Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics
Open accessAbstract
It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (Vo(2)), glucose usage and oxidation, intracellular Ca(2+), and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a "staircase" glucose stimulus, whereas IR and Vo(2) were measured. Vo(2) of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal Vo(2) of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min(-1)·100 islets(-1), and the glucose S(0.5) was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, V(max) of 0.32 ± 0.01 nmol·min(-1)·100 islets(-1), and the S(0.5) shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca(2+) were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective Vo(2), IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for…
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?
Oxidative glucose metabolism is reduced in islets from T2DM donors, and the dose-response relationship is shifted towards slightly higher glucose concentrations.
“Oxidative glucose metabolism (measured as oxygen consumption rate) is reduced in islets from T2DM donors (141) and the dose-response relationship is shifted towards slightly higher concentrations; the half-maximal rate of oxygen production occurred at 4.4 and 5.4 mM glucose in control and T2DM islets, respectively (150).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [150]
In human islets from non-diabetic donors, only a fraction of glucose entering glycolysis proceeds into the Krebs cycle, unlike mouse β-cells.
“Surprisingly, it seems that (unlike mouse β-cells) only a fraction of glucose entering glycolysis proceeds into the Krebs cycle (150).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [150]
In human islets, insulin secretion is detectable at glucose concentrations as low as 3 mM, significantly lower than the secretion threshold in mouse islets (~5 mM).
“In human islets, insulin secretion is detectable at glucose concentrations as low as 3 mM (89, 150, 266), which is significantly lower than the secretion threshold in mouse islets (~5 mM (257)).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [150]
In both mouse and human islets, ramping glucose from <2 mM to >25 mM produces essentially monophasic insulin secretion with little sign of a 1st phase.
“In both mouse and human islets, when the glucose concentration is ramped from a non-stimulatory glucose concentration (<2 mM) to a high concentration (>25 mM) insulin secretion is essentially monophasic with little sign of a 1st phase (150, 494).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [150]
Cites
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
Kahn, S. E., Haffner, S. M., Heise, M. A., Herman, W. H., Holman, R. R., Jones, N. P., Kravitz, B. G., Lachin, J. M., O'Neill, M. C., Zinman, B., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa066224 · Cited by 2,962 · see citing works
Clinical risk factors, DNA variants, and the development of type 2 diabetes
Lyssenko, V., Jonsson, A., Almgren, P., Pulizzi, N., Isomaa, B., Tuomi, T., Berglund, G., Altshuler, D., Nilsson, P., & Groop, L. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0801869 · Cited by 938 · see citing works
Genotype score in addition to common risk factors for prediction of type 2 diabetes
Meigs, J. B., Shrader, P., Sullivan, L. M., McAteer, J. B., Fox, C. S., Dupuis, J., Manning, A. K., Florez, J. C., Wilson, P. W. F., D'Agostino, R. B., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804742 · Cited by 759 · cited 3× · see citing works
“The molecular pathology of T2DM and its usually slow development with aging remains a mystery, although extensive clinical investigations of the pathophysiology have provided an exhaustive phenomenological description, and genome-wide association studies have amassed compelling evidence for linkage of numerous diabete…”
BackgroundThiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1052 · Cited by 521 · see citing works
Dual role of proapoptotic BAD in insulin secretion and beta cell survival
Danial, N. N., Walensky, L. D., Zhang, C.-Y., Choi, C. S., Fisher, J. K., Molina, A. J. A., Datta, S. R., Pitter, K. L., Bird, G. H., Wikstrom, J. D., et al. (2008) · Nature Medicine · doi:10.1038/nm1717 · Cited by 307 · see citing works
Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes
MacDonald, M. J., Longacre, M. J., Langberg, E.-C., Tibell, A., Kendrick, M. A., Fukao, T., & Ostenson, C.-G. (2009) · Diabetologia · doi:10.1007/s00125-009-1319-6 · Cited by 115 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Regulation of Insulin Secretion in Human Pancreatic Islets
Rorsman, P., & Braun, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183754 · Cited by 599 · see citing works
Zhang, Q., Ramracheya, R., Lahmann, C., Tarasov, A., Bengtsson, M., Braha, O., Braun, M., Brereton, M., Collins, S., Galvanovskis, J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.014 · Cited by 225 · see citing works
Zhang, E., Mohammed Al-Amily, I., Mohammed, S., Luan, C., Asplund, O., Ahmed, M., Ye, Y., Ben-Hail, D., Soni, A., Vishnu, N., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.008 · Cited by 171 · see citing works
“In T2D islets, mitochondrial dysfunction underlies the blunted GSIS (Anello et al., 2005; Doliba et al., 2012).”
BackgroundEmerging roles of β-cell mitochondria in type-2-diabetes
Las, G., Oliveira, M. F., & Shirihai, O. S. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.100843 · Cited by 51 · see citing works
Modelling of energy-driven switch for glucagon and insulin secretion
Grubelnik, V., Zmazek, J., Markovič, R., Gosak, M., & Marhl, M. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2020.110213 · Cited by 15 · see citing works
- Authors
- Doliba, N. M., Qin, W., Najafi, H., Liu, C., Buettger, C. W., Sotiris, J., Collins, H. W., Li, C., Stanley, C. A., Wilson, D. F., Grimsby, J., Sarabu, R., Naji, A., & Matschinsky, F. M.
- Affiliations
- University of Pennsylvania (US)
- Department of Biochemistry and Biophysics and Institute for Diabetes, Obesity, and Metabolism;
- Children's Hospital of Philadelphia (US)
- Department of Metabolic Diseases, Roche Research Center, Nutley, New Jersey
- Corresponding author
- Matschinsky, Franz M.
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2012-01-01
- Volume
- 302
- Issue
- 1
- Pages
- E87-E102
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC3328091
- OpenAlex
- W2147284000
- Cited by
- 96
- References
- 6
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 6 · 2015: 9 · 2014: 6 · 2013: 13 · 2012: 5
- FWCI
- 7.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, DK-22122, DK-053012, R01DK053012, P30DK019525)
- 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 › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glucokinase activators, type 2 diabetes, pancreatic islets, glucose-stimulated insulin secretion, ATP production, intracellular calcium, exendin-4, GLP-1 receptor agonists, islet transplantation
- MeSH terms
- Exenatide, Insulin Secretion, Adult, Animals, Diabetes Mellitus, Type 2, Female, Glucokinase, Glucose, Glycolysis, Humans, Hypoglycemic Agents, Insulin, Islets of Langerhans, Male, Middle Aged, Oxidative Phosphorylation, Peptides, Species Specificity, Venoms, Cell Respiration, Calcium Signaling, Enzyme Activators, Benzeneacetamides, Tissue Culture Techniques, Mice, Rats, Glucagon-Like Peptide 1
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
