Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

Abstract

Hu P, Thinschmidt JS, Caballero S, Adamson S, Cole L, Chan-Ling T, Grant MB. Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. Am J Physiol Endocrinol Metab 308: E688 -E698, 2015. First published February 24, 2015 doi:10.1152/ajpendo.00504.2014.-Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12-and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P Ͻ 0.05) and reduced neuronal expression of IGFBP-3 (Ϫ32%, P Ͻ 0.05) and IGF-I (Ϫ15%, P Ͻ 0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P Ͻ 0.01), and IDO ϩ cell density rose by (62%, P Ͻ 0.05). CD39 expression dropped by 30% (P Ͻ 0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P Ͻ 0.05). Our results suggest that increased IDO and early loss of CD39 ϩ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.

Depressed basal hypothalamic neuronal activity in type-1 diabetic mice is correlated with proinflammatory secretion of HMBG1

“…Finally, increases in PVN neuronal excitation in response to glucose may be acutely adaptive, but chronic activation may produce detrimental effects. Our previous findings [26] and other work [15, 40] showing neuronal degeneration following long-term diabetes are consistent with this observation. Thus, it is possible that reduced basal hypothalamic activity in the present report could have resulted from the loss of neurons over time.…”

“…Though the present findings show depressed basal neuronal activity is correlated with HMBG1 translocation to the cytosol, it is quite possible that long term inflammatory conditions involving HMBG1 could also affect neuronal activity and that changes in neuronal activity could produce HMBG1 mediated inflammation [7, 19, 42]. Our previous findings [26, 27] and the present report indicate an inflammatory state in the hypothalamus of diabetic animals involving changes in HMBG1, activation of microglia, depressed hypothalamic neuronal activity, and neuronal atrophy. Future work will concentrate on the sequence in which the above occur, if these processes are causally linked to one another, and an examination comparing inflammatory markers and neuronal activity in STZ-treated, Ins2 Akita , and control mice.…”

“…We suggested that targeting central inflammation may facilitate the management of microvascular complications in diabetes as we found a shift in hematopoiesis toward generation of monocytes and a loss of sympathetic efferent connections from the brain to the bone marrow [27]. More recently, we found other evidence for hypothalamic inflammation in STZ treated mice, including a reduction in the expression of CD39 in microglia and blood vessels, and increased MMP-2 + expression in astrocytes, both of which were reversed with minocycline treatment [26]. …”

Diabetic Retinopathy: Battling the Global Epidemic

“…In diabetes, neuroinflammation of the autonomic centers results in early sympathetic hyperactivity with too much release from the bone marrow and in late stages with neurodegeneration and too little release. Strategies to regulate not only retinal inflammation but also central nervous system inflammation may represent novel approaches to treating DR. 72–74 …”

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

“…RNA and protein samples were isolated from callus tissues, and the expression levels of bone formation-related genes and proteins were evaluated by realtime RT-PCR and Western blot, respectively. In the experiment, we not only examined the classical factors of bone fracture healing such as ALP, TRAP, Col-1, OPG, and RANKL, but also the expression of osteoblastic bone formation-related genes and proteins, Runx2 and IGF-1, which have been demonstrated to be decreased in hyperglycemic and diabetic individuals [46,47].…”