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Insulin resistance plays an intricate role in the development of cardiovascular diseases, hypertension is associated with insulin-resistant states such as diabetes and obesity. However, the underlying mechanism to explain the associations between hypertension and insulin resistance is unknown. The insulin exerts various biological effects in different type of cells. Clinical studies have reported that insulin has been shown to stimulate the protein kinase Akt via activation of PI3K in endothelial cells. Furthermore, insulin stimulated production of nitric oxide (NO) is inhibited by wortmannin in human umbilical vein endothelial cells (HUVECs). We also reported previously that NO contributes to the regulation of blood pressure in central nervous system. The aim of this study was to elucidate the potential mechanisms linking hypertension with insulin resistance and whether insulin signaling may involved in cardiovascular regulation in rat NTS neurons, we investigated the cardiovascular effects of insulin in the nucleus tractus solitarii (NTS) of urethane-anesthetized male spontaneous hypertensive rat (SHR) and normotensive Wistar-kyoto rats (WKY). Unilateral microinjection of insulin (100 IU/ml) into the NTS produced prominent depressor and bradycardic effects in 8/16 week-old WKY. However, no significant cardiovascular effects were found in adult SHR (16 week-old) after insulin injection. Furthermore, young SHR (8 week-old) with normal blood pressure showed depressor and bradycardic effects after insulin injection. Pretreatment with PI3K inhibitor LY294002 and NO synthase inhibitor L-NAME into the NTS attenuated the cardiovascular response evoked by insulin in WKY and young SHR but not in adult SHR. Furthermore, insulin induced Akt phosphorylation in-situ in WKY and SHR rats. Thus, these results indicated that insulin-PI3K-Akt-NOS sensitive mechanisms were involved in WKY and young SHR (normotensive) but not in adult SHR (hypertensive). The results also suggested the possible defective insulin signaling may resulted in the development of hypertension in adult SHR.

Thesis (Ph. D.)--School of Chemical Engineering, Georgia Institute of Technology, 2004. Directed by Athanassios Sambanis. / Includes bibliographical references (leaves 125-135).

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Nursing." Includes bibliographical references (p. 81-87).

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Nov. 30, 2009). Includes bibliographical references (p. [59]-63).

Pancreatic beta-cells secrete insulin in response to increase in blood glucose concentration with a rapid first phase and slower, sustained second phase. This secretion pattern is similar in entire pancreas, isolated islets of Langerhans and single beta-cells and it is disrupted in type 2-diabetes. Insulin stored in secretory vesicles has to undergo preparatory steps upon translocation to the plasma membrane which include docking and priming before being released by exocytosis. A better understanding of the molecules involved in these steps is required to determine the rate limiting factors for sustained secretion. Here these processes were studied in real time using total internal reflection fluorescence microscopy, which enables observation of insulin granules localized at the plasma membrane. A pool of granules morphologically docked at the plasma membrane was found to be depleted upon repeated stimulations. Recovery of the docked pool of granules took tens of minutes and became rate limiting for sustained secretion. Shorter depolarization stimuli did not deplete the docked pool and allowed rapid recovery of releasable granules. When a new granule arrived at the plasma membrane, docking was initiated by de novo formation of syntaxin/munc18 clusters at the docking site. Two-thirds of the granules which arrived at the plasma membrane failed to recruit these proteins and hence failed to dock. Priming involved recruitment of several other proteins including munc13, SNAP25 and Cav1.2 channels. Exocytosing granules were in close proximity to Ca2+ influx sites with high degree of association with Cav1.2 channels. This is because of the association of these channels to exocytosis site through syntaxin and SNAP25. During exocytosis the assembled release machinery disintegrated and the proteins at the release site dispersed. Syntaxin dispersal was initiated already during fusion pore formation rather than after release during exocytosis. This was studied using a newly developed red fluorescent probe - NPY-tdmOrange2 which was the most reliable pH sensitive red granule marker to label insulin granules. Overall these data give new insights into the molecular mechanisms involved in biphasic insulin secretion. Disturbances in the secretion at the level of granule docking and fusion may contribute to the early manifestations of type-2 diabetes.

Recent research suggests that amino acids, such as leucine and isoleucine, can improve glucose tolerance in vivo and in vitro animal models by accelerating glucose uptake in peripheral tissues and stimulate glycogen synthesis in vitro in the absence of insulin. Our laboratory recently found that gavaging normal Sprague-Dawley rats with an amino acid mixture, composed of isoleucine, leucine, cystine, methionine, and valine, improved blood glucose response during an oral glucose challenge without an increase in the plasma insulin response. The blood glucose-lowering effect of the amino acid mixture was due to an increase in skeletal muscle glucose uptake. These results suggest that this amino acid supplement acutely improves muscle insulin sensitivity and blood glucose homeostasis. However, the effect of this amino acid mixture on glucose tolerance and muscle glycogen synthesis in humans has not been investigated. Some studies have also shown that daily supplementation or acute ingestion of amino acids may prevent muscle damage that occurs as a result of a prolonged, intense endurance exercise or strength training and therefore improves force production and exercise performance. However, the effects of the addition of an amino acid mixture to carbohydrate supplement on muscle damage after a prolonged endurance exercise, as well as on the subsequent anaerobic exercise performance, have not been characterized. Therefore, in this series of two studies, the effects of an amino acid mixture, composed of isoleucine, leucine, cyctine, methionine, and valine, on glucose tolerance, muscle glycogen resynthesis, muscle damage, and anaerobic exercise performance were investigated. Study 1 demonstrated that our amino acid mixture lowered the glucose response to an OGTT in healthy overweight/obese subjects in an insulin-independent manner. Study 2 demonstrated that both high and low dosages of amino acid mixture were effective in lowering blood glucose response to a carbohydrate bolus in athletes postexercise. High dosage of amino acid mixture was more potent in glucose regulation by providing a higher insulin response and amino acid effect. However, our amino acid mixture had no effects on post exercise muscle glycogen synthesis, exercise-induced muscle damage or subsequent anaerobic performance. Taken together, the results of this research series suggest that an amino acid mixture, composed of isoleucine and 4 additional amino acids, attenuates the glucose response to a glucose bolus in an insulin-independent manner, but does not enhance muscle glycogen restoration following exercise or prevent exercise-induced muscle damage. / text

The increasing prevalence causes great burden to global health. Although there is not yet an agreement on the effect of SMBG for non-insulin-treating type 2 DM patients in comprehensive management, some guidelines recommended all diabetes patients should conduct SMBG. This literature review of 5 meta-analyses and 13 randomized controlled clinical trials assessed the effectiveness of SMBG in glucose control (HbA1c), detection of hypoglycemia, non-glycemic outcomes and potential influence factors(duration of diabetes, baseline HaB1c level, SMBG frequency, SMBG duration, co-interventions) of SMBG efficacy on type 2 diabetes patients not using insulin. The method of this literature review is through a comprehensive electronic literature search of Ovid MEDLINE, EMBASE, the Cochrane Library and China Journals Full-text Database. Both English and Chinese language literatures were reviewed. All meta-analysis and randomized controlled trials of type 2 diabetes non-insulin-using patients taking SMBG to improve the glycemic control and other outcomes were included. In these studies, absolute HbA1c reduction, recognized episodes of hypoglycemia, wellbeing, QALY, DALY, complication morbidity, mortality were used as outcome measures if available. A score list based on the PRISMA Statement was used to evaluate the quality of meta-analyses. 5 meta-analysis all reported a statistical significant but clinical modest-moderate difference in HbA1c reduction between SMBG and non-SMBG group, a new published randomized controlled trial with small cohort enrolled in none of the meta- analyses did not support this conclusion. Evidence showed frequency of SMBG did not influence the efficacy of SMBG, co-interventions as education/consultation, regimen change played a positive roll on SMBG efficacy. Whether baseline HbA1c, duration of diabetes or SMBG itself have an effect on SMBG efficacy was still unknown. There is inadequate evidence of SMBG efficacy of detection of hypoglycemia of patient-oriented outcomes. No eligible Chinese article was defined to enroll in this review. This review did not support to suggest all type 2 diabetes patients not using insulin to conduct SMBG at the frequency the guidelines recommended. Carefully designed and longer-term trials are needed to obtain evidence that is more robust. Further investigation would provide more evidence of the characteristics of potential influence factors, which may help to define the specific population or optimal mode that guarantee the greatest efficacy of SMBG. / published_or_final_version / Public Health / Master / Master of Public Health

Objective：Low vitamin D has been implicated in the development of type 2 diabetes. However, whether vitamin D continues to have a clinically significant effect in existing diabetes is unclear. The objective of this study was to examine the association of serum vitamin D with glycemic control in established type 2 diabetes. Methods: This was a retrospective analysis of medical records. Characteristics of 487 patients with type 2 diabetes were stratified by vitamin D status and serum glycosylated hemoglobin (HbA1c). Vitamin D deficiency among the subjects was studied. The relationship between vitamin D and glycemic control was explored by multiple linear regression, multivariate analysis of variance (MANOVA) and chi-square test. Patients were stratified into overweight and non-overweight group based on body mass index (BMI), and the association of serum vitamin D concentration with glycemic control was evaluated in each group. Insulin resistance and C-peptide as mediators between vitamin D and HbA1c was tested. The impact of vitamin D on cholesterol metabolism was also assessed. Results: (1) Vitamin D deficiency was highly prevalent, accounting for 88.3% of the study sample. (2) Serum vitamin D levels were significantly inversely associated with serum HbA1c. This correlation was stronger in overweight group than in non-overweight group. There was no significant relationship between serum vitamin D levels and fasting plasma glucose (FPG). HbA1c was significantly lower in vitamin D insufficiency group than in vitamin D severe deficiency group. (3) Insulin resistance partially mediated the association between vitamin D and HbA1c. (4) No significant association of Vitamin D with low density lipoprotein (LDL) or high density lipoprotein (HDL) was found in this study. Conclusions: There was an inverse association between serum vitamin D levels and HbA1c. The inverse correlation of serum vitamin D level and HbA1c was stronger in overweight group than in non-overweight group, which indicates patients with obesity might benefit more from vitamin D supplementation. / published_or_final_version / Public Health / Master / Master of Public Health

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