Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas

Abstract

The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.

Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes

“…Moreover, the sizes of transplanted islets are dependent on the isolation procedure and thus don’t reflect the entire spectrum of sizes represented in the pancreas 32 . OPT imaging lacks the resolution provided by confocal imaging, but on the other hand is superior in giving an understanding of changes occurring in the whole islet population in situ in the pancreas 11 , 15 , thus complementing confocal microscopy data.…”

“…streptozotocin or alloxan 9 ) or in type 1 diabetes models (i.e. in the non-obese diabetic NOD mouse 10 , 11 or the BioBreeding BB-rat 12 , 13 ), an abnormally high number of beta cells can also be observed in the hyperglycemic leptin-deficient ob/ob mouse 14 , 15 . In humans, autopsy studies report substantial differences in the severity of beta cell loss in both type 1 and type 2 diabetic patients, which can be linked to a number of parameters including for example age, body weight, and duration of diabetic symptoms 16 – 18 .…”

Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats

“…A previous study shows that smaller islets contain more insulin per islet volume in situ and secrete insulin more efficiently in vitro [ 43 ]. In addition, large islets may be subjected to both hyperplasia and hypoxia [ 44 ], resulting in impaired beta cell function. Thus, loss of small and medium sized islets may very well impact insulin secretion.…”

On the dynamics of the human endocrine pancreas and potential consequences for the development of type 1 diabetes

“…A frequent finding in the pancreas of most species is that of so-called hyperemic or hemorrhagic islets [22][23][24][25] (Fig. 1), i.e., microvascular bleedings within the islet parenchyma.…”

“…A frequent finding in the pancreas of most species is that of so-called hyperemic or hemorrhagic islets [22][23][24][25]. Also, in humans hemorrhagic events in the islets are seemingly not rare events [24], and it is speculated that this can indeed be regarded as a part of the natural turnover of islets over time in most species.…”