α-Ketoisocaproate-Induced Hypersecretion of Insulin by Islets from Diabetes-Susceptible Mice
Abstract
Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin(ob) mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, alpha-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, alpha-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of alpha-ketoglutarate is a requisite step in the response of mouse islets to KIC. alpha-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that alpha-ketoglutarate may directly stimulate insulin secretion and that increased formation of alpha-ketoglutarate leads to hyperinsulinemia.
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The JAK2/STAT3 pathway is essential for the anorexigenic effect of leptin by stimulating POMC expression and inhibiting NPY.
“The JAK2/STAT3 pathway is essential for the anorexigenic effect of leptin by stimulating the expression of pro-opiomelanocortin (POMC) and inhibiting NPY”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [81]
Leptin regulates energy balance and metabolism by activating its receptor isoform b (LepRb), which triggers multiple intracellular signaling pathways.
“Leptin regulates energy balance and the metabolism by activating its receptor isoform b (LepRb), which triggers multiple intracellular signaling pathways”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [81]
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“The JAK2/STAT3 pathway is essential for the anorexigenic effect of leptin by stimulating the expression of pro-opiomelanocortin (POMC) and inhibiting NPY [81,82].”
- Authors
- Rabaglia, M. E., Gray-Keller, M. P., Frey, B. L., Shortreed, M. R., Smith, L. M., & Attie, A. D.
- Affiliations
- University of Wisconsin–Madison (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2005-08
- Volume
- 289
- Issue
- 2
- Pages
- E218-E224
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2105830561
- Cited by
- 96
- References
- 36
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 11 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 4 · 2013: 2 · 2012: 3
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hv28182-12-0-0)
- National Heart, Lung, and Blood Institute (N01-HV28182)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-58037, R01DK058037)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- alpha-ketoisocaproate, insulin hypersecretion, hyperinsulinemia, pancreatic islets, BTBR mice, alpha-ketoglutarate, glutamate, aminooxyacetic acid, insulin resistance, type 2 diabetes, succinic acid
- MeSH terms
- Insulin Secretion, Transaminases, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Disease Models, Animal, Glutamate Dehydrogenase, Hyperinsulinism, Insulin, Insulin Resistance, Islets of Langerhans, Keto Acids, Ketoglutaric Acids, Mice, Inbred C57BL, Mice, Transgenic, Species Specificity, Glutamic Acid, Leptin, Mice
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