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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
Published on: May 11, 2015
Structural determinants of beta-cell failure in type 2 diabetes: a multimodality imaging study
Hajime Yamazaki1, Sevilay Tokgöz2, Shinichi Tauchi3
1Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence (CiRC2LE), Fukushima Medical University, Fukushima, Japan.
Background:
Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancreatic volume, beta-cell mass, beta-cell function, and T2D risk, and whether intrapancreatic fat deposition (IPFD) modifies these associations.
Methods:
We conducted three complementary studies. In a PET/CT study (N = 52), beta-cell mass was estimated using [68Ga]Ga-NODAGA-exendin-4 PET/CT imaging, and its correlations with CT-measured pancreatic volume, IPFD, and beta-cell function (HOMA2-%B) were evaluated. In a cross-sectional study using UK Biobank (N = 25,212), individuals were classified into four groups according to median pancreatic volume and IPFD on MRI, and the association with T2D prevalence was estimated. Finally, a case-cohort study with 6-year follow-up (N = 2168, subcohort of 658 and 146 incident T2D cases) used CT imaging to assess whether pancreatic volume and IPFD were associated with future T2D.
Results:
In the PET/CT study, smaller pancreatic volume (r = 0.66 [95% CI: 0.47-0.80]) combined with higher IPFD (r = 0.29 [95% CI: 0.011-0.53]) was associated with reduced estimated beta-cell mass, which in turn was linked to lower insulin secretion (r = 0.48 [95% CI: 0.22-0.68]). In the UK Biobank, individuals with small pancreas that contained much fat (small/high-fat pancreas) had the highest T2D likelihood (adjusted-odds ratio: 1.71 [95% CI: 1.42-2.07]) compared to those with large/low-fat pancreas. Validation in the longitudinal study showed adjusted-hazard ratios for T2D of 3.12 (1.40-6.96) for small/high-fat, 0.99 (0.58-1.67) for large/high-fat, and 0.74 (0.26-2.14) for small/low-fat pancreas.
Conclusion:
The combination of a small pancreas and high IPFD is associated with increased T2D risk, supporting a structural phenotype linked to beta-cell failure.
Insights
A small pancreas combined with high intra-pancreatic fat deposition (IPFD) significantly increases type 2 diabetes (T2D) risk. This structural phenotype is linked to beta-cell failure, offering new insights into T2D development.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Medical Imaging
Background:
- Type 2 diabetes (T2D) is associated with reduced pancreatic volume and beta-cell mass, but the causal relationship remains unclear.
- Intra-pancreatic fat deposition (IPFD) is increasingly recognized as a factor in metabolic dysfunction.
Purpose of the Study:
- To investigate the relationship between pancreatic volume, beta-cell mass, beta-cell function, and T2D risk.
- To determine if IPFD modifies these associations in individuals at risk for or with T2D.
Main Methods:
- Utilized PET/CT imaging to correlate beta-cell mass with pancreatic volume, IPFD, and beta-cell function (HOMA2-%B) in 52 individuals.
- Analyzed cross-sectional data from UK Biobank (N=25,212) to assess T2D prevalence based on pancreatic volume and IPFD categories derived from MRI.
- Conducted a 6-year longitudinal case-cohort study (N=2168) using CT imaging to evaluate pancreatic volume and IPFD as predictors of incident T2D.
Main Results:
- Smaller pancreatic volume and higher IPFD were associated with reduced beta-cell mass and lower insulin secretion in the PET/CT study.
- Individuals with a small pancreas and high IPFD exhibited the highest likelihood of T2D in the UK Biobank cohort (aOR=1.71).
- Longitudinal analysis confirmed that a small/high-fat pancreas significantly increased T2D risk (aHR=3.12) compared to a large/low-fat pancreas.
Conclusions:
- A combination of a small pancreas and high intra-pancreatic fat deposition represents a distinct structural phenotype.
- This phenotype is strongly associated with an increased risk of developing type 2 diabetes.
- The findings support the role of beta-cell failure in the pathogenesis of T2D, influenced by pancreatic structure and fat content.
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