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Objective: To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes., Research Design and Methods: Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal., Conclusion: A single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Objective: Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals., Research Design and Methods: Thirty-five healthy volunteers (19 male and 16 female subjects age 32 +/- 2 years, BMI 26 +/- 2 kg/m(2), A1C 5.1 +/- 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 +/- 3 years, BMI 24 +/- 2 kg/m(2), A1C 7.7 +/- 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic or hypoglycemic (2.9 +/- 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study., Results: Insulin levels were similar (602 +/- 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 +/- 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 +/- 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes., Conclusions: In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

Importance of the Field: Type 2 diabetes mellitus (T2DM) is increasingly prevalent throughout the world; controlling glycemia is an important part of preventing serious complications of diabetes. Sulfonylureas have been used in the treatment of type 2 diabetes for many years., Areas Covered in This Review: This article reviews the pharmacological and clinical aspects of glimepiride, a second-generation sulfonylurea. Literature search was conducted in PubMed, and articles selected for relevance to pharmacology or clinical efficacy data from 1994 to 2009, with older references sought as indicated., What the Reader Will Gain: Pharmacology of glimepiride, data regarding clinical efficacy, key comparisons to other agents and emerging concepts related to glimepiride are discussed., Take Home Message: Therapy with glimepiride improves the relative insulin secretory deficit found in T2DM, has antihyperglycemic efficacy equal to other secretagogues with reduced potential for hypoglycemia and may have additional actions contributing to glycemic control in T2DM.

Objective: Antecedent hypoglycemia can blunt neuroendocrine and autonomic nervous system responses to next-day exercise in type 1 diabetes. The aim of this study was to determine whether antecedent increase of plasma cortisol is a mechanism responsible for this finding., Research Design and Methods: For this study, 22 type 1 diabetic subjects (11 men and 11 women, age 27 +/- 2 years, BMI 24 +/- 1 kg/m(2), A1C 7.9 +/- 0.2%) underwent four separate randomized 2-day protocols, with overnight normalization of blood glucose. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic- (9 pmol x kg(-1) x min(-1)) euglycemic clamps (5.1 mmol/l), hypoglycemic clamps (2.9 mmol/l), or euglycemic clamps with a physiologic low-dose intravenous infusion of cortisol to reproduce levels found during hypoglycemia or a high-dose infusion, which resulted in further twofold greater elevations of plasma cortisol. Day 2 consisted of 90-min euglycemic cycling exercise at 50% Vo(2max)., Results: During exercise, glucose levels were equivalently clamped at 5.1 +/- 0.1 mmol/l and insulin was allowed to fall to similar levels. Glucagon, growth hormone, epinephrine, norepinephrine, and pancreatic polypeptide responses during day 2 exercise were significantly blunted following antecedent hypoglycemia, low- and high-dose cortisol, compared with antecedent euglycemia. Endogenous glucose production and lipolysis were also significantly reduced following day 1 low- and high-dose cortisol., Conclusions: Antecedent physiologic increases in cortisol (equivalent to levels occurring during hypoglycemia) resulted in blunted neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses during subsequent exercise in subjects with type 1 diabetes. These data suggest that prior elevations of cortisol may play a role in the development of exercise-related counterregulatory failure in those with type 1 diabetes.

Objective: The physiology of counterregulatory responses during hypoglycemia in intensively treated type 2 diabetic subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower A1C <7.0% would blunt autonomic nervous system (ANS) responses to hypoglycemia, and 2) antecedent hypoglycemia will result in counterregulatory failure during subsequent hypoglycemia in patients with suboptimal and good glycemic control., Research Design and Methods: Fifteen type 2 diabetic patients (8 men/7 women) underwent 6-month combination therapy of metformin, glipizide XL, and acarbose to lower A1C to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight nondiabetic subjects participated in a single 2-day repeated hypoglycemic clamp study., Results: Six-month therapy reduced A1C from 10.2 +/- 0.5 to 6.7 +/- 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 +/- 0.1 mmol/l) and insulinemia (1,722 +/- 198 pmol/l) were similar during all clamp studies. Intensive therapy reduced (P < 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P < 0.05) of neuroendocrine, ANS, and metabolic counterregulatory responses during subsequent hypoglycemia before and after intensive therapy in type 2 diabetic patients and in nondiabetic control subjects., Conclusions: Intensive oral combination therapy and antecedent hypoglycemia both blunt physiological defenses against subsequent hypoglycemia in type 2 diabetes. Prior hypoglycemia of only 3.3 +/- 0.1 mmol/l can result in counterregulatory failure in type 2 diabetic patients with suboptimal control and can further impair physiological defenses against hypoglycemia in intensively treated type 2 diabetes.

Objective: Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes., Research Design and Methods: Eighteen type 1 diabetic patients (14 men/4 women aged 19-48 years with BMI 25 +/- 3 kg/m(2) and A1C 7.0 +/- 0.4%) participated in randomized, double-blind 2-h hyperinsulinemic (9 pmol . kg(-1) . min(-1))-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n = 8) or identical placebo (n = 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography., Results: Hypoglycemia (2.8 +/- 0.1 mmol/l) and insulinemia (646 +/- 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P < 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia., Conclusions: This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice.

Objective: Hypoglycemia commonly occurs in intensively-treated diabetic patients. Repeated hypoglycemia blunts counterregulatory responses, thereby increasing the risk for further hypoglycemic events. Currently, physiologic approaches to augment counterregulatory responses to hypoglycemia have not been established. Therefore, the specific aim of this study was to test the hypothesis that 6 weeks' administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine would amplify autonomic nervous system (ANS) and neuroendocrine counterregulatory mechanisms during hypoglycemia., Research Design and Methods: A total of 20 healthy (10 male and 10 female) subjects participated in an initial single-step hyperinsulinemic (9 pmol . kg(-1) . min(-1))-hypoglycemic (means +/- SE 2.9 +/- 0.1 mmol/l) clamp study and were then randomized to receive 6 weeks' administration of fluoxetine (n = 14) or identical placebo (n = 6) in a double-blind fashion. After 6 weeks, subjects returned for a second hypoglycemic clamp. Glucose kinetics were determined by three-tritiated glucose, and muscle sympathetic nerve activity (MSNA) was measured by microneurography., Results: Despite identical hypoglycemia (2.9 +/- 0.1 mmol/l) and insulinemia during all clamp studies, key ANS (epinephrine, norepinephrine, and MSNA but not symptoms), neuroendocrine (cortisol), and metabolic (endogenous glucose production, glycogenolysis, and lipolysis) responses were increased (P < 0.01) following fluoxetine., Conclusions: This study demonstrated that 6 weeks' administration of the SSRI fluoxetine can amplify a wide spectrum of ANS and metabolic counterregulatory responses during hypoglycemia in healthy individuals. These data further suggest that serotonergic transmission may be an important mechanism in modulating sympathetic nervous system drive during hypoglycemia in healthy individuals.

The effects of oral carbohydrate on modulating counterregulatory responses in humans remain undecided. This study's specific aim was to determine the effects of oral carbohydrate on autonomic nervous system (ANS) and neuroendocrine responses during hyperinsulinemic hypoglycemia and euglycemia. Nineteen healthy volunteers were studied during paired, single blind experiments. Nine subjects underwent two-step glucose clamps consisting of 60 min of euglycemia (5.0 mmol/l) followed by either 15 g of oral carbohydrate (cal) as orange juice or a noncaloric control (nocal) and subsequent 90 min of clamped hypoglycemia (2.9 mmol/l). Ten other subjects underwent two randomized 150-min hyperinsulinemic-euglycemic clamps with cal or nocal control administered at 60 min. Oral carbohydrate initially blunted (P < 0.05) epinephrine, norepinephrine, cortisol, glucagon, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), symptom, and systolic blood pressure responses during hypoglycemia. However, by the end of 90 min of hypoglycemia, plasma epinephrine and norepinephrine responses had rebounded and were increased (P < 0.05) compared with control. MSNA and cortisol levels remained suppressed during hypoglycemia (P < 0.05) after cal, whereas pancreatic polypeptide, glucagon, symptom, and blood pressure responses increased similar to control following initial suppression. Oral carbohydrate had no effects on neuroendocrine or ANS responses during hyperinsulinemic euglycemia. These results demonstrate that oral carbohydrate can have differential effects on the time course of ANS and neuroendocrine responses during hypoglycemia. We conclude that gastro-splanchnic-portal sensing of an amount of carbohydrate recommended for use in clinical practice for correction of hypoglycemia can have widespread and significant effects on central nervous system mediated counterregulatory responses in healthy humans.

The Diabetes Control and Complications Trial demonstrated that tight control of diabetes management greatly reduces the risk of microvascular complications of diabetes. Unfortunately, tight control of blood glucose can also result in hypoglycemia, especially in patients with type 1 diabetes mellitus (T1DM). It is now widely recognized that antecedent hypoglycemia can blunt neuroendocrine, autonomic nervous system (ANS), and metabolic counterregulatory responses to subsequent hypoglycemia. Thus, blunted counterregulatory defenses against falling plasma glucose levels are a major risk factor for hypoglycemia in people with diabetes. This risk is also complicated by a difference in responses between males and females. Because of the qualitative similarity of neuroendocrine, ANS, and metabolic responses to hypoglycemia and exercise, we developed studies to determine whether neuroendocrine and ANS counterregulatory dysfunction play a role in the pathogenesis of exercise-related hypoglycemia in T1DM. Results from these studies have shown that neuroendocrine (catecholamine and glucagon), ANS (muscle sympathetic nerve activity), and metabolic (lipolysis and glucose kinetics) responses are blunted during exercise after antecedent hypoglycemia, and that there is a sexual dimorphism in responses. Similarly, antecedent episodes of exercise can blunt counterregulatory responses during subsequent hypoglycemia, thereby creating reciprocal feed-forward vicious cycles that increase the risk of hypoglycemia during either stress.

Inhaled human insulin (Exubera ® ) has been approved by the FDA and other regulatory bodies for treatment in Type 1 and 2 diabetes in the USA. It is the first alternative to injectable insulin since the discovery of the insulin compound to treat diabetes. This article will review results of recent clinical studies that support the therapeutic efficacy and safety of inhalable insulin for use in patients with diabetes. The pharmacological profile of inhaled insulin with particular reference to inhaled human insulin and the potential to influence diabetes care is also discussed.

The purpose of this study was to assess students' knowledge and understanding of the nursing process in preparation for the NCLEX-RN examination. A descriptive correlational research design was used. Fifty-one students in both associate degree and bachelors degree programs in an urban public university, participated in the pilot study. A survey tool was developed which asked students to define and give examples of the steps in the nursing process. Short answer responses were required. Students did not consistently give correct definitions and examples. A second study was developed to determine if students performed differently on a short answer examination and a multiple choice examination. Ninety-five students in both associate degree and bachelors degree programs participated in the second study. Students did more poorly on the multiple choice examination than on the short answer survey. Students in the pilot study performed better in some areas compared to students in the follow-up study.

Some African Americans with (or at risk for) diabetes underutilize health care services. We report short-term results of a "training of trainers" workshop designed to address this problem. The training program includes culturally sensitive educational materials, including materials developed for the ADA's African American Program (AAP). Workshops were presented to a) the 1996 national meeting of the predominantly black National Missionary Baptist Convention's Nurses Guilds, b) a minority-owned, TN based managed care organization's "community outreach workers," and c) other interested community organizations. Evaluations were based on program satisfaction and an "intention to change" procedure that assessed participants' actions and the obstacles they faced 6 months later. Sixty-four group representatives from 13 states participated. They completed a satisfaction questionnaire and were asked to complete a form that asked them to check any of 12 diabetes-related actions (distributing ADA risk tests, offering AAP classes, etc.) they intended their church/community group to take within six months. Activities not listed could be added. Follow-up contact information was solicited. Satisfaction surveys were positive. 39 (61%) returned checklists with complete contact information. Intentions included: arrange for congregation/community group to take risk test (71% of respondents), distribute diabetes materials at community health fairs or church services (67%), present AAP modules (59%), promote healthy foods at pot luck suppers (56%) and arrange cooking or exercise classes (38%). Respondents were contacted by telephone 6 months post-workshop and asked whether they had fulfilled their intentions. Contact information for 6 (15%) was no longer valid, and we were unable to reach 7 others despite repeated attempts. Approximately 30% of intentions were fulfilled by nurses guild members, but less than 10% by other groups. Half of all fulfilled intentions occurred in a community served by an active ADA AAP Coalition. Barriers to fulfilling intentions included lack of time/support, group not ready to act or doing other programs, and failure to collaborate with the ADA or others for mutual assistance. Existing agencies, especially churches with nurses guilds, offer a means for promoting diabetes screening and awareness in African American communities. A training workshop was well received and influenced some participant groups' self-reported actions. Participants appear more likely to fulfill intentions to conduct diabetes-related programs when they collaborate with other churches, agencies and/or the ADA.

Identifying valid variables to predict success of nursing students on the NCLEX-RN has captivated the interest of nursing educators for decades. The determination of such variables would enable nursing programs to devise pertinent admission criteria, identify and intervene with students at risk of failing, and provide needed advisement and academic supports to increase the likelihood of passing the NCLEX-RN. This study examined six academic and non-academic variables. Study variables included: pre-admission GPA, failing a clinical nursing course, two NLN test scores, age, and race. These variables have been explored in numerous past studies to predict success on the NCLEX-RN. However, the majority of studies have examined these variables in baccalaureate of science nursing (BSN) student populations. Few studies on associate degree nursing (ADN) student populations were found. The purpose of this study was to examine six academic and non-academic variables, explored in previous studies that mostly looked at BSN students, to determine if these same variables could predict success or failure on the NCLEX-RN for students of an ADN program. Data were obtained from a convenience sample of thirty-eight, May 1997 nursing student graduates from a public urban university's ADN program. Findings from the study indicated that four of the variables had significant relationships with NCLEX-RN success.