Number Of Pancreatic Beta Cells Research Articles

The potentials of Robusta (Coffea Robusta L.) and Arabica (Coffea Arabica L.) coffee leaf by-product as anti-diabetic drinks

1) Background: It has been known that coffee leaf contain various bioactives and antioxidants. While diabetes can be indicated by the damage of pancreatic beta cells, numerous studies have reported that many kinds of antioxidants can recover the beta cells. As a result, coffee leaf tea has the potential to be developed as an anti-diabetic beverage. The current study used in vivo experiments to investigate the functionality of coffee leaf tea for diabetic therapy; 2) Methods: Robusta and Arabica coffee leaf were processed as oolong tea. All samples were soft-infused. Healthy and diabetic rats (induced with STZ intraperitonially at 80 mg/kg BW) were treated by injecting the softly infused coffee leaf tea 12 ml/kg BW/day for 28 days; 3) Results: Compared to the glibenclamide treatment, diabetic rats injected with Robusta coffee leaf tea were better at lowering blood sugar (p-value <0.05), as well as maintaning body weight. This is supported by the fact that the number of pancreatic beta cells in diabetic rats injected with Robusta coffee leaf tea was significantly higher than in glibenclamide treated rats (pvalue <0.05). Coffee leaf tea tend to have a lighter sensory profile than oolong tea; 4) Conclusions: It can be concluded that Robusta coffee leaf tea tends to be potentially developed as anti-diabetic drink since it can recover damaged pancreatic beta cells better than glibenclamide, thus helping to decrease blood sugar.

1224-P: Glucagon Secretion Increases with Age in People with Type 2 Diabetes

It has been shown that the decline in the number of pancreatic beta cells and the insulin-secreting capacity of individual pancreatic beta cells progressively decreases with age, and this functional decline is accelerated by the addition of hyperglycemia. While, glucagon (GCG) is elevated in diabetes, and elevated GCG not only increases blood glucose levels (GLUs), but also decreases muscle mass due to protein metabolism leading to decrease in muscle glucose uptake, making blood glucose control more difficult. However, there are no reports yet regarding to age-related changes in GCG secretion. In this study, we analyze the age-related changes in GCG secretion in people with type 2 diabetes (T2D) after insulin treatment to remove glucose toxicity. A retrospective analysis was performed on people with T2D hospitalized for a period of 5 years from December 2017 in whom a test meal load (carbohydrate 75.5-70g, protein 8.5g, fat 28.5g) was performed before and after insulin treatment, and GLUs and GCG were measured. Insulin (IRI) and/or C-peptide (CPR) were also measured. A total of 121 patients (70 males, age 64.2 ± 11.6 years) were included in the analysis. After insulin treatment, GCG secretion was almost all lower than before treatment. GCG secretion increased with age (P=0.014). Insulinogenic Index decreased with age (R=-0.286 P=0.004), and IRI/GLU and CPR/GLU at 120 minutes after the test meal load also decreased with age (R=-0.314 P=0.001, R=-0.324 P=0.001). We confirmed that there is an increase in GCG secretion with aging in people with T2D. This might be one of the reasons for the decrease in muscle mass and physical activity in elderly people with T2D. Further studies are needed to expand the number including people with normal glucose and impaired glucose tolerance. Acknowledgments:The Cookie Testing Study Group provided support. Disclosure S.Kaneko: Advisory Panel; Lilly Diabetes, Speaker's Bureau; AstraZeneca, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Lilly Diabetes, Bayer Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd. K.Motohashi: None. Y.Ueba: None. S.Tokumoto: None. Funding Cookie Testing Study Group

The Effect Of Kersen (<i>Muntingia calabura</i>) Extract On The Number Of Pancreatic Beta Cells: Experiment Study In Rat

Type 2 diabetes mellitus is a common type of diabetes which can be caused by an increase in blood sugar levels resulting in a decrease in the number of pancreatic beta cells, dysfunction or apoptosis. To increase the number of pancreatic beta cells, antioxidants are needed. The antioxidant content of kersen leaves can improve pancreatic beta cell disorders due to high blood sugar levels by reducing ROS and RNF so that oxidative stress decreases and the number of pancreatic beta cells increases. Aim of this research, to determine the effect and the most effective dose of kersen leaves ethanol extract on the number of pancreatic beta cells of white rats wistar strain induced by streptozotocin-nicotinamide (STZ-NA). This study used a true experiment post-test only with control group design with STZ-NA-induced KI-KV group and normal control KVI group. KI-KIII was given kersen leaves extract at a dose of 0.3; 0.5 ;0.7 mg/gBW. KIV positive control. KV negative control. At the end of the study, the pancreas of rats was made preparations with immunohistochemical staining and the average pancreatic beta cells from the 5 islets of Langerhans were calculated. The average number of pancreatic beta cells that were most effective from the kersen leaves treatment group was KI (dose of 0.3 mg/gBW) with an average of 39.9. There is an effect of ethanol extract of kersen leaves on increasing the number of pancreatic beta cells in white rats of wistar strain induced by STZ-NA with an effective dose of 0.3 mg/gBW.

β-(1,3)-D-glucan from <em>Pleurotus ostreatus</em> correlates with lower plasma IL-6, IL-1β, HOMA-IR, and higher pancreatic beta cell count in High-Fat and High-Fructose Diet (HFFD) rats

Introduction: The increasing consumption of high-fat and high-fructose foods contributes to the increasing prevalence of global obesity. Low-grade chronic inflammation in obesity is a significant risk factor for insulin resistance and type 2 diabetes. Therefore, this study aimed to determine the effect of β-(1,3)-D-glucan from oyster mushroom (Pleurotus ostreatus) extract on rats fed with a high-fat and high-fructose diet. Design and Methods: This experimental study was conducted on 35 male Sprague-Dawley rats aged eight weeks. The rats were divided into groups given a normal (N) diet, a high-fat and high-fructose diet (HFFD), D1 (HFFD+125 mg/kg BW β-glucan), D2 (HFFD+250 mg/kg BW β glucan), and D3 (HFFD+375 mg/kg BW β-glucan) with an intervention of 14 weeks. IL-6 and IL-1β levels were measured by the ELISA method, while HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) was calculated by the fasting insulin (ng/mL) x fasting blood glucose (mg/dL)/405 formula. Pancreatic beta-cell counts were measured by hematoxylin and eosin (H&E) staining. Results: The results showed no differences in IL-6 and IL-1β between the treatment groups. However, there were significant differences in HOMA-IR and pancreatic beta-cell counts between groups. There were negative correlations between the dose of β-glucan and IL-6, IL-1β, and HOMA-IR levels. Also, there was a positive correlation between the dose of β-glucan and the number of pancreatic beta cells. Conclusions: Administration of β-(1,3)-D-glucan from oyster mushroom (Pleurotus ostreatus) extract prevented hyperglycemia and insulin resistance, also reduced inflammation in rats fed with HFFD regardless of weight gain.

Differentiation of Alginate-Encapsulated Wharton Jelly-Derived Mesenchymal Stem Cells into Insulin Producing Cells.

Objective Insulin insufficiency due to the reduced pancreatic beta cell number is the hallmark of diabetes, resulting in an intense focus on the development of beta-cell replacement options. One approach to overcome the problem is to search for alternative sources to induce insulin-producing cells (IPCs), the advent of mesenchymal stem cells (MSCs) holds great promise for producing ample IPCs. Encapsulate the MSCs with alginate improved anti-inflammatory effects of MSC treatment. This study aimed to evaluate the differentiation of wharton jelly-derived MScs into insulin producing cells using alginate encapsulation. Materials and Methods In this experimental study, we established an efficient IPCs differentiation strategy of human MSCs derived from the umbilical cord’s Wharton jelly with lentiviral transduction of Pancreas/duodenum homeobox protein 1 (PDX1) in a 21-day period using alginate encapsulation by poly-L-lysine (PLL) and poly-L-ornithine (PLO) outer layer. During differentiation, the expression level of PDX1 and secretion of insulin proteins were increased. Results Results showed that during time, the cell viability remained high at 87% at day 7. After 21 days, the differentiated beta-like cells in microcapsules were morphologically similar to primary beta cells. Evaluation of the expression of PDX1 and INS by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on days 7, 14 and 21 of differentiation exhibited the highest expression on day 14. At the protein level, the expression of these two pancreatic markers was observed after PDX1 transduction. Results showed that the intracellular and extracellular insulin levels in the cells receiving PDX1 is higher than the control group. The current data showed that encapsulation with alginate by PLL and PLO outer layer permitted to increase the microcapsules’ beta cell differentiation. ConclusionEncapsulate the transduced-MSCs with alginate can be applied in an in vivo model in order to do the further analysis.

The physiological and pharmacological effects of Ziziphoratenuior L.: A review study.

Objective:Many reports have revealed preventive and therapeutic effects of Ziziphoratenuior; however, few systematic reviews have evaluated such effects. The present study reviews the physiological and pharmacological effects of Z. tenuior extract and its components.Materials and Methods:English articles were searched in international databases, such as Embase, Scopus, and PubMed; Persian studies were also searched in national databases such as SID and Magiran. Results:Pulegone is one of the most important effective compounds of Z. tenuior, which has analgesic, anti-inflammatory, and anti-stress properties as it affects serotonergic and opioidergic systems and decreases the gastric acid secretion. Moreover, this compound inhibits cholesterol absorption and synthesis, resulting in hyperlipidemic effects and weight loss. In addition to its antioxidant, antitumor, and antibacterial properties, this herb contains an antidiabetic effect mediated by increasing the number of pancreatic beta cells and insulin secretion, and inhibiting alpha-amylase. Although its effective dosage has no side effects, the overuse of its effective compounds, such as pulegone, may raise some liver and pulmonary disorders.Conclusion: Z. tenuior and its extract can have preventive and therapeutic effects on diabetes and hyperlipidemia-associated diseases. Since most studies on this herb were in vivo, it is necessary to design clinical trials to evaluate its effects.

Intravenous Wharton's Jelly stem cell increased the number of ? cells pancreas and reduced the fasting blood glucose level in diabetes mellitus Wistar rat male (Rattus norvegicus)

Introduction: Diabetes mellitus is a metabolic disease characterized by hyperglycemic and disorders of carbohydrate, protein and fat metabolism due to abnormalities in insulin secretion, insulin sensitivity or both. Based on previous research, Wharton's Jelly's mesenchymal stem cells have anti-inflammatory, immunoregulatory properties that can improve metabolic control and have the ability to differentiate into pancreatic lineage cells that function as insulin-producing cells in vitro culture. The purpose of this study was to prove that administration of mesenchymal stem cells Wharton's Jelly can increase the number of pancreatic beta cells and reduce fasting blood glucose levels in male rats (Rattus norvegicus) Wistar strain of diabetes mellitus.Methods: The research design used was pure experimental with post-test only control group design using 36 white male rats. All samples were induced with Streptozotocin and Nicotinamide. The selected samples were divided into two groups: the control group given glibenclamide + 0.9% NaCl, and the treatment group was given glibenclamide + mesenchymal stem cells from Wharton's Jelly. Calculation of the number of pancreatic beta cells and measurement of blood glucose levels were carried out after 14 days of treatment.Result: The results showed that the treatment group had a higher number of pancreatic beta cells than the control group (105.17 ± 16.379 cells/field of view vs. 54.00 ± 11.366 cells/field of view) (p <0.001). In addition, the treatment group had lower fasting blood glucose levels than the control group (109.06 ± 16.71 mg/dl vs 122.78 ± 10.14 mg / dl) (p <0.05).Conclusion: It was concluded that intravenous administration of Wharton's Jelly mesenchymal stem cells increased the number of pancreatic beta cells and decreased fasting blood glucose levels in male rats (Rattus norvegicus) Wistar strain of diabetes mellitus.

The Effect of Verapamil on TXNIP Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin.

IntroductionType 2 diabetes mellitus (T2DM) is the most common type of diabetes. A decrease in the number of pancreatic beta cells is a pathological sign of diabetes, and to date there is no drug treatment that targets damage to these cells. Pancreatic beta cells have a weak antioxidant system and are highly sensitive to oxidative stress reactions that occur within cells. Thioredoxin interacting protein (TXNIP) inhibits thioredoxin, which is part of the intracellular antioxidant system, thereby accelerating oxidative stress and apoptosis of pancreatic beta cells. Verapamil is a non-dihydropyridine calcium channel blocker. The efficacy of this drug to improve beta cell survival and glucose homeostasis by inhibiting TXNIP expression has been demonstrated in in vitro studies. Although several retrospective studies have shown a lower incidence of T2DM with verapamil treatment, no prospective intervention studies have determined the efficacy of this drug in patients with T2DM.MethodsThe aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of oral verapamil administration in T2DM patients. In this 90-day study, the effects of verapamil on fasting blood sugar (FBS), hemoglobin A1C (HbA1c), and the lipid profile were evaluated and compared with those of the placebo.ResultsThere was a significant decrease in HbA1c (about 0.5%) in the verapamil group at the end of the intervention period. The effects of verapamil on TXNIP gene expression and glucagon-like peptide-1 receptor (GLP1R) mRNA were compared with those of the placebo (at baseline, after 15 and 30 days, and at the end of the study). During the first month of the study, decreased TXNIP gene expression and increased GLP1R mRNA were associated with the administration of verapamil when compared with the placebo, although the differences were not significant.ConclusionVerapamil can lead to better control of T2DM by reducing TXNIP gene expression and increasing beta cell survival and, possibly, by other mechanisms.Clinical Trial RegistrationIRCT registration no.: IRCT20180417039339N1 (https://www.IRCT.ir).

Hypoglycemic Effect of a Combined Andrographis paniculata and Caesalpinia sappan Extract in Streptozocin-Induced Diabetic Rats.

Introduction Researchers usually use herbal combinations to explore and develop traditional medicine to obtain additional benefits in the treatment of diseases, including diabetes. This study aims to evaluate the hypoglycemic effect of the combination of Andrographis paniculata (Burm. f.) Wall ex Nees and Caesalpinia sappan Linn extract (APCSE) on diabetes-induced rats. There has not been sufficient research on this combination; however, single extract studies of these plants have been widely conducted. Materials and Methods Male Sprague Dawley rats (160–200 g) were induced by injecting a low dose of streptozotocin (35 mg/kg BW) twice and fed with a high-fat diet containing 25% fat, whereas control animals received only standard feed. Rats were treated with APCSE at doses of 100 mg and 200 mg/kg BW for seven days and compared to the APE and CSE groups treated with the extract at 100 mg, respectively. For the control group, rats were treated with metformin with a dose of 250 mg/kg. The antihyperglycemic and antihyperlipidemic effects were determined by measuring blood glucose levels and lipid profiles (cholesterol, triglycerides, HDL, and LDL). To assess the impact of the extract on pancreatic and adipose tissue, the number of pancreatic beta cells and adipocytes was evaluated through histopathological and immunohistochemical study. Results and Discussion. In a nonfasting state, the blood glucose change in APCSE 200 mg was 18.65% and was significantly lower from the DM group. However, a single extract of APE and CSE showed lower fasting blood glucose levels compared to the combined extract. Lipid profiles show no significant differences in cholesterol levels between groups; however, all treatment groups, including metformin, showed higher triglyceride levels. The APE-treated group showed significantly lower HDL and LDL, whereas CSE only showed lower LDL. The β-cell number was significantly higher after treatment with single extract CSE. The CSE and the combined extract groups showed hyperplasia adipocytes. Conclusion The combined extract of APCSE has a moderate antihyperglycemic effect; however, a single extract may have better potential than the combined extract.

PENGARUH EKSTRAK RUMPUT LAUT (EUCHEMA SP.) TERHADAP HISTOLOGI SEL Β PANKREAS PADA RATTUS NOVERGICUS GALUR WISTAR DENGAN DIABETES MELLITUS YANG DI INJEKSI ALOKSAN

Metabolic diseases such as diabetes mellitus tends to increase, diabetes is not well controlled can cause oxidative stress. Oksidatf stress can increase ROS and antioxidants in our bodies may decrease, resulting in cell damage one pancreatic β cells. To overcome the effects of free radicals on penderit DM and the possibility of complications that need an exogenous antioxidants include seaweed. The purpose of this study was to determine the effect of seaweed extract (Euchema SP.) Against pancreatic β cell histology in wistar rats with alloxan-induced hyperglycemia.
 This research type experimental dalah Post Test Only Control Group Design conducted on 25 male rats aged 2-3 months ISTAR. Rats were divided into five kelompokyaitu 1 negative control group (KN) were given a standard diet, the first group of positive control (KP) induced alloxan in Intra Peritoneal 150 mg / kg, 3 Kelompom induced alloxan and given a seaweed extract (PI): 174mg / 200gr BB rats (P2): 352, 8 mg / 200 g BB rat, (P3): 529.2 mg / 200 g BB rats. The treatment was done for 48 days. Data were statistically processed using ANOVA test formula with a 95% confidence level.
 Results showed The average number of pancreatic β cells in the negative control (45.8 ± 8.871), the group of the positive controls (110 ± 1581) on the treatment kelompk occurred increasing the number of pancreatic beta cells, PI (176.6 ± 2.074), P2 (17.25 ± 2.02) P3 (30.6 ± 40.99). Annova test showed significant difference with P Value 0.0005 Alpha P ≤ 0.05. It is concluded that the extract of seaweed (Euchema SP.) On histological cell β pancreas in rats Wistar hyperglycemia induced by alloxan, the results of this study can be applied in humans, especially people with diabetes because it has been tested, it extracts umput sea can repair cells pancreatic β on the state of hyperglycemia.

Pengaruh Suplementasi Besi (Fe) Dosis Tinggi Terhadap Kondisi Sel Beta Pankreas pada Tikus Putih (Rattus Norvegicus) Strain Wistar Bunting

During pregnancy, pregnant women need various nutrients. One of the nutrients need is iron. Iron functions for the formation of hemoglobin. Excess iron can increase free radicals and trigger oxidative stress. The aim of this study was to determine the effect of high doses of iron supplementation on the condition of the beta cells pancreas of the pregnant wistar white rat (Rattus novergicus). The condition of pancreatic beta cells seen is the number of beta cells calculated using a microscope with 400x magnification. Iron supplementation was given 18 days with 3 different doses (0.54mg, 1.08mg, and 2.16mg). The number of pancreatic beta cells differed significantly between the control and treatment groups (p = 0,000), the mean number of the smallest pancreatic beta cells in the group (P3) 12,17. Iron supplementation can reduce the number of pancreatic beta cells in pregnant wistar white rat (Rattus novergicus).

Nitrate induces a type 1 diabetic profile in alligator hatchlings

Type 1 diabetes (T1D) is a chronic autoimmune disease that affects 1 in 300 children by age 18. T1D is caused by inflammation-induced loss of insulin-producing pancreatic beta cells, leading to high blood glucose and a host of downstream complications. Although multiple genes are associated with T1D risk, only 5% of genetically susceptible individuals actually develop clinical disease. Moreover, a growing number of T1D cases occur in geographic clusters and among children with low risk genotypes. These observations suggest that environmental factors contribute to T1D etiology. One potential factor, supported primarily by epidemiological studies, is the presence of nitrate and nitrite in drinking water. To test this hypothesis, female hatchling alligators were exposed to environmentally relevant concentrations of nitrate in their tank water (reference, 10mg/L, or 100mg/L NO3-N) from hatch through 5 weeks or 5 months of age. At each time point, endpoints related to T1D were investigated: plasma levels of glucose, triglycerides, testosterone, estradiol, and thyroxine; pancreas, fat body, and thyroid weights; weight gain or loss; presence of immune cells in the pancreas; and pancreatic beta cell number, assessed by antibody staining of nkx6.1 protein. Internal dosing of nitrate was confirmed by measuring plasma and urine nitrate levels and whole blood methemoglobin. Cluster analysis indicated that high nitrate exposure (most animals exposed to 100mg/L NO3-N and one alligator exposed to 10mg/L NO3-N) induced a profile of endpoints consistent with early T1D that could be detected after 5 weeks and was more strongly present after 5 months. Our study supports epidemiological data correlating elevated nitrate with T1D onset in humans, and highlights nitrate as a possible environmental contributor to the etiology of T1D, possibly through its role as a nitric oxide precursor.

THE EFFECT OF SOURSOP LEAF EXTRACT ON PANCREATIC BETA CELL COUNT AND FASTING BLOOD GLUCOSE IN MALE WISTAR RATS EXPOSED TO A HIGH-FAT DIET AND STREPTOZOTOCIN

Based on some researches known that soursop leaf extract can improve beta cell injury. The aims of this study was to analyze the effect of soursop leaf extract on fasting blood glucose (FBG) and pancreatic beta cell number in male Wistar rats wich were exposed to a high-fat diet and streptozotocin. This study design is the only randomized posttest control group design. The total sample size is 50 male Wistar rats. The independent variable: high-fat diet, STZ, and soursop leaf extract; the dependent variable: pancreatic beta cells number, and FBG3. Data tested for normality with Kolmogorov-Smirnov (a=0.05) and tested of homogeneity with Levene (a =0.05). Comparison test between groups with Kruskal-Wallis (a=0.05), followed by Mann Whitney. Correlation test with Pearson (a=0.05) between dose of the soursop leaf extract and FBG3, and between dose and the number of pancreatic beta cells. The results of this study showed that the soursop leaf extract at a dose of 100 mg/kg and 150 mg/kg have an effect on fasting blood glucose levels and panreatic beta cells number;2)There is a significant negative correlation between the orograstric lavage of soursop leaf extract with FBG3 (r=-0.647;p<0.001), the increasing doses of soursop leaf extract, further lowering fasting blood glucose levels;3)There is a significant positive correlation between the orograstric lavage of soursop leaf extract with the number of pancreatic beta cells (r=0,759;p<0,001), the increasing doses of soursop leaf extract, further increasing pancreatic beta cells number. In conclusion, increasing doses of soursop leaf extract, further lowering fasting blood glucose and increasing the number of pancreatic beta cells.

Diabetes Mellitus Influences the Pattern of Distribution of Irisin in Pancreatic Islet Cells

Irisin is a newly discovered myokine, which enhances the turnover of white adipose cells into brown fat cells. Irisin is derived from FNDC5, a membrane‐bound protein. Moreover, irisin has been shown to play an important role in energy regulation especially in muscle cells. Although, irisin has been detected in many organs including the exocrine pancreas, liver, testes and sebaceous gland, a precise localization of this polypeptide in pancreatic islet cells has not been undertaken. Immunohistochemistry was used to determine the pattern of distribution of irisin in streptozotocin‐induced (60 mg/Kg body weight) diabetes in rats. Image J® software was used to quantify the number of irisin‐immunoreactive cells in diabetic and non‐diabetic rat pancreas. Our study shows that irisin is present in a large number of pancreatic beta cells where it co‐localizes with insulin. In contrast, irisin does not co‐localize with glucagon in normal rat pancreas. However, this pattern of distribution changes after the onset of diabetes mellitus (DM). DM is characterized by increased number of glucagon immunopositive cells. The newly formed glucagon‐positive cells now contain irisin as well. The reason why irisin co‐localizes with glucagon in diabetic rat pancreas and not in non‐diabetic rats is unclear. It is possible that in diabetic rats, insulin, the natural inhibitor of glucagon has been removed paving way for glucagon expression in pancreatic beta cells devoid of insulin. The presence of irisin in insulin secreting beta cells suggests that the beneficial effect of irisin on glucose metabolism could indeed be via the endocrine pancreas.Support or Funding InformationUnited Arab Emirates University

Intraperitoneal co-administration of thymosin α-1 ameliorates streptozotocin-induced pancreatic lesions and diabetes in C57BL/6 mice

We investigated the effects of the in vivo administration of thymosin alpha-1 (Talpha-1) on streptozotocin (STZ)-induced pancreatic lesions and diabetes. Mice were randomly divided into four experimental groups: normoglycemic control, STZ-treated, STZ plus 0.1 microg/kg body weight/day Talpha-1-treated, and STZ plus 1 microg/kg/day Talpha-1-treated. Blood glucose was assayed periodically, and serum insulin was determined at the end of the experiment using the ELISA Kit. Aldehyde fuchsin staining was used for histopathological examination of the pancreas. Parameters for oxidative stress were measured with pancreatic malondialdehyde (MDA) level, glutathione (GSH) content and enzymatic activities of superoxide dismutase and catalase. Fourteen days after the initiation of Talpha-1 treatment and up to day 35 when the treatment was stopped, both of the two STZ and Talpha-1-co-treated mouse groups had significant lower levels of blood glucose than the STZ-treated but Talpha-1-untreated mice, although both remained higher than that of the normoglycemic controls. At the end of the Talpha-1 treatment, the serum insulin level for STZ-treated mice receiving 1 microg/kg/day Talpha-1 for 35 days was 2-fold (P<0.001) as much as that of the Talpha-1-untreated STZ-diabetic mice, although not completely restored to the normal level. Pancreatic aldehyde fuchsin staining showed that STZ treatment caused significant pancreatitis, islet atrophy, and a significant reduction in the number of pancreatic beta cells. These histological lesions, however, were significantly alleviated by 1 microg/kg/day Talpha-1 treatment for 35 days. Furthermore, compared with the Talpha-1- untreated STZ-diabetic mice, the pancreatic GSH level of the 1 microg/kg/day Talpha-1-treated STZ-induced mice was 1.92-fold that of the untreated STZ-induced mice (P<0.01), whereas the pancreatic MDA level was only 81.9% that of the untreated STZ-diabetic mice (P<0.05). Together these results demonstrate that co-administration of Talpha-1 leads to significant protection against STZ-induced pancreatic damage and diabetes, and part of the protection might be achieved through enhancing pancreatic antioxidative capability.

Assessment of Relationship between Fyn-related Kinase Gene Polymorphisms and Overweight/Obesity in Korean Population

The fyn-related kinase (FRK) belongs to the tyrosine kinase family of protein kinases. Recent studies have shown that Frk affects pancreatic beta cell number during embryogenesis and promotes beta cell cytotoxic signals in response to streptozotocin. To investigate the genetic association between FRK polymorphisms and the risk of obesity in Korean population, single nucleotide polymorphisms (SNPs) in the FRK gene region were selected and analyzed. The body mass index (BMI) was calculated, and biochemical data (systolic blood pressure, diastolic blood pressure, hemoglobin A1C, triglyceride, total cholesterol, high density lipoprotein, and low density lipoprotein) of blood sample from each subject were also measured. One hundred fifty five healthy control and 204 overweight/obesity subjects were recruited. Genotype frequencies of six SNPs [rs6568920 (+8391G>A), rs3756772 (+56780A>G), rs3798234 (+75687C>T), rs9384970 (+68506G>A), rs1933739 (+72978G>A), and rs9400883 (+75809A>G)] in the FRK gene were determined by Affymetrix Targeted Genotyping Chip data. According to the classification of Korean Society for the Study of Obesity, control (BMI 18 to <23) and overweight/obesity (BMI>/=23) subjects were recruited. For the analysis of genetic data, EM algorithm, SNPStats, Haploview, HapAnalyzer, SNPAnalyzer, and Helixtree programs were used. Multiple logistic regression analysis (codominant, dominant, and recessive models) was performed. Age and gender as covariates were adjusted. For biochemical data, Student's t test was used. The mean value of BMI in the control and overweigh/obesity groups was 21.1+/-1.2 (mean+/-SD) and 25.6+/-2.0, respectively. All biochemical data of the overweight/obesity group were statistically significance, compared with the control group. Among six SNPs, two linkage disequilibrium (LD) blocks were discovered. One block consisted of rs1933739 and rs9400883, and the other comprised rs3756772 and rs3798234. One SNP (rs9384970, +68506G>A) showed an association with overweight/obesity in the codominant model (p=0.03). Interestingly, the AA genotype distribution in the overweight/obesity group (n=7, 3.5%) was higher than those in the control group (n=1, 0.6%), which is not found in either Japanese or Chinese subjects. Therefore, the AA genotype of rs9384970 may be a risk factor for development of obesity in Korean population. The results suggest that FRK may be associated with overweight/obesity in Korean population.

Anti-Diabetic Activity of a Fraction from Cissus verticillata and Tyramine, its Main Bioactive Constituent, in Alloxan-Induced Diabetic Rats

Cissus verticillata (syn. C. sycioides, fam. Vitaceae) is a medicinal plant popularly used in Brazil, for the treatment of diabetes mellitus. The anti-diabetic activity of a fraction from leaves of Cissus verticilllata (MSF, methanol soluble fraction), as well as that of tyramine (TYR) were investigated, in the model of alloxan-induced diabetes, in male Wistar rats. The biochemical parameters studied were: serum glucose, triglycerides (TG), total cholesterol (TC) and very low density lipoprotein (VLDL), urea, creatinine, AST and ALT levels. Besides, glycated hemoglobin and liver glycogen concentrations were also determined. The MSF (50 and 100 mg kg−1, p.o.), tyramine (1 and 2 mg kg−1, p.o.), glibenclamide (GLI 5 mg kg−1, p.o.) and metformin (MET, 50 mg kg−1, p.o.) were administered daily, for 5 days, 48 h after the alloxan injection (40 mg kg−1, i.v.). Drugs were administered alone or associated. Alloxan-diabetic rats showed significant reductions in plasma glucose, triglycerides and total cholesterol, after the treatment with the MSF, tyramine and glibenclamide, as compared to diabetic controls. The MSF and TYR effects were not potentiated by their association with GLI. Besides, MSF or TYR did not reverse DZ-induced hyperglycemia. However, MSF and TYR effects were significantly potentiated by MET, suggesting that these drugs act by a mechanism similar to that of MET. The other biochemical parameters were unaltered. The treatment of diabetic animals with the MSF increased the number of pancreatic beta cells. TYR also decreased the concentration of glycated Hb. While a 61% decrease in glycogen concentration was observed in diabetic controls, a total and partial recoveries of alloxan effects were seen after treatment of diabetic animals with the MSF (100 mg kg−1, p.o.) and measurements carried out 2 and 24 h after amyloglicosidase addition, respectively. In conclusion, our results showed that the MSF and TYR, when administered by gavage for 5 days, may reduce glucose, TG and TC levels by a mechanism at least in part similar to that of MET. These results point to the insulin-like effects of C. verticillata, probably due to the presence of tyramine in the plant.

Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function

Prenatal stress or glucocorticoid administration has persisting "programming" effects on offspring in rodents and other model species. Multiple doses of glucocorticoids are in widespread use in obstetric practice. To examine the clinical relevance of glucocorticoid programming, we gave 50, 120, or 200 microg/kg/d of dexamethasone (dex50, dex120, or dex200) orally from mid-term to a singleton-bearing nonhuman primate, Chlorocebus aethiops (African vervet). Dexamethasone dose-dependently reduced maternal cortisol levels without effecting maternal blood pressure, glucose, electrolytes, or weight gain. Birth weight was unaffected by any dexamethasone dose, although postnatal growth was attenuated after dex120 and dex200. At 8 months of age, dex120 and dex200 offspring showed impaired glucose tolerance and hyperinsulinemia, with reduced (approximately 25%) pancreatic beta cell number at 12 months. Dex120 and dex200 offspring had increased systolic and diastolic blood pressures at 12 months. Mild stress produced an exaggerated cortisol response in dex200 offspring, implying hypothalamic-pituitary-adrenal axis programming. The data are compatible with the extrapolation of the glucocorticoid programming hypothesis to primates and indicate that repeated glucocorticoid therapy and perhaps chronic stress in humans may have long-term effects.

A role of FRK in regulation of embryonal pancreatic beta cell formation

The fyn-related-kinase (FRK) is a non-receptor tyrosine kinase expressed in various tissues, and among them, is the islets of Langerhans. The role of FRK in pancreatic beta cells has been addressed by studies of knockout or FRK transgenic mice. These experiments have shown that FRK overexpression in beta cells leads to an increased susceptibility to the beta cell toxin streptozotocin and to cytotoxic cytokines, suggesting that FRK may participate in events leading to beta cell destruction. However, these mice also exhibit an increased relative beta cell volume and increased beta cell replication following partial pancreatectomy, suggesting a positive role for FRK in the regulation of beta cell number as well. To further assess the significance of FRK for beta cell replication, we studied the beta cell area and islet cell replication in FRK null mice. We currently observed that the FRK knockout mouse showed no difference in the insulin positive cell area or in the percentage of Ki67-stained proliferating islet cells at adulthood, when compared to wild-type control. In addition, adult FRK −/− mice performed normally when subjected to an intravenous glucose tolerance test. To elucidate whether FRK affects pancreatic beta cell number during embryogenesis and shortly after birth, pancreata were collected from FRK −/− mice at these stages. Histological analysis of insulin stained pancreatic sections showed that the insulin positive cell area in FRK −/− mice was reduced at embryonal day 15 and at birth to 31 and 70% of that of wild-type mice, respectively. FRK −/− pancreas weight on day 1 neonatally was similar to that of the control, indicating that the obtained results were not due to altered pancreatic growth. Taken together, these results show that FRK affects beta cell number during embryogenesis and early in life, but is probably redundant for beta cell number and function in adult animals under normal conditions.

Regulation of Pancreatic Beta-Cell Mass

Beta-cell mass regulation represents a critical issue for understanding diabetes, a disease characterized by a near-absolute (type 1) or relative (type 2) deficiency in the number of pancreatic beta cells. The number of islet beta cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, beta-cell neogenesis stops and a small proportion of cycling beta cells can still expand the cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury. Likewise, chronically increased metabolic demands can lead to beta-cell failure to compensate. Neogenesis from progenitor cells inside or outside islets represents a more potent mechanism leading to robust expansion of the beta-cell mass, but it may require external stimuli. For therapeutic purposes, advantage could be taken from the surprising differentiation plasticity of adult pancreatic cells and possibly also from stem cells. Recent studies have demonstrated that it is feasible to regenerate and expand the beta-cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others. Treatment with these external stimuli can restore a functional beta-cell mass in diabetic animals, but further studies are required before it can be applied to humans.