Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jun 25:12:714348.
doi: 10.3389/fendo.2021.714348. eCollection 2021.

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

Takaaki Murakami  1 , Hiroyuki Fujimoto  2 , Nobuya Inagaki  1
Affiliations
Review

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

Takaaki Murakami et al. Front Endocrinol (Lausanne). .

Abstract

Pancreatic beta (β)-cell dysfunction and reduced mass play a central role in the development and progression of diabetes mellitus. Conventional histological β-cell mass (BCM) analysis is invasive and limited to cross-sectional observations in a restricted sampling area. However, the non-invasive evaluation of BCM remains elusive, and practical in vivo and clinical techniques for β-cell-specific imaging are yet to be established. The lack of such techniques hampers a deeper understanding of the pathophysiological role of BCM in diabetes, the implementation of personalized BCM-based diabetes management, and the development of antidiabetic therapies targeting BCM preservation and restoration. Nuclear medical techniques have recently triggered a major leap in this field. In particular, radioisotope-labeled probes using exendin peptides that include glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist have been employed in positron emission tomography and single-photon emission computed tomography. These probes have demonstrated high specificity to β cells and provide clear images accurately showing uptake in the pancreas and transplanted islets in preclinical in vivo and clinical studies. One of these probes, 111indium-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4), has captured the longitudinal changes in BCM during the development and progression of diabetes and under antidiabetic therapies in various mouse models of type 1 and type 2 diabetes mellitus. GLP-1R-targeted imaging is therefore a promising tool for non-invasive BCM evaluation. This review focuses on recent advances in non-invasive in vivo β-cell imaging for BCM evaluation in the field of diabetes; in particular, the exendin-based GLP-1R-targeted nuclear medicine techniques.

Keywords: beta-cell imaging; diabetes mellitus; exendin; glucagon-like peptide-1; islet transplantation; positron emission tomography; single photon emission computed tomography; β-cell mass.

PubMed Disclaimer

Conflict of interest statement

NI received clinical commissioned/joint research grants from Daiichi Sankyo, Terumo, and Drawbridge Inc.; speaker honoraria from Kowa, MSD, Astellas Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Takeda, Eli Lilly Japan, Sumitomo Dainippon Pharma, and Mitsubishi Tanabe Pharma; scholarship grants from Kissei Pharmaceutical, Sanofi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Takeda, Japan Tobacco, Kyowa Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, MSD, Eli Lilly Japan, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Novartis Pharma, Teijin Pharma, and Life Scan Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The expected benefits of non-invasive β-cell mass (BCM) evaluation. Loss of BCM has a central role in the onset and progression of type 2 diabetes mellitus. The establishment of non-invasive BCM evaluation methods will open the door to elucidating and understanding the pathophysiology of diabetes, the evaluation of therapeutic efficacies aimed at preserving and restoring BCM, the implementation of personalized diabetes management based on individual BCM, and drug development targeting BCM preservation and restoration.
Figure 2
Figure 2
An overview of the potential targets of β-cell-specific imaging probes. The identification of ideal probe targets highly specific to β cells is essential for realizing β-cell imaging. The various molecules whose expression is observed specifically in β cells have been explored. SUR1, glucose transporter 2 (GLUT-2), voltage-dependent calcium channel (VDCC), G protein-coupled receptors (GPRs), D2 and D3 dopamine receptors, serotonergic system, vesicular monoamine transporter 2 (VMAT2), and GLP-1 receptors have been reported as leading potential probe targets. KATP channel, ATP-sensitive potassium channel; 5-HT receptor, 5-hydroxytryptamine receptor.
Figure 3
Figure 3
An overview of the leading compounds for GLP-1R-targeted probes. In the development of GLP-1R-targeted imaging probes, exendin-related peptides such as exendin-3, exendin-4, and exendin (9-39) have been investigated as promising compounds. These compounds have approximately 50% homology with human GLP-1 (hGLP-1) and show high stability in vivo and high affinity to GLP-1R, which qualifies their potential as tracers for in vivo β-cell imaging. Exendin-4 differs from exendin-3 by two amino acid substitutions (in orange). C-terminally modified derivatives tended to show superior specificity, whereas the modified derivatives on the residue Lys12 of exendin-4 (in blue) demonstrated high affinity to GLP-1R and in vivo stability as in vivo imaging probes for β cells.
Figure 4
Figure 4
An 111Indium(In)-labeled exendin-4 derivative: [Lys12(111In-BnDTPA-Ahx)]exendin-4. (A) Chemical structure of [Lys12(111In-BnDTPA-Ahx)]exendin-4. Exendin-4 was labeled with 111In via isothiocyanate-benzyl-diethylenetriaminepentaacetic acid (BnDTPA) and 6-aminohexanoic (Ahx) attached to the epsilon amino group at the lysine-12 residue. (B) Representative in vivo axial abdominal image of [Lys12(111In-BnDTPA-Ahx)]exendin-4 single-photon emission computed tomography (SPECT)/computed tomography (CT) in a mouse. [Lys12(111In-BnDTPA-Ahx)]exendin-4 successfully visualized the pancreas (white dotted circle). Maximum to minimum SPECT intensity: red > orange > yellow > green > blue > black. R, right; L, left; V, ventral.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. International Diabetes Federation . Idf Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; (2019). Available at: http://www.idf.org/diabetesatlas.
    1. Rhodes CJ. Type 2 Diabetes-A Matter of Beta-Cell Life and Death? Science (2005) 307:380–4. 10.1126/science.1104345 - DOI - PubMed
    1. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical Application of Incretin-Based Therapy: Therapeutic Potential, Patient Selection and Clinical Use. Am J Med (2009) 122(Suppl):S37–50. 10.1016/j.amjmed.2009.03.015 - DOI - PubMed
    1. Weir GC, Gaglia J, Bonner-Weir S. Inadequate β-Cell Mass Is Essential for the Pathogenesis of Type 2 Diabetes. Lancet Diabetes Endocrinol (2020) 8:249–56. 10.1016/S2213-8587(20)30022-X - DOI - PMC - PubMed
    1. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A Novel Subtype of Type 1 Diabetes Mellitus Characterized by a Rapid Onset and an Absence of Diabetes-Related Antibodies. Osaka Iddm Study Group. N Engl J Med (2000) 342:301–7. 10.1056/NEJM200002033420501 - DOI - PubMed

Publication types

MeSH terms

Substances

-