Islet microvasculature provides key architectural and functional roles, yet the morphological features of islets from patients with type 1 diabetes are poorly defined. We examined islet and exocrine microvasculature networks by multiplex immunofluorescence imaging of pancreases from organ donors with and without type 1 diabetes ( n=17 and n=16, respectively) and determined vessel diameter, density, and area. We also analyzed these variables in insulin-positive and insulin-negative islets of 7 type 1 diabetes donors. Control islet vessel diameter was significantly larger (7.6 ± 1.1 μm) compared with vessels in diabetic islets (6.2 ± 0.8 μm; p<0.001). Control islet vessel density (number/islet) was significantly lower (5.3 ± 0.6) versus diabetic islets (9.3 ± 0.2; p<0.001). Exocrine vessel variables were not significantly different between groups. Islets with residual beta-cells were comparable to control islets for both vessel diameter and density and were significantly different from insulin-negative islets within diabetic donors ( p<0.05). Islet smooth muscle actin area had a significant positive correlation with age in both groups ( p<0.05), which could negatively impact islet transplantation efficiency from older donors. These data underscore the critical relationship of islet beta-cells and islet vessel morphology in type 1 diabetes. These studies provide new knowledge of the islet microvasculature in diabetes and aging.
Reduced reproduction extends lifespan of females in many animals. To test the effects of reproduction on storage of macronutrients, we block reproductive output in the lubber grasshopper by injecting RNAi against the precursor to egg-yolk protein, vitellogenin, in early adulthood. Controls were injected with either buffer or RNAi against the major storage protein in the hemolymph, hexamerin-90. Vitellogenin RNAi greatly reduced both levels of mRNA for vitellogenin and ovarian growth, in comparison to both controls. Fat body mass was increased upon vitellogenin RNAi, but concentrations of the three hexameric storage proteins from the hemolymph were not. Surprisingly, hemolymph vitellogenin levels were increased upon vitellogenin RNAi. Total reproductive protein (hemolymph vitellogenin plus ovarian vitellin) was unchanged by vitellogenin RNAi, as reproductive protein was diverted to the hemolymph. Similarly, the increased lipid storage upon vitellogenin RNAi was largely attributable to the reduction in lipid in the ovary, due to decreased ovarian growth. A BLAST search revealed that the 515 bp sequence of vitellogenin used for RNAi had three 11 bp regions identical to the vitellogenin receptor of the cockroach Leucophaea maderae. This suggests that our treatment, in addition to reducing levels of vitellogenin transcript, may have also blocked transport of vitellogenin from the hemolymph to the ovary. This would be consistent with halted ovarian growth simultaneous with high levels of vitellogenin in the hemolymph. Nonetheless, the accumulation of vitellogenin, instead of hexameric storage proteins, is inconsistent with a simple model of the trade-off between reproduction and storage. This was observed in young females; future studies will address whether investment of proteins may shift to the soma as individuals age. Overall, our results suggest that blockage of reproduction in young grasshoppers redirects lipids to storage and reproductive proteins to the hemolymph.
The pancreas has long been known to be densely innervated with parasympathetic, sympathetic, and visceral afferent fibers that are believed to exert significant influence on local endocrine activity and vascular function. Yet the extent to which these interactions depend on neurovascular dynamics in the normal and pathological states remain largely unknown. Herein we describe a new method for high resolution functional imaging of the rat pancreas in vivo. The method comprises a number of elements: a stability-optimized preparation in dorsal recumbency immobilizing several square centimeters of intact pancreas for upright fluorescent imaging while leaving access for concurrent manipulation of abdominal nerves, a full-frame two-photon imaging protocol and analysis pipeline supporting high-throughput (100+) monitoring of islet and acinar microvessel diameter dynamics simultaneously, and a first adaptation of random-access linescan imaging to the pancreas capable of tracking internal blood flow speeds up to 5 mm/s at 20 Hz across multiple microvessels. These methods were then deployed in concert to characterize the capacity of parasympathetic fibers to modulate pancreatic microvascular dynamics with compartment specificity. Electrical stimulation was repeatedly applied to the abdominal vagal trunks at various current magnitudes while imaging islet and acinar microvascular populations in the pancreas. Vagal stimulation consistently elicited increases in both islet and acinar capillary population motility in a current-dependent manner, with only acinar responsive vessels trending toward dilation. Further, we found vagal stimulation to profoundly and reversibly disrupt all traces of fast-wave vasomotor oscillation across a lobular arteriole-venule pair, and this was associated with a significant increase in average flow speed. Together, these findings add to mounting evidence that vagal projections exert tangible reversible influence on pancreatic microvascular activity and underscore the potential for new neuromodulation-based strategies to address diabetes, pancreatitis, or other diseases of the pancreas under autonomic nervous influence.
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