Diabetogenic Activities Research Articles

Ferulic acid improves glucose homeostasis by modulation of key diabetogenic activities and restoration of pancreatic architecture in diabetic rats.

There are increasing concerns on the rising cases of diabetes mellitus with type 2 diabetes (T2D) being of major interest as well as the cost of its treatment. Plant phenolic compounds are natural and potent antioxidants that have been widely reported for their antidiabetic activities properties, one of which is ferulic acid. The effect of ferulic acid (FA) on major diabetogenic activities and pancreatic architecture linked to T2D was investigated in T2D rats. T2D was induced in male Sprague-Dawley rats using the fructose-streptozotocin model. Diabetic rats were treated with FA at 150 or 300 mg/kg bodyweight (bw). Normal control consisted of rats administered with food and water, while diabetic control consisted of untreated diabetic rats. Metformin was used as the standard drug. The rats were humanely sacrificed after 5weeks of treatment. Their blood, liver, and pancreas were collected for analysis. Total glycogen content and carbohydrate metabolic enzymes activities were analyzed in the liver, while the pancreas and serum from blood were analyzed for oxidative stress biomarkers, purinergic and cholinergic enzyme activities, and amylase and lipase activities. The pancreatic tissue was further subjected to microscopic and histological examinations. FA caused a significant (p < 0.05) decrease in blood glucose level, with concomitant increase in serum insulin level. Treatment with FA also led to elevated levels of GSH, HDL-c, SOD, and catalase activities, while concomitantly suppressing malondialdehyde, cholesterol, triglyceride, LDL-c, NO, ALT, AST, creatinine, urea, and uric acid levels, acetylcholinesterase, ATPase, ENTPDase, 5'-nucleotidase, lipase, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-biphosphatase activities. Histology analysis revealed an intact pancreatic morphology in FA-treated diabetic rats. While transmission electron microscopy (TEM) analysis revealed an intact pancreatic ultrastructure and increased number of insulin granules in β-cells. Taken together, these results portray that the antidiabetic potentials of ferulic acid involves modulation of major diabetogenic activities and maintenance of the pancreatic ultrastructure architecture.

Lipid Peroxidation Linking Diabetes and Cancer: The Importance of 4-Hydroxynonenal.

Significance: It is commonly believed that diabetes mellitus may be associated with cancer. Hence, diabetic patients are at higher risk for hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and breast cancer, but the mechanisms that may link these two severe diseases are not well understood. Recent Advances: A number of factors have been suggested to promote tumorigenesis in diabetic patients, including insulin resistance, hyperglycemia, dyslipidemia, inflammation, and elevated insulin-like growth factor-1 (IGF-1), which may also promote pro-oxidants, and thereby alter redox homeostasis. The consequent oxidative stress associated with lipid peroxidation appears to be a possible pathogenic link between cancer and diabetes. Critical Issues: Having summarized the above aspects of diabetes and cancer pathology, we propose that the major bioactive product of oxidative degradation of polyunsaturated fatty acids (PUFAs), the reactive aldehyde 4-hydroxynonenal (4-HNE), which is also considered a second messenger of free radicals, may be the key pathogenic factor linking diabetes and cancer. Future Directions: Because the bioactivities of 4-HNE are cell-type and concentration-dependent, are often associated with inflammation, and are involved in signaling processes that regulate antioxidant activities, proliferation, differentiation, and apoptosis, we believe that further research in this direction could reveal options for better control of diabetes and cancer. Controlling the production of 4-HNE to avoid its cytotoxicity to normal but not cancer cells while preventing its diabetogenic activities could be an important aspect of modern integrative biomedicine. Antioxid. Redox Signal. 37, 1222-1233.

A hypomorphic Ephb2 gene variant contributes to autoimmune diabetes in NOD mice associated with altered Mapk3 activities in B-lymphocytes

Abstract β-cell destruction in type 1 diabetes (T1D) is considered a T-cell mediated autoimmune disease, but based on studies in the NOD mouse model, B-lymphocytes also play a critical pathogenic role. They do so by serving as a preferential subset of pathogenic APC that expand diabetogenic T cells. Immunological tolerance induction mechanisms that normally eliminate or inactivate autoreactive B-lymphocytes are defective in NOD mice and also in T1D patients. We previously mapped a faulty NOD B-lymphocyte tolerance phenotype to a 6.22Mb region on Chromosome 4. With a combination of differential gene expression and ingenuity pathway analyses (IPA) we identified a hypomorphic Ephb2 allelic variant within this region on Chromosome 4 as a potential candidate gene interacting with human T1D susceptibility genes in a common pathway modulating Mapk3 activities. Ephrin-B1 ligand engagement of Ephb2 attenuated B-cell receptor (BCR) induced Mapk3 phosphorylation in vitro. We tested the candidacy of Ephb2 by introducing into NOD mice a transgenic higher expression variant of Ephb2 derived from the B6 strain (NOD-Ephb2B6). Elevated expression of Ephb2 afforded significant T1D protection due to changes in hematopoietic cells. Despite having enhanced proliferative capacity, B-lymphocytes from NOD-Ephb2B6 mice had diminished diabetogenic activity associated with attenuated Mek-Erk signaling. Introduction of the Ephb2 transgene into NOD BCR transgenic models expressing autoreactive peripherin (Per) specific Ig molecules also inhibited the accelerated T1D development characterizing these stocks. Thus, signaling via Ephb2 in B-lymphocytes can fine-tune BCR signaling that ultimately determine their diabetogenic activities.

Adoptive transfer of islet antigen–autoreactive T cell clones to transgenic NOD.Ea dmice induces diabetes indicating a lack of I-E mediated protection against activated effector T cells

Transgenic insertion of the MHC class II Ea dgene in NOD mice restores I-E expression and prevents T-cell-mediated autoimmune diabetes (IDDM). The specific molecular and cellular mechanisms responsible for the diabetes resistance of transgenic NOD.Ea dmice remain unclear. We adoptively transferred islet antigen-specific T cell clones into NOD and transgenic NOD.Ea dmice to evaluate the level of protection provided by I-E expression against activated effector T cells. We have found that neither neonatal or 3–5-week-old I-E-expressing NOD.Ea dmice can completely inhibit the diabetogenic activities of activated islet antigen-specific T cell clones. These data indicate that E α protein expression in NOD antigen presenting cells (APC) does not reduce islet autoantigen presentation in the context of I-A g7below the threshold required for stimulation of effector/memory diabetogenic T cells. Our results suggest that the mechanism of E α protein-mediated diabetes resistance in NOD mice may be “antigen ignorance,” in which the quantity of islet autoantigens presented in the context of I-A g7by APC is reduced below the threshold required to activate naı̈ve islet antigen-specific T cells.

22-kDa and 20-kDa hGH Isoforms Show Differential-Effects When Assayed in 3T3-F442A and 3T3-F442A/C4 Adipocytes

To know whether 22.0-kDa human growth hormone (hGH22K) and the 20.0-kDa isoform (hGH20K) show different activities, we used 3T3-F442A and 3T3-F442A/C4 cells to evaluate their adipogenic and metabolic effects. Both isoforms had similar adipogenic and insulinlike activities. Lipolytic and diabetogenic effects of hGH22K were, respectively, 12.5 and 1.7-fold higher than those found for hGH20K. The 3T3-F442A/C4 clone was not responsive to insulinlike and diabetogenic effects of hGH. The results suggest that adipogenic and lipolytic effects of hGH are mediated by mechanisms different from those involved in insulin-like and diabetogenic activities.

Effects of Recombinant Bovine Somatotropin on Nutritional Status and Liver Function of Lactating Dairy Cows

Twenty-four high producing, multiparous Holstein cows were utilized to evaluate effects of long-term administration of sustained-release rbST on blood pH, gases, buffer capacity, circulating metabolites and hormones, and on liver lipid content and functions during lactation. Treatment, commencing 98 to 112 d postpartum and continued until d 305, consisted of a subcutaneous injection of a placebo or 350mg of rbST every 14 d. Milk and 3.5% FCM were increased significantly by rbST, but milk fat and protein content, feed intake, energy balance, corrected feed efficiency for milk production, and body condition scores were unaffected. Somatotropin decreased blood pH and buffer capacity by decreasing bicarbonate without affecting blood partial pressures of oxygen or carbon dioxide. Concentration of plasma albumin was decreased and nonesterified fatty acids, glucose, insulin, rbST and insulin-like growth factor-I were increased by treatment. Total plasma proteins and cortisol, hemoglobin, and hematocrit were unaffected. Liver DM, total lipid and triacylglycerol contents, and plasma 3-hydroxybutyrate and glutamic oxalacetic transaminase were not affected by rbST, but the percentage of triacylglycerol in total lipids was increased. Results of this experiment suggest that rbST exhibited lipolytic and diabetogenic activities in lactating dairy cows in vivo and that these effects might be important for the increase in nutrient partitioning toward the mammary gland elicited by rbST.

The heterogeneity of bovine growth hormone. Extraction from the pituitary of components with different biological and immunological properties

Bovine growth hormone (somatotropin) was extracted from anterior pituitaries and fractionated into four protein peaks (A-D) by chromatography on DEAE-Sephacel. Analysis by high-pressure liquid chromatography and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis indicated that the homogeneity of the material increased from fraction A through to D. The properties of the fractions were examined in the following manner: immunological activity (radioimmunoassays for ruminant growth hormone and prolactin); growth-promoting activity (rat tibia test); lipolytic activity (release of glycerol from rat epididymal fat in the presence of dexamethasone); diabetogenic activity (rate of glucose transport in epididymal fat of hypophysectomized rats and intravenous insulin-tolerance tests in goats). None of the fractions contained immunoreactive prolactin and all were equally lipolytic. Although fraction A contained a small quantity of immunoreactive growth hormone it had no growth-promoting or diabetogenic activities. Both fractions B and C were diabetogenic and contained high concentrations of immunoreactive growth hormone, consistent with their growth-promoting activity. Although the growth-promoting activity of fraction D was higher than that of the other three fractions, it was not diabetogenic and was only weakly immunoreactive. These results for bovine growth hormone support the contention that growth hormone, as commonly extracted, is a mixture of different molecular forms and that these different metabolic properties of the hormone might be explained in terms of this heterogeneity.

DIABETOGENIC ACTION OF HUMAN GROWTH HORMONE Synthesis and Activity of C‐terminal Fragments

Three peptides corresponding to the C-terminal region of human growth hormone have been synthesized by the solid-phase method: HGH-(177--191), HGH-(178--191) and HGH-(179--191). The diabetogenic activities of these synthetic peptides are reported. The data indicate that extension of HGH-(179--191) at its NH2-terminus is required for in vivo activity. The reduced and S-carbamidomethylated form of HGH-(177--191) was also active, indicating that the disulphide bond is possibly not a prerequisite for biological activity.

Alkyl streptozotocin analogues with improved biological activities.

Alkyl 16alpha- and -beta-glycosides of a series of N3-alkyl homologues of streptozotocin were synthesized from glucosamine hydrochloride. These compounds, when tested against ascites Sarcoma 180, Ehrlich ascites carcinoma, or leukemia L1210, exhibited potent antitumor activities, and antibacterial and diabetogenic activities were eliminated. Furthermore, the acute toxicities of these compounds were lower than that of streptozotocin. The methyl, ethyl, n-propyl, and n-butyl glycosides of streptozotocin, whether alpha- or beta-anomers, all showed higher antitumor activities than streptozotocin itself. The most active compound was found to be the methyl beta-streptozotocin.

An Hyperglycemic-Glycogenolytic Response to Pituitary Growth Hormone in Man.

Summary1. A rapid 30 minute intravenous infusion of 100 mg of a sample of growth hormone derived from pork pituitary glands by the technic of Raben and Wester-meyer resulted in a prompt hyperglycemia in man, which lasted during the infusion and rapidly subsided thereafter. 2. The hyperglycemia was due to an augmented output of glucose by the liver and was not associated with any change in splanchnic blood flow, oxygen consumption, or amino and urea nitrogen or ketone balances. 3. The hyperglycemic response to the extract was not modified by boiling at pH 3.5, was decreased by boiling in 0.2 N HCl or when the hormone was made up at pH 9.5, and was destroyed by standing in 0.1 N NaOH for 18 hours. Growth and diabetogenic activities in the rat were likewise destroyed by alkali treatment and unmodified by boiling at pH 3.5. Ketogenic and adipo-kinetic activities were destroyed by acid boiling and unaffected by alkali treatment. 4. The significance of these findings is discussed in light of the evidence that g...