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Antidiabetic Effects of Bisamide Derivative of Dicarboxylic Acid in Metabolic Disorders

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Antidiabetic Effects of Bisamide Derivative of Dicarboxylic Acid in Metabolic Disorders

Angelina Vladimirovna Pakhomova et al. Int J Mol Sci.

Abstract

In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes it challenging to develop effective treatment options for complications such as diabetes. In our study, experiments were performed on male C57BL/6 mice where metabolic disorders have been introduced experimentally by a combination of streptozotocin-treatment and a high-fat diet. We evaluated the biological effects of Bisamide Derivative of Dicarboxylic Acid (BDDA) and its impact on pancreatic stem cells in vivo. To assess the impact of BDDA, we applied a combination of histological and biochemical methods along with a cytometric analysis of stem cell and progenitor cell markers. We show that in mice with metabolic disorders, BDDA has a positive effect on lipid and glucose metabolism. The pancreatic restoration was associated with a decrease of the inhibitory effects of inflammation and obesity factors on pancreatic stem cells. Our data shows that BDDA increases the number of pancreatic stem cells. Thus, BDDA could be used as a new compound for treating complication of the metabolic syndrome such as diabetes.

Keywords: Bisamide Derivative of Dicarboxylic Acid; diabetes; metabolic disorders; regeneration; tissue-specific stem cells.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lipid profile measurements in the blood of male C57BL/6 mice at d70. (A) The very low-density lipoprotein level (Mmol/L); (B) high-density lipoprotein level (Mmol/L); (C) the level of triglycerides in serum (Mmol/L); (D) the atherogenic index; (E) the ratio of triglycerides to high-density lipoproteins (TG/HDL). Groups: Intact—a control group from intact mice, MD—mice with MD, MD + BDDA—mice with MD treated BDDA. *: significance of difference compared with intact (p < 0.05); ●: significance of difference compared with the MD group (p < 0.05).
Figure 2
Figure 2
Blood glucose level (A), glucose tolerance test (B), and insulin level in serum of mice at d70 (C). Groups: intact—a control group from intact mice, MD—mice with MD, MD + BDDA—mice with MD treated BDDA. Results are presented as the mean ± SEM. *: significance of difference compared with intact (p < 0.05); ●: significance of difference compared with the MD group (p < 0.05). #: significance of difference compared with the baseline (0) (p < 0.05).
Figure 3
Figure 3
Caro (A) indices and HOMA-IR (B), QUICKI (C), UE were measured at d70. The Caro index and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were estimated using the following formulas: Caro = GN/IN and HOMA−IR= (IN × IG)/22.5, where IN-insulin is fasting, IU/ml; GN—fasting glucose, Mmol/L. Groups: intact—a control group from intact mice, MD—mice with MD, MD+BDDA—mice with MD treated BDDA. *: significance of difference compared with controls (p < 0.05); ●: significance of difference compared with the MD group (p < 0.05).
Figure 4
Figure 4
The level of interleukins (1beta, 4, 5, 13, 17, 23), IL-1ra, TNF-alpha, IFN-gamma, EPO, GIP and GLP-1 in the serum of male C57BL/6 mice at d70. Groups: intact—a control group from intact mice, MD—mice with metabolic disorders (MD), MD + BDDA—mice with MD treated BDDA. Results are presented as the mean ± SEM. *: significance of difference compared with intact (p<0.05); ●: significance of difference compared with the MD group (p < 0.05).
Figure 5
Figure 5
Photomicrographs of representative pancreas sections obtained from male C57BL/6 mice at d70. Tissues were stained with haematoxylin-eosin. (A) Sections from control group; (B) Sections from mice with metabolic disorders (MD); (C) Sections from mice with MD treated with BDDA from d49-d70. Langerhans islets were examined morphologically by measuring the islet area, total islet cells and the amount of pyknotic cells. At least 10 photomicrographs of the pancreas tissue at × 400 magnification were taken for each experimental animal from all experimental groups. (D) Number of Langerhans islets, total cellularity of the Langerhans islets, percentage of pyknotic cells in Langerhans islets and the area Langerhans islets. Groups: intact—a control group from intact mice, MD—mice with metabolic disorders (MD), MD+BDDA—mice with MD treated by BDDA. Results are presented as the mean ± SEM. *: significance of difference compared with control (p < 0.05); ●: significance of difference compared with the MD group (p < 0.05).
Figure 6
Figure 6
Characterization of multipotent beta cell progenitors (CD45-TER119-c-kit-Flk-1-), oligopotent beta cell precursors (CD45-TER119-CD133+CD49flow) and PDX1+ beta cells isolated from pancreata of male C57BL/6 mice on d70 (A). Groups: intact—a control group from intact mice, MD—mice with MD, MD + BDDA mice with MD treated BDDA. Results are presented as mean ± SEM. *: significance of difference compared with control (p < 0.05); ●: significance of difference compared with the MS group (p < 0.05). Cells were analyzed by flow cytometry using antibodies against mouse CD45, TER119, CD133, CD49f, c-kit, Flk-1 and PDX1. The population of CD45 and TER119 negative cells was defined as c-kit and Flk-1 negative and positive for CD133 and CD49f at the same time in the two specimens (specimen 1 - subpopulation of cells with phenotype CD45-TER119-c-kit-Flk-1- and specimen 2 - subpopulation of cells with phenotype CD45-TER119-CD133+CD49flow). The PDX1 positive cells population was sorted from third specimen. (B) Histogram of isotype control for IgG2a (PE), (C) Phenotype and qualitative analysis of CD45 (PerCP), TER119 (APC-Cy7) expression, (D) Histogram of PDX1 PE expression.
Figure 7
Figure 7
Graphical scheme of the metabolic disorders’ protocols.
Figure 8
Figure 8
Structural formula of pharmacological compound Bisamide Derivative of Dicarboxylic Acid (BDDA), chemical formular N1,N5-bis[2-(1H-imidazole-2-Il)ethyl]glutaramide.

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