Polymer-Based Delivery of Peptide Drugs to Treat Diabetes: Normalizing Hyperglycemia and Preventing Diabetic Complications

Jeon, Hye‐Yoon; Lee, Ah-Jun; Ha, Kwon‐Soo

doi:10.1007/s13206-022-00057-0

Cited by 17 publications

(30 citation statements)

References 131 publications

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“…As a result, preventing both neuronal damage and microvascular abnormalities in the early stages is necessary to prevent DR. 6,9,10 Human proinsulin C-peptide is a 31-amino acid polypeptide which is released into the portal circulation by the pancreatic βcells in equimolar concentrations with insulin. 11 C-peptide has emerged as a potential candidate for treating diabetic complications in type 1 diabetes, including DR. [11][12][13][14] C-peptide showed beneficial effects on hyperglycemia-induced nerve dysfunction and cognitive failure in patients and animal models with type 1 diabetes. 11 Subcutaneous supplementation of C-peptide ameliorates hyperglycemia-induced vasculopathy by inhibiting mitochondrial dysfunction 15,16 and improves impaired wound healing by activating angiogenesis in type 1 diabetic mice.…”

Section: Introductionmentioning

confidence: 99%

Systemic C‐peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF‐induced pathological events in diabetes

et al. 2023

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Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C‐peptide has been shown to be beneficial against hyperglycemia‐induced microvascular leakage in the retina of diabetes; however, the effect of C‐peptide on diabetes‐induced retinal neurodegeneration remains unknown. Moreover, extraocular C‐peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C‐peptide supplementation using osmotic pumps or biopolymer‐conjugated C‐peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor‐induced pathological events, but not hyperglycemia‐induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C‐peptide inhibited hyperglycemia‐induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C‐peptide supplementation alleviates hyperglycemia‐induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.

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Section: Introductionmentioning

confidence: 99%

Systemic C‐peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF‐induced pathological events in diabetes

et al. 2023

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“…Diabetes mellitus (DM) is a serious metabolic disorder characterized by chronic hyperglycemia with impaired metabolism of carbohydrate, fat, and protein resulting from a defect in insulin secretion or insulin action [1,2]. Chronic hyperglycemia in diabetes is accompanied by high mortality and morbidity due to concomitant vascular complications, which are grouped into macrovascular and microvascular types [3].…”

Section: Introductionmentioning

confidence: 99%

“…Chronic hyperglycemia in diabetes is accompanied by high mortality and morbidity due to concomitant vascular complications, which are grouped into macrovascular and microvascular types [3]. Microvascular complications caused by damage to the small blood vessels include diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic peripheral neuropathy (DPN) [2,4]. DR, which affects about one-third of diabetic patients worldwide, is a leading cause of visual disability and blindness [5].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous attenuation of hyperglycemic memory-induced retinal, pulmonary, and glomerular dysfunctions by proinsulin C-peptide in diabetes

Jeon

Moon

Kim

et al. 2023

BMC Med

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Background Hyperglycemic memory (HGM) is a pivotal phenomenon in the development of diabetic complications. Although coincident diabetic complications are reported, research on their development and treatment is limited. Thus, we investigated whether C-peptide can simultaneously inhibit HGM-induced retinal, pulmonary, and glomerular dysfunctions in diabetic mice supplemented with insulin. Methods Insulin-treated diabetic mice were supplemented with human C-peptide by subcutaneous implantation of K9-C-peptide depots for 4 weeks, and reactive oxygen species (ROS) generation, transglutaminase (TGase) activity, and vascular leakage were examined in the retina, lung, and kidney. Results We found hyperglycemia-induced persistent ROS generation and TGase activation after blood glucose normalization in the retina, lung, and kidney of insulin-supplemented diabetic mice. These pathological events were inhibited by systemic supplementation of human C-peptide via subcutaneous implantation of a thermosensitive biopolymer-conjugated C-peptide depot. ROS generation and TGase activation were in a vicious cycle after glucose normalization, and C-peptide suppressed the vicious cycle and subsequent endothelial permeability in human retinal endothelial cells. Moreover, C-peptide supplementation ameliorated HGM-induced retinal vascular leakage and neurodegeneration, pulmonary vascular leakage and fibrosis, and glomerular adherens junction disruption and vascular leakage. Conclusions Overall, our findings demonstrate that C-peptide supplementation simultaneously attenuates vascular and neuronal dysfunctions in the retina, lung, and glomerulus of insulin-supplemented diabetic mice.

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“…The underlying mechanisms of HGM have been investigated to uncover the pathophysiology of diabetic microvascular and macrovascular complications 16 . Reactive oxygen species (ROS) generation is critically involved in the persistent hyperglycemic stress caused by HGM in endothelial cells and experimental animals 17–19 .…”

Section: Introductionmentioning

confidence: 99%

“…The underlying mechanisms of HGM have been investigated to uncover the pathophysiology of diabetic microvascular and macrovascular complications. 16 Reactive oxygen species (ROS) generation is critically involved in the persistent hyperglycemic stress caused by HGM in endothelial cells and experimental animals. [17][18][19] Hyperglycemia induced upregulation of the pro-oxidant enzymes protein kinase C (PKC) β and NADPH oxidase subunit p47phox that persisted after restoration of normoglycemia in the retinas of diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

Dopamine ameliorates hyperglycemic memory‐induced microvascular dysfunction in diabetic retinopathy

et al. 2022

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Dopamine is a neurotransmitter that mediates visual function in the retina and diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness; however, the role of dopamine in retinal vascular dysfunction in DR remains unclear. Here, we report a mechanism of hyperglycemic memory (HGM)-induced retinal microvascular dysfunction and the protective effect of dopamine against the HGM-induced retinal microvascular leakage and abnormalities. We found that HGM induced persistent oxidative stress, mitochondrial membrane potential collapse and fission, and adherens junction disassembly and subsequent vascular leakage after blood glucose normalization in the mouse retinas. These persistent hyperglycemic stresses were inhibited by dopamine treatment in human retinal endothelial cells and by intravitreal injection of levodopa in the retinas of HGM mice. Moreover, levodopa supplementation ameliorated HGM-induced pericyte degeneration, acellular capillary and pericyte ghost generation, and endothelial apoptosis in the mouse retinas. Our findings suggest that dopamine alleviates HGM-induced retinal microvascular leakage and abnormalities by inhibiting persistent oxidative stress and mitochondrial dysfunction.

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Polymer-Based Delivery of Peptide Drugs to Treat Diabetes: Normalizing Hyperglycemia and Preventing Diabetic Complications

Cited by 17 publications

References 131 publications

Systemic C‐peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF‐induced pathological events in diabetes

Systemic C‐peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF‐induced pathological events in diabetes

Simultaneous attenuation of hyperglycemic memory-induced retinal, pulmonary, and glomerular dysfunctions by proinsulin C-peptide in diabetes

Dopamine ameliorates hyperglycemic memory‐induced microvascular dysfunction in diabetic retinopathy

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