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OBJECTIVERecent 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 METHODSThirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m2, 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/m2, A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg−1 · 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.RESULTSInsulin 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.CONCLUSIONSIn 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.

IN BRIEF The threat and incidence of hypoglycemia is the major limiting factor in intensive glycemic control for both type 1 and type 2 diabetes. This article reviews the physiology of the normal counterregulatory responses to hypoglycemia and the deficient counterregulatory defenses that occur in patients with diabetes. Treatment paradigms for establishing good glycemic control while limiting hypoglycemia are also discussed.

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 Ͻ7.0% 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 Ϯ 0.5 to 6.7 Ϯ 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 Ϯ 0.1 mmol/l) and insulinemia (1,722 Ϯ 198 pmol/l) were similar during all clamp studies. Intensive therapy reduced (P Ͻ 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P Ͻ 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 Ϯ 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. Diabetes 58:701-709, 2009 L arge randomized controlled multicenter clinical trials have demonstrated the benefit of improved glycemic control on microvascular complications in both type 1 and type 2 diabetes (1,2). These compelling data have produced a paradigm shift in the treatment of diabetes (particularly type 2 diabetes) striving for A1C values Ͻ7.0% (3). The major drawbacks of tight metabolic control in patients with type 1 diabetes are well documented and include increased hypoglycemia and weight gain (4 -8).Recently, three large studies have investigated the effects of rigorous metabolic control (A1C Ͻ7.0%) on the prevalence of macrovascular disease in type 2 diabetes (9 -11). The overall conclusion of these studies was that A1C values Ͻ7.0% did not produce a statistically significant reduction in macrovascular events but did produce a marked increase in hypoglycemia in type 2 diabetes. The effects of intensive therapy on physiological counterregulatory responses during hypoglycemia in type 2 diabetes have not been thoroughly investigated. Burge et al. (12) demonstrated that improving glycemic control during an 8-day in-patient admission could lower sy...

OBJECTIVE-Hypoglycemia commonly occurs in intensivelytreated 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 ⅐ kg Ϫ1 ⅐ min Ϫ1 )-hypoglycemic (means Ϯ SE 2.9 Ϯ 0.1 mmol/l) clamp study and were then randomized to receive 6 weeks' administration of fluoxetine (n ϭ 14) or identical placebo (n ϭ 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 Ϯ 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 Ͻ 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. Diabetes 57:2453-2460, 2008 S everal reports have indicated that fluoxetine could have metabolic effects and influence carbohydrate metabolism (1-3). In fact, there have been three case studies reporting the occurrence of hypoglycemia related to the use of selective serotonin reuptake inhibitors (SSRIs) in depressed patients with and without diabetes (4 -6). However, although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (7). This could increase sympathetic outflow activity (2,8). Baudrie and Chaouloff (9) have previously reported an increased hyperglycemic response to 2-deoxy-D-glycose in conscious rats following serotononergic receptor antagonists, implying increased counterregulation in these animals.A subsequent study by Perry and Fuller (2) demonstrated that systemic injection of the SSRI fluoxetine in rats resulted in threefold increases of hypothalamic norepinephrine release, thereby providing a mechanistic basis for SSRIs to modulate sympathetic nervous system activity. A later study by Bymaster et al. (3) examined the specificity of five different SSRIs (fluoxetine, citalopram, fluvoxamine, paroxe...

OBJECTIVETo determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSTwenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 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.RESULTSGlargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-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 μmol/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.CONCLUSIONA single subcutaneous injection of glargine at a dose of ≥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-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. )-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n ϭ 8) or identical placebo (n ϭ 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography. RESEARCH DESIGN AND METHODS-EighteenRESULTS-Hypoglycemia (2.8 Ϯ 0.1 mmol/l) and insulinemia (646 Ϯ 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 Ͻ 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. Diabetes 57:3315-3322, 2008 S elective serotonin reuptake inhibitors (SSRIs) are effective drugs for the treatment of depressive disorders associated with reduced serotonergic function. Serotonergic neurons play an important role in the regulation of neuroendocrine function carried out via both sympathoadrenal and hypothalamic-pituitaryadrenal (HPA) pathways.Two studies have reported increased hypoglycemia and loss of awareness to hypoglycemia related to the use of SSRIs in depressed patients with type 1 diabetes (1,2). Although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (3,4). This would be predicted to increase sympathetic outflow activity (4 -7). Supporting this, previous studies by a number of investigators have demonstrated that SSRIs can modulate sympathetic nervous system activity and increase counterregulation in rats (8).Two recent studies in healthy humans (9) and conscious rats (10) have provided further insight into the effects of SSRIs on counterregulatory physiology during hypoglycemia. Briscoe et al. (9) investigated the effects of 6 weeks of high-dose fluoxetine administration on physiological responses to hypoglycemia in a group of healthy, nondepressed humans. Key sympathetic nervous system (epinephrine, norepinephrine,...