It is well established that diabetes can lead to multiple microvascular

It is well established that diabetes can lead to multiple microvascular and macrovascular complications. prior hypoglycemia and/or exercise. Work from several laboratories has recognized multiple physiologic mechanisms involved in the pathogenesis of this hypoglycemia and exercise-associated counterregulatory failure. By continuing MK-0822 to study these mechanisms some promising approaches to amplify counterregulatory responses to hypoglycemia are being discovered. INTRODUCTION Large multicenter randomized controlled trials in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) have shown that rigorous metabolic control can reduce microvascular and to a certain extent macrovascular complications of the disease (1 2 However all have shown that with better glucose control as measured by decreasing glycosylated hemoglobin the rates of severe hypoglycemia have increased. Thus severe hypoglycemia threatens to limit the common implementation and therefore advantages of rigorous therapy in diabetic subjects. The rate of severe hypoglycemia is also related to disease duration in both T1DM and T2DM (2). People with T2DM treated for less than 2 years MK-0822 with oral medications or insulin experienced a reduced incidence of hypoglycemic events as compared to those treated with insulin and oral medications for more than 5 years. However in T1DM individuals with disease period of more than 5 years the rate of severe hypoglycemic episodes is usually increased a further twofold (2). With disease progression there is also a reduced homeostatic counterregulatory response to decreasing blood glucose levels. When blood glucose levels decrease a well-coordinated response of physiologic counterregulatory mechanisms are activated. The first is to decrease endogenous insulin secretion which occurs at MK-0822 plasma glucose levels of ～80 mg/dL. As glucose levels continue to decrease (～70 mg/dL) the powerful metabolic counterregulatory (anti-insulin) hormones glucagon epinephrine growth hormone cortisol norepinephrine aldosterone and adrenocorticotropic hormone are released. This in turn stimulates hepatic glucose production and adipose tissue lipolysis (release of glycerol and free fatty acids) and inhibits skeletal muscle mass glucose uptake thereby increasing circulating glucose. In an individual with T1DM and those with longer period T2DM there is either none or very little endogenous insulin to turn off and thus the first line of defense MK-0822 against decreasing plasma glucose levels is usually lost. The patient is usually therefore exposed to the presence of exogenous insulin that cannot be modulated and if an imbalance is created with reduced energy intake or increased exercise MK-0822 then a risk of hypoglycemia is created. With disease progression glucagon responses (an important second line of defense against decreasing plasma glucose levels) are either completely lost in T1DM or diminished in T2DM which therefore places epinephrine as the crucial defense against hypoglycemia (3). Regrettably with increasing disease period rigorous glucose control and hypoglycemic episodes even epinephrine responses become attenuated (4). Furthermore symptom consciousness to hypoglycemia also becomes attenuated. This is relevant as epinephrine can compensate for a reduced glucagon response during hypoglycemia. If glucagon and epinephrine counterregulatory mechanisms fail then the risk for severe CREBBP hypoglycemia is usually increased ～25-fold. Thus with disease progression and repeated hypoglycemia all of the body’s crucial physiologic defenses against decreasing blood glucose levels become impaired creating a vicious cycle for further hypoglycemia. EXERCISE Exercise is usually a cornerstone to managing diabetes. In individuals taking insulin or insulin secretagogue medications even moderate exercise can lead to hypoglycemia. Exercise can result in hypoglycemia during and any time up to MK-0822 24 hours after the bout. The causes for exercise-associated hypoglycemia are multifactorial and traditionally have included exercise-associated increases in insulin sensitivity and thus glucose uptake inadequately replenishing endogenous hepatic and muscle mass glycogen stores and balancing oral carbohydrate intake with exogenous insulin delivery. More recently several studies have shown that hypoglycemia can also blunt counterregulatory responses to subsequent exercise (5-7). Two 2-hour periods of antecedent hypoglycemia (50 mg/dL) blunted exercise-induced increases in glucagon catecholamine cortisol endogenous glucose production (EGP) and lipolysis during next-day exercise (90 moments at 50%VO2maximum) in both healthy.