Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

Lau, Peter; Zhang, Y.; Kelly, Darren J.; Stapleton, David

doi:10.1007/s00125-012-2805-9

Cited by 16 publications

(11 citation statements)

References 11 publications

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“…Animals with Type 1 diabetes have increased renal glycogen [25] but decreased liver glycogen [24] whereas animals with Type 2 diabetes have increased fasting liver glycogen [26] and increased cardiac muscle glycogen [27]. In this study we report that mdx dystrophic mice have impaired glucose tolerance, increased skeletal muscle glycogen and decreased liver glycogen.…”

Section: Discussionmentioning

confidence: 57%

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

et al. 2014

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BackgroundDuchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice.ResultsDystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype.ConclusionWe identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen.

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Section: Discussionmentioning

confidence: 57%

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

et al. 2014

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“…A number of diabetic rat models have demonstrated Armanni-Ebstein lesions in the renal tubules, some were spontaneously diabetic, and others were treated with alloxan or streptozotocin (3,(5)(6)(7)(8)(23)(24)(25)(26)(27)(28)(29). Serum glucose levels reported in these rats ranged from 13.9 to approximately 40.0 mmol/L (250.2-720.0 mg/dL) (3,(5)(6)(7)(8)(23)(24)(25)(26)(27)(28)(29) with only one study reporting a glucose level of 66.7 mmol/L (1200.6 mg/dL) in one rat (5). In contrast, the highest vitreous glucose level associated with Armanni-Ebstein lesions in the current study was 77.3 mmol/L (1391.4 mg/dL), and 10 of the 27 cases (37%) with Armanni-Ebstein lesions had a vitreous glucose level of >40 mmol/L (720 mg/dL).…”

Section: Discussionmentioning

confidence: 99%

“…Although there have been numerous animal studies in diabetic rats (3,(5)(6)(7)(8), there are limited reports of Armanni-Ebstein lesions in a forensic context, and none that have investigated its correlation with terminal glucose levels. The phenomenon was originally observed in autopsy studies performed by Armanni in 1872 and appeared in Cantani's Textbook of Internal Medicine in 1875 only as an observation without correlations to glucose levels at death (9,10).…”

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confidence: 99%

Armanni–Ebstein Lesions in Terminal Hyperglycemia

Zhou

Yool

Byard

2016

Journal of Forensic Sciences

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Armanni-Ebstein lesions (AEL) occur in deaths related to uncontrolled diabetes mellitus. To investigate the relationship between AEL and terminal hyperglycemia, we retrospectively reviewed 71 cases with vitreous glucose levels ≥11.1 mmol/L; 27 (38%) cases had AEL (vitreous glucose 14.0-77.3 mmol/L); and 44 cases (62%) did not (vitreous glucose 11.1-91.9 mmol/L). There was no significant difference (p = 0.271) in vitreous glucose levels between the cases with AEL (mean 39.2, SD 16.7 mmol/L) and those without (mean 34.2, SD 19.8 mmol/L). Similarly, there was no difference in the degree of dehydration, renal failure, or osmolality. However, there was a significantly higher level of β-hydroxybutyrate among the cases with AEL compared to those without (p = 0.007), suggesting that ketoacidosis may facilitate the development of AEL. Given the possible synergistic role of β-hydroxybutyrate, the correlation between AEL and terminal hyperglycemia in animal studies may not be applicable to humans. AEL may also possibly occur with sublethal elevations in glucose.

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“…In pilot studies, one of its derivatives, 3- methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics) was shown to reduce albuminuria in a rat model of diabetic nephropathy 161 . In cell culture studies, FT011 inhibits both TGFB- and PDGF-induced collagen production 162 .…”

Section: Targeting Fibrosismentioning

confidence: 99%

The next generation of therapeutics for chronic kidney disease

Breyer

Suszták

2016

Nat Rev Drug Discov

215

183

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Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for the disease, with current treatment strategies relying on blood pressure control through blockade of the renin angiotensin system and glycemic control. Such approaches only delay end stage kidney disease development, and can be associated with significant side effects. Recent identification of several novel mechanisms contributing to CKD development - including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation – has revealed new potential therapeutic approaches for CKD. This review will assess emerging strategies and agents for CKD treatment, highlighting associated challenges in their clinical development.

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Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

Cited by 16 publications

References 11 publications

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

Armanni–Ebstein Lesions in Terminal Hyperglycemia

The next generation of therapeutics for chronic kidney disease

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