The Effect of C-Peptide on Cognitive Dysfunction and Hippocampal Apoptosis in Type 1 Diabetic Rats

To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)- positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide.

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Human C-peptide Dose Dependently Prevents Early Neuropathy in the BB/Wor-rat

International Journal of Experimental Diabetes Research ◽

10.1155/edr.2001.187 ◽

2001 ◽

Vol 2 (3) ◽

pp. 187-193 ◽

Cited By ~ 42

Author(s):

W. Zhang ◽

M. Yorek ◽

C. R. Pierson ◽

Y. Murakawa ◽

A. Breidenbach ◽

...

Keyword(s):

Diabetic Neuropathy ◽

Axonal Degeneration ◽

Diabetic Rats ◽

Nerve Fibers ◽

C Peptide ◽

Conserved Sequence ◽

Structural Abnormalities ◽

Onset Of Diabetes ◽

Dose Dependent

In order to explore the neuroprotective and crossspecies activities of.C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant Cpeptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 μg of hrC-peptide/kg body weight/ day from onset of diabetes. After 2 months of hrC-peptide administration, 100 μg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neuralNa+/K+-ATPase activity in diabetic rats with 500 μg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide

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An extract from date seeds stimulates endogenous insulin secretion in streptozotocin-induced type I diabetic rats

Functional Foods in Health and Disease ◽

10.31989/ffhd.v3i11.33 ◽

2013 ◽

Vol 3 (11) ◽

pp. 441 ◽

Cited By ~ 5

Author(s):

Ahmed F. El Fouhil ◽

Aly M. Ahmed ◽

Muhammad Atteya ◽

Raeesa A. Mohamed ◽

Amr S. Moustafa ◽

...

Keyword(s):

Blood Glucose ◽

Diabetic Rats ◽

Group Iv ◽

Seed Extract ◽

Control Group ◽

Type I ◽

C Peptide ◽

Date Seed ◽

Endogenous Insulin

Background: The efficacy of an extract from date seeds has been tested successfully on the glycemic control of type I diabetes mellitus in rats. A suggestion that date seed extract could stimulate certain cells to differentiate into insulin-secreting cells has been proposed. In order to investigate such a possibility, this study was conducted to measure C-peptide levels in the serum of type 1 diabetic rats treated with date seed extract.Methods: Two hundred rats were divided into 4 groups. Group I served as the control. Group II was given daily ingestions of 10 ml of date seed extract. Groups III and IV were made diabetic by streptozotocin injection and were given daily subcutaneous injections of 3 IU/day of insulin for 8 weeks. Group IV received, in addition, daily ingestions of 10 ml of seed extract. At the end of experiment, blood samples were collected from each rat, and blood glucose and serum C-peptide levels were measured.Results: No significant differences in the means of blood glucose and serum C-peptide levels were observed between groups I (control group) and II (date seed extract-treated control group). Group IV (date seed extract-insulin-treated diabetic group) showed a statistically significant reduction in the mean blood glucose level compared to Group III (insulin-treated diabetic group). The mean serum C-peptide level was significantly higher in group IV compared to group III.Conclusion: Biochemical results suggested an increase in endogenous insulin secretion in the case of type 1 diabetic rats treated with date seed extract, which might be the cause of its hypoglycemic effect.Keywords: Date seed extract; type 1 diabetes; serum C-peptide

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SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes

10.21203/rs.3.rs-29323/v1 ◽

2020 ◽

Author(s):

Lijun Hao ◽

Jun Mi ◽

Liping Song ◽

Yinnan Guo ◽

Yanli Li ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cognitive Dysfunction ◽

Low Frequency ◽

Latency Period ◽

Diabetic Rats ◽

Blood Oxygenation ◽

Morris Water Maze Test ◽

Diabetic Rat ◽

Dependent Signal

Abstract Objective: Cognitive dysfunction often accompanies diabetes. Both hypoglycemia and hyperglycemia cause cognitive dysfunctions. However, the underlying pathophysiology remains unclear. Recent evidence show that ferroptosis primarily triggers nerve cell death, Alzheimer's disease (AD), Huntington’s disease (HD), and Parkinson's disease (PD). We purposed to investigate whether ferroptosis is a vital pathogenic pathway in diabetes-induced cognitive dysfunction. Methods and results: Type 1 diabetic rat model was created by intraperitoneal injection of streptozotocin (STZ). Significant cognitive dysfunction was observed in the diabetic rats as evidenced by increase in latency period to find a hidden platform and decreased cumulative time spent in the target quadrant in the Morris water maze test. We detected the amplitude of low-frequency fluctuation (ALFF) of the BOLD (Blood Oxygenation Level-Dependent) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Consequently, we found that the ALFF values, as well as the T2 relaxation time of the bilateral hippocampus, were reduced in Type 1 diabetic rats. We detected Fe2+ level and lipid peroxidation products (MDA and 4-HNE) in the hippocampus. Mitochondria and neuron injury in the STZ-induced diabetic rats were determined using a Transmission Electron Microscope and Nissl body staining. Iron overload and ferroptosis were detected in the hippocampus. Furthermore, mRNA microarray analysis revealed 201 dysregulated mRNAs in STZ-induced type 1 diabetes (T1D). Pathway enrichment analyses indicated that differentially expressed mRNAs associated-coding genes were associated with ferroptosis. Among ferroptosis signaling pathway genes, Slc40a1 gene (ferroportin) was downregulated.Conclusion: We show that ferroptosis is associated with diabetic cognitive dysfunction and Slc40a1 mediates ferroptosis in Type 1 diabetes.

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SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes

10.21203/rs.3.rs-29323/v2 ◽

2020 ◽

Author(s):

Lijun Hao ◽

Jun Mi ◽

Liping Song ◽

Yinnan Guo ◽

Yanli Li ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cognitive Dysfunction ◽

Low Frequency ◽

Latency Period ◽

Diabetic Rats ◽

Blood Oxygenation ◽

Morris Water Maze Test ◽

Diabetic Rat ◽

Dependent Signal

Abstract Objective: Cognitive dysfunction often accompanies diabetes. Both hypoglycemia and hyperglycemia cause cognitive dysfunctions. However, the underlying pathophysiology remains unclear. Recent evidence show that ferroptosis primarily triggers nerve cell death, Alzheimer's disease (AD), Huntington’s disease (HD), and Parkinson's disease (PD). We purposed to investigate whether ferroptosis is a vital pathogenic pathway in diabetes-induced cognitive dysfunction. Methods and results: Type 1 diabetic rat model was created by intraperitoneal injection of streptozotocin (STZ). Significant cognitive dysfunction was observed in the diabetic rats as evidenced by increase in latency period to find a hidden platform and decreased cumulative time spent in the target quadrant in the Morris water maze test. We detected the amplitude of low-frequency fluctuation (ALFF) of the BOLD (Blood Oxygenation Level-Dependent) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Consequently, we found that the ALFF values, as well as the T2 relaxation time of the bilateral hippocampus, were reduced in Type 1 diabetic rats. We detected Fe2+ level and lipid peroxidation products (MDA and 4-HNE) in the hippocampus. Mitochondria and neuron injury in the STZ-induced diabetic rats were determined using a Transmission Electron Microscope and Nissl body staining. Iron overload and ferroptosis were detected in the hippocampus. Furthermore, mRNA microarray analysis revealed 201 dysregulated mRNAs in STZ-induced type 1 diabetes (T1D). Pathway enrichment analyses indicated that differentially expressed mRNAs associated-coding genes were associated with ferroptosis. Among ferroptosis signaling pathway genes, Slc40a1 gene (ferroportin) was downregulated.Conclusion: We show that ferroptosis is associated with diabetic cognitive dysfunction and Slc40a1 mediates ferroptosis in Type 1 diabetes.

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SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes

10.21203/rs.3.rs-29323/v3 ◽

2020 ◽

Author(s):

Lijun Hao ◽

Jun Mi ◽

Liping Song ◽

Yinnan Guo ◽

Yanli Li ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cognitive Dysfunction ◽

Low Frequency ◽

Latency Period ◽

Diabetic Rats ◽

Blood Oxygenation ◽

Morris Water Maze Test ◽

Diabetic Rat ◽

Dependent Signal

Abstract Objective : Cognitive dysfunction often accompanies diabetes. Both hypoglycemia and hyperglycemia cause cognitive dysfunctions. However, the underlying pathophysiology remains unclear. Recent evidence show that ferroptosis primarily triggers nerve cell death, Alzheimer's disease (AD), Huntington’s disease (HD), and Parkinson's disease (PD). We purposed to investigate whether ferroptosis is a vital pathogenic pathway in diabetes-induced cognitive dysfunction. Methods and results : Type 1 diabetic rat model was created by intraperitoneal injection of streptozotocin (STZ). Significant cognitive dysfunction was observed in the diabetic rats as evidenced by increase in latency period to find a hidden platform and decreased cumulative time spent in the target quadrant in the Morris water maze test. We detected the amplitude of low-frequency fluctuation (ALFF) of the BOLD (Blood Oxygenation Level-Dependent) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Consequently, we found that the ALFF values, as well as the T2 relaxation time of the bilateral hippocampus, were reduced in Type 1 diabetic rats. We detected Fe 2+ level and lipid peroxidation products (MDA and 4-HNE) in the hippocampus. Mitochondria and neuron injury in the STZ-induced diabetic rats were determined using a Transmission Electron Microscope and Nissl body staining. Iron overload and ferroptosis were detected in the hippocampus. Furthermore, mRNA microarray analysis revealed 201 dysregulated mRNAs in STZ-induced type 1 diabetes (T1D). Pathway enrichment analyses indicated that differentially expressed mRNAs associated-coding genes were associated with ferroptosis. Among ferroptosis signaling pathway genes, Slc40a1 gene (ferroportin) was downregulated. Conclusion : We show that ferroptosis is associated with diabetic cognitive dysfunction and Slc40a1 mediates ferroptosis in Type 1 diabetes.

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The Effects of C-peptide on Type 1 Diabetic Polyneuropathies and Encephalopathy in the BB/Wor-rat

Experimental Diabetes Research ◽

10.1155/2008/230458 ◽

2008 ◽

Vol 2008 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Anders A. F. Sima ◽

Weixian Zhang ◽

Zhen-guo Li ◽

Hideki Kamiya

Keyword(s):

Type 1 Diabetes ◽

Cognitive Dysfunction ◽

Neurotrophic Factors ◽

Neuronal Loss ◽

Diabetic Polyneuropathy ◽

Neurological Complications ◽

Cytoskeletal Proteins ◽

C Peptide ◽

Beneficial Effects

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.

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