Current recommendations are that people with Type 1 and Type 2 diabetes mellitus exercise regularly. However, in cases in which insulin or insulin secretagogues are used to manage diabetes, patients have an increased risk of developing hypoglycemia, which is amplified during and after exercise. Repeated episodes of hypoglycemia blunt autonomic nervous system, neuroendocrine and metabolic defenses (counter-regulatory responses) against subsequent episodes of falling blood glucose levels during exercise. Likewise, antecedent exercise blunts counter-regulatory responses to subsequent hypoglycemia. This can lead to a vicious cycle, by which each episode of either exercise or hypoglycemia further blunts counter-regulatory responses. Although contemporary insulin therapies cannot fully mimic physiologic changes in insulin secretion, people with diabetes have several management options to avoid hypoglycemia during and after exercise, including regularly monitoring blood glucose, reducing basal and/or bolus insulin, and consuming supplemental carbohydrates. Keywordsexercise; hypoglycemia; hypoglycemia-associated autonomic failure; insulin; insulin secretagogues; physical activity; Type 1 diabetes mellitus; Type 2 diabetes mellitus Diabetes is a chronic disease state characterized by absolute or relative insulin deficiency and is a leading cause of death and disability in the USA. In 2008, the CDC reported that approximately 23.6 million people in the USA have diabetes and, of that population, 5.7 million cases are undiagnosed [1].Approximately 5-10% of individuals with diabetes have Type 1 diabetes mellitus (T1DM), an autoimmune disorder involving pancreatic β-cell destruction and consequent abolition of insulin secretion. Comprising the bulk (90-95%) of diabetes cases [1], Type 2 diabetes mellitus (T2DM) results from a combination of environmental and genetic factors, which lead to insufficient insulin secretion and insulin resistance.Diabetes can lead to an array of microvascular and macrovascular complications. It is the main cause of kidney failure, limb amputation and new-onset blindness in American adults

Pramlintide significantly reduces hemoglobin A(1c) and body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.

Background The comparative effects of acute moderate hyperglycemia and hypoglycemia on in-vivo endothelial function together with pro-inflammatory and pro-atherothrombotic responses in healthy individuals have not been determined. Methods To investigate this question 45 healthy subjects were compared during glucose clamp studies consisting of euinsulinemic hyperglycemia and hyperinsulinemic hyperglycemia (plasma glucose 11.1 mmol/L, both with pancreatic clamps) and hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia (plasma glucose 5.1 and 2.9 mmol/L, respectively). Two D doppler ultrasound was used to determine brachial artery endothelial function. Results Insulin levels during euinsulinemia hyperglycemia were 194±23 and (850±49–988±114) pmol/L during all hyperinsulinemic protocols. Responses of VCAM-1, ICAM-1, E-Selectin, P-selectin, PAI-1, and IL-6 were increased (p<0.05-0.0001) during euinsulinemic hyperglycemia or hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia. PAI-1 was increased (p<0.04) during hypoglycemia as compared to euinsulinemic hyperglycemia, TNF-α responses were also increased during hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia (p<0.05). In vivo endothelial function was similarly blunted by acute moderate hyperglycemia or hypoglycemia. Conclusion In summary, acute moderate hypoglycemia and euinsulinemic hyperglycemia can result in similar endothelial dysfunction and pro-atherothrombotic responses. Fibrinolytic balance was reduced by a greater extent by hypoglycemia as compared to moderate hyperglycemia. Acutely, hyperinsulinemia can prevent the acute pro-atherothrombotic and pro-inflammatory effects of moderate hyperglycemia but not hypoglycemia.

We tested the hypothesis that acute administration of oral dehydroepiandrosterone (DHEA) during episodes of repeated hypoglycemia can prevent the development of hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans. Twenty-seven individuals (16 men, 11 women) participated in two separate randomized, single-blind, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hypoglycemic clamps (2.9 mmol/L) with 800 mg of DHEA or placebo administered before each clamp. Day 2 consisted of a single 2-h hypoglycemic clamp (2.9 mmol/L) following either DHEA (1,600 mg) or placebo. A 3-tritiated glucose was used to determine glucose kinetics during hypoglycemia on day 2. Antecedent hypoglycemia with placebo resulted in significant reductions of epinephrine, norepinephrine, glucagon, growth hormone, cortisol, endogenous glucose production, and lipolytic and symptom responses. During hypoglycemia on day 2, DHEA prevented blunting of all neuroendocrine, autonomic nervous system (ANS), metabolic, and symptom counterregulatory responses following hypoglycemia on day 1. In summary, DHEA can acutely preserve a wide range of key neuroendocrine, ANS, and metabolic counterregulatory homeostatic responses during repeated hypoglycemia. We conclude that DHEA may have acute effects to protect against hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans.

Objective Recent studies in type 2 diabetes have reported an association between hypoglycemia and severe cardiovascular adverse events, which are relatively increased in standard versus intensively treated individuals. The aim of this study was to determine the effects of equivalent sympathetic nervous system (SNS) activity during moderate hypoglycemia on in-vivo endothelial function, pro-inflammatory, pro-atherothrombotic, and pro-coagulant responses in healthy and standard treated type 2 diabetes individuals. Research design and methods Eleven type 2 diabetes and 16 healthy individuals participated in single 2 day studies. Day 1 involved a 2 hr hyperinsulinemic/euglycemic clamp and day 2, a 2 hr hyperinsulinemic/hypoglycemic clamp of 3.2±1 mmol/L in type 2 diabetes and (2.9±0.1 mmol/L) in healthy individuals. Results ICAM-1, VCAM-1, P-selectin, PAI-1, VEGF and endothelin-1 (ET-1) fell during hyperinsulinemic euglycemia but increased during hypoglycemia in type 2 diabetes and healthy individuals. Epinephrine and norepinephrine levels were equivalent during hypoglycemia in type 2 DM and healthy individuals. However, despite similar SNS drive but milder and hypoglycemia there were greater ICAM-1, VCAM-1, PAI-1, VEGF and ET-1 responses in the type 2 diabetes group. Endogenous and exogenous nitric oxide mediated arterial vasodilation were also impaired only during hypoglycemia in type 2 diabetes. Conclusion We conclude that, milder hypoglycemia but equivalent SNS activation results in more diffuse endothelial dysfunction and a greater pro-inflammatory, pro-atherothrombotic and pro-coagulant state in standard treated type 2 diabetes as compared to healthy individuals.