: a retrospective cohort study.Frontiers in nutrition · 2025Article
- The Modulation of Euglycemic Endocrine and Exocrine Pancreatic Secretions in Iron Deficiency.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2024Article
- A Glimpse into Milestones of Insulin Resistance and an Updated Review of Its Management.Nutrients · 2023Review
- Mathematical modeling clarifies the paracrine roles of insulin and glucagon on the glucose-stimulated hormonal secretion of pancreatic alpha- and beta-cells.Frontiers in endocrinology · 2023Article
- Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs.Science advances · 2022Article
- Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg.Frontiers in endocrinology · 2022Review
- Alpha cell regulation of beta cell function.Diabetologia · 2020Review
- Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation.Advanced materials (Deerfield Beach, Fla.) · 2020Review
- The Local Paracrine Actions of the Pancreatic α-Cell.Diabetes · 2020Review
- Relationship between serum insulin and point-of-admission blood glucose of ill neonates at a tertiary health facility in Nigeria.The Pan African medical journal · 2020Article
- Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell.Nature metabolism · 2019Article
- How does homeostasis happen? Integrative physiological, systems biological, and evolutionary perspectives.American journal of physiology. Regulatory, integrative and comparative physiology · 2019Review
- Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point.Cell metabolism · 2018Article
- Linking Stress, Catecholamine Autotoxicity, and Allostatic Load with Neurodegenerative Diseases: A Focused Review in Memory of Richard Kvetnansky.Cellular and molecular neurobiology · 2018Review
- Homeostatic systems, biocybernetics, and autonomic neuroscience.Autonomic neuroscience : basic & clinical · 2017Review
- A Comprehensive Survey of the Roles of Highly Disordered Proteins in Type 2 Diabetes.International journal of molecular sciences · 2017Article
- TFPI2AS1, a novel lncRNA that inhibits cell proliferation and migration in lung cancer.Cell cycle (Georgetown, Tex.) · 2017Article
- Pharmacokinetic/pharmacodynamic modelling in diabetes mellitus.Clinical pharmacokinetics · 2008Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic alpha- and beta-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.