Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats
Abstract
Gluconeogenesis is increased in type 2 diabetes and contributes significantly to fasting and postprandial hyperglycemia. We recently reported the discovery of the first potent and selective inhibitors of fructose 1,6-bisphosphatase (FBPase), a rate-controlling enzyme of gluconeogenesis. Herein we describe acute and chronic effects of the lead inhibitor, MB06322 (CS-917), in rodent models of type 2 diabetes. In fasting male ZDF rats with overt diabetes, a single dose of MB06322 inhibited gluconeogenesis by 70% and overall endogenous glucose production by 46%, leading to a reduction in blood glucose of >200 mg/dl. Chronic treatment of freely feeding 6-week-old male Zucker diabetic fatty (ZDF) rats delayed the development of hyperglycemia and preserved pancreatic function. Elevation of lactate ( approximately 1.5-fold) occurred after 4 weeks of treatment, as did the apparent shunting of precursors into triglycerides. Profound glucose lowering ( approximately 44%) and similar metabolic ramifications were associated with 2-week intervention therapy of 10-week-old male ZDF rats. In high-fat diet-fed female ZDF rats, MB06322 treatment for 2 weeks fully attenuated hyperglycemia without evidence of metabolic perturbation other than a modest reduction in glycogen stores ( approximately 20%). The studies confirm that excessive gluconeogenesis plays an integral role in the pathophysiology of type 2 diabetes and suggest that FBPase inhibitors may provide a future treatment option.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In diabetic rodents, the prodrug CS-917 produced a promisingly lower rate of gluconeogenesis and endogenous glucose production.
“In diabetic rodents, the prodrug CS-917 produced a promisingly lower rate of gluconeogenesis and endogenous glucose production.”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [114]
Clinical tests of CS-917 in individuals with T2DM showed a good safety profile and clinically significant decreases in fasting glucose levels.
“Clinical tests of CS-917 conducted later on in individuals with T2DM showed a good safety profile and clinically significant decreases in fasting glucose levels.”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [114]
FBPase has emerged as a key target in T2DM therapy due to the recognized importance of excessive endogenous glucose synthesis in hyperglycemia.
“FBPase, a rate-regulating gluconeogenesis enzyme, has emerged as a key target in T2DM therapy due to the recognized importance of excessive endogenous glucose synthesis in the hyperglycemia that defines the condition.”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [114]
Because most existing antidiabetic drugs primarily target insulin resistance or insufficiency rather than directly or efficaciously reducing gluconeogenesis, inhibitors of FBPase have been expected to address an unmet medical need.
“Since most of the existing antidiabetic drugs primarily target insulin resistance or insufficiency rather than directly or efficaciously reducing gluconeogenesis, inhibitors of FBPase have been expected to address an unmet medical need (114).”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [114]
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
Mechanism by which metformin reduces glucose production in type 2 diabetes.
Hundal, R. S., Krssak, M., Dufour, S., Laurent, D., Lebon, V, Chandramouli, V, Inzucchi, S. E., Schumann, W. C., Petersen, K. F., Landau, B. R., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2063 · Cited by 1,052 · see citing works
Self-citationMayerson, A. B., Hundal, R. S., Dufour, S., Lebon, V., Befroy, D., Cline, G. W., Enocksson, S., Inzucchi, S. E., Shulman, G. I., & Petersen, K. F. (2002) · Diabetes · doi:10.2337/diabetes.51.3.797 · Cited by 647 · see citing works
Mitrakou, A., Kelley, D., Mokan, M., Veneman, T., Pangburn, T., Reilly, J., & Gerich, J. (1992) · New England Journal of Medicine · doi:10.1056/nejm199201023260104 · Cited by 595 · see citing works
Tiikkainen, M., Häkkinen, A.-M., Korsheninnikova, E., Nyman, T., Mäkimattila, S., & Yki-Järvinen, H. (2004) · Diabetes · doi:10.2337/diabetes.53.8.2169 · Cited by 524 · see citing works
DeFronzo, R. A., Ferrannini, E., & Simonson, D. C. (1989) · Metabolism · doi:10.1016/0026-0495(89)90129-7 · Cited by 515 · see citing works
Contributions of gluconeogenesis to glucose production in the fasted state
Landau, B. R., Wahren, J., Chandramouli, V, Schumann, W. C., Ekberg, K., & Kalhan, S. C. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118803 · Cited by 487 · see citing works
Self-citationTaylor, R., Magnusson, I., Rothman, D. L., Cline, G. W., Caumo, A., Cobelli, C., & Shulman, G. I. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118379 · Cited by 258 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kowalski, G. M., & Bruce, C. R. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00165.2014 · Cited by 154 · see citing works
New hepatic targets for glycaemic control in diabetes
Agius, L. (2007) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2007.09.001 · Cited by 155 · see citing works
Tegegne, B. A., Adugna, A., Yenet, A., Yihunie Belay, W., Yibeltal, Y., Dagne, A., Hibstu Teffera, Z., Amare, G. A., Abebaw, D., Tewabe, H., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1440456 · Cited by 61 · see citing works
- Authors
- van Poelje, P. D., Potter, S. C., Chandramouli, V. C., Landau, B. R., Dang, Q., & Erion, M. D.
- Affiliations
- From the Departments of Biochemistry and Medicinal Chemistry, Metabasis Therapeutics, La Jolla, California
- Case Western Reserve University (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2006-06-01
- Volume
- 55
- Issue
- 6
- Pages
- 1747-1754
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2118479946
- Cited by
- 87
- References
- 8
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 8
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UCLA - Biblioteca de Ciencias de la Salud (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- fructose-1,6-bisphosphatase, gluconeogenesis, endogenous glucose production, hyperglycemia, type 2 diabetes, Zucker diabetic fatty rats, lactate, triglyceride synthesis, glycogen stores, high-fat diet, pancreatic function
- MeSH terms
- Alanine, Animals, Blood Glucose, Body Weight, Cholesterol, Diabetes Mellitus, Type 2, Eating, Female, Gluconeogenesis, Glucose, Fructose-Bisphosphatase, Hyperglycemia, Insulin, Ketone Bodies, Male, Organophosphorus Compounds, Pancreas, Rats, Zucker, Triglycerides, Molecular Structure, Lactic Acid, Rats, Organophosphonates
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
