Class of 2008 Abstract / Objectives: Inhaled insulin is indicated for the treatment of type 1 and type 2 diabetes mellitus. This project was designed to evaluate the level of pharmacist knowledge concerning inhaled insulin therapy. Methods: An invitation to complete a questionnaire concerning inhaled insulin was sent via email to pharmacists registered in Arizona and preceptors for the University of Arizona College of Pharmacy. Respondents completed a 36 item questionnaire, including 25 knowledge questions. To determine overall pharmacist knowledge of inhaled insulin, the questionnaire results were aggregated into a total correct score. Independent t-tests were used to compare mean scores based on status as a preceptor, completion of a residency, attendance of an inhaled insulin training session, and pharmacist-reported level of confidence in counseling on inhaled insulin use. Results: The mean total correct score for 60 pharmacists who completed the questionnaire was 13.6 (SD = 6.7) out of 25. The mean scores for preceptor pharmacists and non-preceptor pharmacists were not statistically different. Only pharmacist-reported level of confidence in counseling patients on the use of inhaled insulin was significantly related to total score. Pharmacists who reported they were either “very confident” or “confident” in counseling patients about inhaled insulin achieved a higher total correct score compared to pharmacists reporting lower levels of confidence ( p = 0.009). Conclusions: This study identified an overall lack of knowledge regarding therapy with inhaled insulin among participating pharmacists. Pharmacists who self-reported that they were confident in providing counseling regarding inhaled insulin were significantly more knowledgeable.

In this work, rainbow trout were used as a model system to examine the regulation of insulin (INS)- and insulin receptor (IR)-encoding mRNA expression profiles. INS- and IR-encoding mRNAs were isolated, cloned, and sequenced; and shown to be differentially expressed within and among multiple tissue types. Regulation was examined through various nutritional and hormonal treatments (in vivo and in vitro). A real-time quantitative-PCR assay was developed to measure the respective levels of mRNA expression. Fasting, growth hormone (GH), and somatostatin (SS) differentially regulated INS and IR mRNAs within selected tissues, in vivo. Glucose, GH, SS, and insulin-like growth factor-1 (IGF-I) differentially regulated INS and IR mRNAs within selected tissues, in vitro. The results of this dissertation research display the identification and differential regulation of multiple INS- and IR-encoding mRNAs and suggest that independent mechanisms may serve to regulate the various isoforms in a tissue-specific manner. Future studies are also suggested.

Although feeding is important for optimal development and growth in insects, there are several points during the insect life cycle that are non-feeding: metamorphosis, pupation, and overwintering. Non-feeding periods also occur in response to internal cues, such as feedback from nutrient thresholds and immune responses being activated. Additionally, as an insect goes through different developmental stages, its nutritional requirements change in response to or in preparation for non-feeding periods. Most physiological responses like feeding are regulated through an interconnection of pathways, but how these networks change in response to different energy demands, such as immune challenges or changes in metabolism, is poorly understood. One significant pathway that is involved in regulating several physiological processes is the insulin signaling pathway. In my dissertation research, I tested hypotheses explaining the regulation of physiological processes during non-feeding periods in two agriculturally relevant insects, Manduca sexta and Megachile rotundata. First, I investigated how internal cues such as dietary lipid content and immune challenges cause non-feeding periods in M. sexta. Then, I investigated how insulin signaling regulates development during a non-feeding period like overwintering changes in M. rotundata. Since the insulin signaling (IIS) pathway is critical for development and growth, I focused on testing if this pathway plays a role in regulating non-feeding periods. My research showed that increased dietary lipid content causes a cessation of feeding, which suggests there is a possible lipid threshold that when reached, causes M. sexta to switch from lipid consumption for storage to lipid excretion. When looking at another cue like immune challenges, my results showed that during a bacterial infection, a Toll-mediated suppression of IIS pathway may be regulating feeding and causing a non-feeding period exhibited as sickness-induced anorexia. Lastly, my results also showed that the IIS pathway is suppressed in overwintering M. rotundata, and that this process can change in response to temperature. Overall, my dissertation research showed that the insulin signaling pathway and nutrient content play a vital role in regulating non-feeding periods. Investigating insulin signaling, lipid metabolism, and innate immunity in these species closes a gap in knowledge of invertebrate development.

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Cows in first (n = 163) and second (n = 101) lactation were studied to determine if reproduction, progesterone (P4), IGF-I, insulin, NEFA, and milk production differed between genetic groups. Thirty-five cows were Holstein-Jersey (HJ) crosses, 48 were Jersey-Holstein (JH) crosses, 51 were Holsteins (HH), and 29 were Jerseys (JJ). Days open (DO) was affected by genetic group. HH had 168.6 ± 9.6 DO which was different from HJ (142.9 ± 11.3 d), JJ (132.1 ± 12.1 d), and JH (127.2 ± 9.3 d). HH had 2.4 ± 0.1 services per conception which was different from JH (1.9 ± 0.1), but not different from HJ (2.1 ± 0.2) or JJ (2.1 ± 0.2). In HH P4 concentrations (1.6 ± 0.11 ng/mL) were not different from HJ (1.5 ± 0.12 ng/mL), but lower than JH (1.8 ± 0.10 ng/mL) and JJ (1.8 ± 0.13 ng/mL). NEFA concentrations were greater in lactation 2 (0.52 ± 0.02 mEq/L) than in lactation 1 (0.45 ± 0.02 mEq/L). Insulin in HH (0.83 ± 0.03 ng/mL) was not different from HJ (0.87 ± 0.04 ng/mL) or JH (0.76 ± 0.03 ng/mL), but was greater than JJ (0.66 ± 0.04 ng/mL). IGF-I gradually increased over the 10 wk period. The HH produced 10,348 ± 208 kg of milk, which was greater than the HJ (9,129 ± 230 kg), the JH (9,384 ± 192 kg), and the JJ (7,080.9 ± 261 kg). Reproductive measures, milk yield, hormones and metabolites were affected by genetic groups. / Master of Science

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Glucose and lipid metabolism are dysregulated in obese horses. Altered glucose metabolism is evidenced by the development of insulin resistance and increased fasting plasma insulin concentrations (hyperinsulinemia) while altered lipid metabolism is evidenced by increased plasma lipid concentrations. Obesity in horses also increases the risk of the painful hoof disease, laminitis. Three experiments were performed to investigate the regulation of nutrient metabolism in skeletal muscle and adipose tissue of lean, healthy horses. Adipose tissue was found to be the primary lipogenic tissue of horses, with acetate being the primary lipogenic substrate. Secondly, ten, lean horses were used to investigate the effects of acute hyperinsulinemia on nutrient metabolism. Increasing plasma insulin concentrations to >1,000 mIU/L for six hours decreased transcript abundance of glucose transporters and the insulin receptor in adipose tissue, and decreased protein abundance of the insulin receptor in skeletal muscle, potentially indicating that hyperinsulinemia potentiates insulin resistance. Insulin infusion also reduced mRNA abundance of lipid transporters in adipose tissue while increasing them in skeletal muscle. The final experiment investigated the influence of the insulin-sensitizing drug, pioglitazone, and lipopolysaccharide, on nutrient metabolism in skeletal muscle and adipose tissue, and their association with insulin sensitivity. Pioglitazone treatment did not increase insulin sensitivity; however it did increase skeletal muscle transcript abundance of the insulin receptor and the non-insulin sensitive glucose transporter and adipose tissue protein abundance of the insulin-sensitive glucose transporter (GLUT4). Lipopolysaccharide decreased insulin sensitivity regardless of pioglitazone pre-treatment, which was associated with decreased transcript abundance of GLUT4 in skeletal muscle and adipose tissue of untreated horses, but not adipose tissue of pioglitazone treated horses. / Ph. D.

The objective of the study was to investigate and characterize the effects of a continuous rate infusion of dextrose or dextrose and insulin on glucose and insulin dynamics in both healthy and endotoxin-exposed horses. Administration of a low dose of endotoxin has been used in horses to mimic the clinicopathologic changes seen in endotoxemia, including the development of an inflammatory response. Our hypothesis was that a continuous rate infusion of insulin at a rate of 0.07 IU/kg/hr would prevent the development of hyperglycemia induced by administration of dextrose in both healthy and endotoxin-exposed horses. Nine healthy adult horses were used in the study. In Phase 1 of the experiment, horses received a saline infusion or a dextrose infusion in a balanced crossover design. In Phase 2 of the experiment, horses received a dextrose and insulin infusion, both prior to and after receiving a low dose of endotoxin (no LPS group and LPS group respectively) in a balanced crossover design. Blood samples were collected at regular intervals throughout both phases for measurement of plasma glucose and insulin concentrations. Infusion of dextrose alone resulted in hyperglycemia for nearly the entire study period. Insulin concentration was also increased in comparison to the saline infusion. When comparing the dextrose treatment group to the combined dextrose and insulin treatment group (no LPS group), the insulin levels were significantly greater over time in the latter group and resulted in maintenance of euglycemia. When comparing the no LPS group to the LPS group, both the glucose and insulin concentrations were higher in the LPS group but euglycemia was still achieved. These results serve to validate the dose of insulin used in this study (0.07 IU/kg/hr) in regards to effective prevention of hyperglycemia when administered concurrently with a dextrose infusion. Hyperglycemia was prevented in both healthy and endotoxin-exposed horses. In addition, the dose of insulin used was demonstrated to be safe, as hypoglycemia did not occur in any of the horses. / Master of Science