Theses (M.S)--Marshall University, 2007. / Title from document title page. Includes abstract. Document formatted into pages: contains vii, 96 pages. Bibliography: p.87-92.

Tierärztl. Hochsch., Diss., 2004--Hannover.

Orientador: Doris Hissako Sumida / Banca: Nancy Alfieri Nunes / Banca: Cléa Adas Saliba Garbin / Banca: Doris Hissako Sumida / Resumo: Nos últimos anos tem ocorrido uma redução acentuada nos índices de cárie dentária em diversas regiões do planeta, fato que tem se atribuído ao consumo de produtos fluoretados. Entretanto, o flúor, quando ingerido em excesso, causa intoxicação crônica ou aguda, como a fluorose dentária e distúrbios na homeostase da glicose. As crianças se tornam foco de preocupação, principalmente às portadoras de diabetes mellitus (DM), pois geralmente ingerem grandes quantidades de dentifrício fluoretado durante a escovação, ultrapassando a dose preconizada como limite de ingestão diária de flúor de 0,05 a 0,07mg/F/kg de peso corpóreo. Este trabalho, que foi dividido em duas partes, pretende realizar uma breve revisão de literatura sobre os efeitos decorrentes da ingestão de NaF no metabolismo de carboidratos e avaliar os efeitos da ingestão do fluoreto na sensibilidade à insulina e na transdução do sinal insulínico. A primeira parte, baseada em artigos científicos publicados, procura discorrer sobre os efeitos da ingestão de flúor no metabolismo de carboidratos, na tolerância à glicose e no sinal insulínico, e algumas considerações sobre o diabetes mellitus e sobre as possíveis complicações que a ingestão de NaF pode ocasionar às crianças portadoras desta doença. Estes trabalhos demonstraram que o tratamento agudo ou prolongado com altas doses de fluoreto de sódio interfere na homeostase da glicose. Convém salientar que esta alteração é similar à observada em casos de diabetes mellitus. Além do mais, o flúor quando ingerido em excesso, também ocasiona diminuição da secreção de insulina, inibição da glicólise e depleção de glicogênio. Muitas dessas respostas sugerem que o NaF pode promover resistência à insulina. Portanto, a ingestão em excesso de NaF pode prejudicar a saúde, principalmente de crianças portadora de DM. / Abstract: Over the last few years there has been a significant reduction in the incidence of dental caries in several regions of the world. This has been attributed to the consumption of fluoridated products. However, excess of fluoride intake can cause chronic or acute intoxication, such as dental fluorosis and impaired glucose homeostasis. Concern is focused on children, especially those with diabetes mellitus, because children usually swallow large amounts of fluoridated dentifrice during tooth brushing, in excess of the maximum recommended daily fluoride dose of 0.05 to 0.07 mg/F/kg of body weight. This report, divided into two parts, intends to make a brief literature review about effects of NAF intake on glucose metabolism, and to determine the effects of this intake on insulin sensitivity and insulin signal transduction. The first part, based on published scientific articles, endeavors to describe the effects of NaF intake on glucose metabolism, glucose tolerance and insulin signal, and put forward considerations concerning diabetes mellitus (DM), and the possible complications that NaF intake could cause in children with DM. These reports demonstrated that the acute or chronic treatment with high sodium fluoride dose interferes in glucose homeostasis, resulting in conditions such as hyperglycemia. This alteration is similar to that observed in DM. Furthermore, NaF ingestion in high doses can produce abnormalities in insulin secretion, glycolysis inhibition, and glycogen depletion. Many of these evidences suggest that NaF can induce insulin resistance. Thus, excessive fluoride consumption could worsen health, particularly of diabetic children. Based on that fluoride can interfere in the glucose metabolism, it is important for the second part of this report to determine the acute effect of fluoride on insulin sensitivity and pp185 (IRS-1/IRS-2) phosphorylation in insulin sensitive tissues. / Mestre

OBJECTIVES: Data on the effect of diabetes type (insulin-dependent vs. noninsulin- dependent) on short- and long-term outcomes after lower extremity revascularization for chronic limb-threatening ischemia (CLTI) are lacking. We sought to address this paucity of information by evaluating outcomes in patients with insulin-dependent and noninsulin-dependent diabetes after first-time bypass and endovascular interventions. METHODS: We reviewed all limbs undergoing a first-time infrainguinal bypass (BPG) or percutaneous transluminal angioplasty with or without stent (PTA/S) for CLTI at our institution from 2005-2014. Based on preoperative medication regimen, patients were categorized as having insulin-dependent diabetes (IDDM), noninsulin-dependent diabetes (NIDDM), or no diabetes (NDM). Outcomes included wound healing, major amputation, RAS events (revascularization, major amputation, or stenosis), major adverse limb events (MALE), and mortality. Outcomes were evaluated using Chi-square, Kaplan-Meier, and Cox regression analyses. RESULTS: Of 2,869 infrainguinal revascularizations from 2005-2014, 1,294 limbs (646 BPG, 648 PTA/S) fit our criteria and underwent a first-time revascularization for CLTI. Overall, 703 IDDM, 262 NIDDM, and 329 NDM limbs were included in our analysis. IDDM patients, compared to NIDDM and NDM, were younger (69 vs. 73 vs. 77 years; P<.001) and more often presented with tissue loss (89% vs. 77% vs. 67%; P<.001), coronary artery disease (57% vs. 48% vs. 43% P<.001), and end-stage renal disease (26% vs. 13% vs. 12%; P<.001). Perioperative complications, including mortality (3% vs. 2% vs. 5%; P=.07), did not differ between the three groups; however, complete wound healing at 6-month follow-up was significantly worse among IDDM patients (36% vs. 40% vs. 51%; P<.001). Irrespective of intervention type, IDDM patients had significantly higher three-year major amputation rates (BPG: 24% vs. 16% vs. 10%, P=.04; PTA/S: 21% vs. 6% vs. 5%, P<.001). Multivariable analyses illustrated that, compared to NDM, IDDM was associated with significantly higher risk of both major amputation and RAS events following any first-time intervention (Hazard Ratio (HR) 2.5, 95% Confidence Interval [CI] 1.2-5.2 and 1.4 [1.1-1.9], respectively). Similar associations were found for a PTA/S-first intervention (3.1 [1.1-9.0] and 1.5 [1.1-2.2], respectively), while IDDM patients undergoing a BPG-first intervention were only associated with incomplete wound healing (1.5 [1.3-2.9]). Lastly, when compared to NDM, NIDDM was associated with lower late mortality (0.6 [0.5-0.8]). CONCLUSIONS: As compared to NDM, IDDM was associated with similar perioperative and long-term mortality but a higher risk of incomplete wound healing, major amputation, and future RAS events, especially after a PTA/S-first approach. Interestingly, NIDDM was associated with lower long-term mortality and not associated with any adverse limb events. Overall, these data demonstrate both the importance in distinguishing between diabetes types, as well as potential long-term benefit of a bypass-first strategy in appropriately selected IDDM patients with CLTI. / 2018-07-11T00:00:00Z

Approximately 25.8 million people, 8.3% of the population in the United States have diabetes mellitus (DM), which makes this disease one of the biggest public health problems facing this country. Type 2 diabetes (T2DM) is a heterogeneous disease characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Currently, the insulin secretagogues known as sulfonylureas represent the major mainline drug class for long-term treatment. However, serious side effects, such as hypoglycemia and loss of potency with long-term use necessitate the development of novel insulin secretagogues. Transient receptor potential (TRP) channels have been reported to be involved in pancreatic insulin secretion. TRPA1 is a Ca2+-permeable nonselective cation channel. TRPA1 can be activated by molecules produced during oxidative glycolysis. TRPA1 may be an attractive candidate for drug development because of its involvement in the mechanism of insulin secretion. Previous studies have shown TRPA1 is expressed in rat pancreatic islets and that its activation promotes insulin release. This study was designed to determine if TRPA1 is expressed in mouse and human pancreatic β cells and whether it can promote insulin secretion. I demonstrated that TRPA1 is expressed in mouse and human pancreatic islets. I measured TRPA1-induced membrane currents using patch-clamp and used Ca2+ imaging to demonstrate that TRPA1 agonists induce Ca2+ influx in rat β cell-derived RINm5F cells. I confirmed that TRPA1 KO mice have no TRPA1 mRNA or protein in pancreatic β cells. I used isolated islet cells to demonstrate TRPA1-induced Ca2+ influx using Ca2+ imaging. By using pancreatic islets obtained from wild-type and TRPA1 KO mice, I determined that TRPA1 is important for insulin secretion. Finally, I determined that intraperitoneal administration of a TRPA1 agonist and antagonist affected blood glucose levels and plasma insulin levels in a manner consistent with the TRPA1 acting to increase insulin secretion. Furthermore, glucose tolerance was impaired in TRPA1 KO mice upon intraperitoneal glucose tolerance test (IPGTT) challenge compared to wild-type mice. In summary, I have shown TRPA1 is expressed not only in rat pancreatic islets but also in mouse and human pancreatic islets. I confirmed the localization of TRPA1 in pancreatic β cells. All of the experimental results are consistent with the concept that TRPA1 acts as to increase the insulin-secreting capacity of pancreatic β cells. According to my data, TRPA1 may play a role in promoting insulin secretion in patients with T2DM. Therefore, pharmacological activation of TRPA1 may be a novel therapeutic method for the treatment of diabetes.

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Insulin resistance is a precursor to type II diabetes mellitus and in conjunction with dyslipidaemia, hypertension, and obesity, these abnormalities constitute the metabolic syndrome. Insulin resistance usually develops before these other diseases and therefore identifying and successfully treating insulin resistant patients may have potentially great preventive value. Insulin resistance, obesity, and subsequently type II diabetes mellitus have increased dramatically and have reached epidemic proportions. The incidence of diabetes, and in particular type II diabetes mellitus, is increasing in developing countries and throughout the world and this is mainly as a result of increasingly sedentary lifestyle and obesity in an aging population. The specific aim of this study was to explore and describe the effect of a 14-week strength-based resistance training programme on insulin resistance amongst individuals aged 25 to 68 years, who are pre-diabetic, have T2DM, and/or are overweight. The research approach used in this investigation was explorative, experimental, and quantitative in nature. The quasi-experimental design consisted of a pre-test and post-test for an experimental and comparison group who were chosen through convenience and snowball sampling. A total of 30 participants were involved in this study, 15 participants in each group. The following dependent variables were selected, namely: body weight; BMI; body composition; waist-to-hip ratio; total cholesterol levels; triglyceride levels; HOMA-IR; and muscle strength for upper and lower body. Pre-and post-test analysis was performed at the Biokinetics and Sport Science Unit, located at the Nelson Mandela Metropolitan University (NMMU). Blood samples of the participants were drawn by nurses at the Health Clinic at the Nelson Mandela Metropolitan University and these blood plasma samples were stored at the Department of Microbiology and Biochemistry at NMMU for later analysis of glucose and insulin. The experimental group trained three times per week for a period of fourteen weeks, performing strength training exercises with progressive increments in the intensity of the exercise. The control group remained sedentary throughout the intervention period. Analysis of the data was conducted utilizing descriptive and inferential statistics. Analysis of variance (ANOVA) was used as a hypothesis-testing procedure to evaluate the mean differences. The following dependent variables showed a decrease in mean values: body weight, body mass index, body fat percentage, waist minimum, cholesterol and insulin. However these differences in results were not practically and statistically significant. The following dependent variables showed an increase in mean values: hip maximum, arm relaxed, arm flexed, thigh circumference, glucose and HOMA-IR. However these results were not practically and statistically significant. The mean differences in the plasma insulin level, pre- to post-test, between both groups indicated that a significant difference (t = -1.77, p = 0.044) existed between them. Cohen‟s d revealed a value of 0.64, which indicates moderate practical significance. The only dependent variable which showed both statistical and practical significance was sum of skinfolds. The findings for sum of skinfolds revealed that the mean differences, from pre- to post-test, between both groups indicated that a significant difference (t = -2.30, p = 0.015) existed between them. Cohen‟s d revealed a value of 0.84, which indicated a large practical significance. Although the sample size was too small to indicate generalisations to the diabetic population as a whole, strength training should be furthermore explored as an alternative and successful modality in the existing range of options available to the health and exercise professional to address the needs of the person with T2DM. The researcher proposed that a bigger sample size be used for the experimental and control group, the intervention period increased as well as various differences related to frequency, intensity and duration of strength training could possibly result in significant changes.

The metabolic disorder diabetes; is a global epidemic affecting people in developed countries and increasingly in developing countries. In two decades time, 350 million people will be diabetic at the current rate of prevalence. In a preliminary study, insulin resistant rats were treated with Prunus Africana (plant A) for 28 days. Plasma samples obtained from P. africana treated rats had increased insulin levels compared to normal and untreated insulin resistant rats (Karachi, 2009). The treatment of insulin resistant rats with P. africana also showed increased glucose uptake in rat adipose tissue (Karachi, 2009), suggesting that P. africana had anti-diabetic properties. The aim of the study was to investigate the mechanism of the anti-diabetic properties of P africana extract. Increased insulin secretion was confirmed by the increased Cpeptide concentration in plasma samples of rats treated with P. africana. In order to explain the high insulin levels, several hypothesis’ were investigated: (1) P. africana may increase insulin secretion in β cells, hence the effect of P. africana on insulin secretion by INS-1 cells was investigated; (2) P. africana may increase insulin secretion by prolonging the half-life of glucagon like peptide-1 (GLP-1) by decreasing dipeptidyl peptidase IV (DPP IV) activity; the effect of P. africana on DPP IV activity was determined spectrophotometrically, (3) P. africana may increase the half-life of insulin in the plasma by decreasing the activity of insulin degrading enzyme (IDE); the effect of P. africana on IDE in rat muscle and spleen samples was investigated. To explain the increased glucose uptake in adipose tissue observed in the previous study two parameters were investigated: (1) increased GLUT4 expression in P. africana treated rats; the effect of P. africana treatment on the expression of glucose transporter 4 (GLUT4) was determined using real-time polymerase chain reaction (RT-PCR), (2) P. africana may increase glucose utilization; the effect of P. africana on glucose utilization was determined in 3T3-L1 cells. The plant extract did not significantly increase insulin secretion by INS-1 cells in the absence of glucose. P. africana decreased DPP IV activity in rat plasma when compared to the untreated insulin resistant rats and this could be a mechanism by which insulin secretion is increased during plant treatment. P. africana decreased IDE activity (however not significantly) when compared to the untreated insulin resistant The effects of a Kenyan antidiabetic plant on insulin homeostasis KY Suleiman VII rats. P. africana appeared to have no effect on GLUT4 expression. The plant appeared to increase glucose utilization in 3T3-L1 cells in the absence of insulin suggesting that P. africana may have insulin like activity. In summary, this study indicates that P. africana is indirectly involved in inhibiting DDPIV. This in turn can increase the half life of GLP-1, which in turn can enhance the secretion of insulin. P. africana increases glucose utilization although there was no evidence that the GLUT 4 transporter has a higher expression in the plant treated rats. Further studies should be conducted to investigate the expression of GLUT1 under the same conditons.

The preadipocyte is crucial for healthy adipose tissue (AT) remodeling, and insulin resistance in these cells may contribute to AT dysfunction. Chronic exposure to insulin and high glucose induces insulin resistance in the 3T3-L1 mouse adipocyte cell line in vitro, however, whether this occurs in human preadipocytes is not known. To investigate this, human preadipocytes were isolated from subcutaneous AT obtained from 6 female patients undergoing elective surgery (Research Ethics Board-approved). Human preadipocytes were incubated in 5 mM glucose or 25 mM glucose in the presence or absence of 0.6 nM insulin for 48 hours, followed by acute 100 nM insulin stimulation. 25 mM glucose + 0.6 nM insulin inhibited insulin-stimulated tyrosine phosphorylation of IR-β (77%) and IRS-1 (81%) compared to NG (p<0.01), however, insulin-stimulated Ser473 Akt phosphorylation was not affected. 25 mM glucose and/or 0.6 nM insulin did not significantly change levels of pro-inflammatory adipokines. 25 mM glucose and/or 0.6 nM, prior to and/or during 14 days of adipogenic induction, did not affect levels of adipogenic markers or intracellular triglyceride accumulation.