Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice

Biochim Biophys Acta Mol Basis Dis. 2022 Apr 1;1868(4):166339. doi: 10.1016/j.bbadis.2022.166339. Epub 2022 Jan 8.


The pancreatic islet vasculature is of fundamental importance to the β-cell response to obesity-associated insulin resistance. To explore islet vascular alterations in the pathogenesis of type 2 diabetes, we evaluated two insulin resistance models: ob/ob mice, which sustain large β-cell mass and hyperinsulinemia, and db/db mice, which progress to diabetes due to secondary β-cell compensation failure for insulin secretion. Time-dependent changes in islet vasculature and blood flow were investigated using tomato lectin staining and in vivo live imaging. Marked islet capillary dilation was observed in ob/ob mice, but this adaptive change was blunted in db/db mice. Islet blood flow volume was augmented in ob/ob mice, whereas it was reduced in db/db mice. The protein concentrations of total and phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 were increased in ob/ob islets, while they were diminished in db/db mice, indicating decreased eNOS activity. This was accompanied by an increased retention of advanced glycation end-products in db/db blood vessels. Amelioration of diabetes by Elovl6 deficiency involved a restoration of capillary dilation, blood flow, and eNOS phosphorylation in db/db islets. Our findings suggest that the disability of islet capillary dilation due to endothelial dysfunction impairs local islet blood flow, which may play a role in the loss of β-cell function and further exacerbate type 2 diabetes.

Keywords: Blood flow; Endothelial nitric oxide synthase; Pancreatic islet; Type 2 diabetes; Vasculature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Flow Velocity
  • Blood Vessels / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Fatty Acid Elongases / deficiency
  • Fatty Acid Elongases / genetics
  • Female
  • Glycation End Products, Advanced / metabolism
  • Insulin / metabolism
  • Insulin Resistance
  • Islets of Langerhans / anatomy & histology
  • Islets of Langerhans / blood supply
  • Islets of Langerhans / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphorylation


  • Elovl6 protein, mouse
  • Glycation End Products, Advanced
  • Insulin
  • Nitric Oxide Synthase Type III
  • Fatty Acid Elongases