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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...