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Stephen N Davis

Publications and source records attributed to Stephen N Davis.

29 records · Page 2Linked to original sources
PubMed2003

Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia.

This study tested the hypothesis that estrogen is the mechanism responsible for the sexual dimorphism present in the neuroendocrine and metabolic responses to hypoglycemia. Postmenopausal women receiving (E2; n = 8) or not receiving (NO E2; n = 9) estrogen replacement were compared with age- and BMI-matched male subjects (n = 8) during a single-step 2-h hyperinsulinemic-hypoglycemic clamp. Plasma insulin (599 +/- 28 pmol/l) and glucose (2.9 +/- 0.03 mmol/l) levels were similar among all groups during the glucose clamp. In response to hypoglycemia, epinephrine (2.8 +/- 0.6 vs. 5.8 +/- 0.8 and 4.4 +/- 0.5 nmol/l), glucagon (57 +/- 8 vs. 77 +/- 8 and 126 +/- 18 ng/l), and endogenous glucose production (2 +/- 2 vs. 10 +/- 2 and 6 +/- 3 micro mol x kg(-1) x min(-1)) were significantly lower in E2 vs. both NO E2 and male subjects (P < 0.05). These reduced counterregulatory responses resulted in significantly greater glucose infusion rates (16 +/- 2 vs. 6 +/- 2 and 6 +/- 3 micro mol x kg(-1) x min(-1); P < 0.01) in E2 vs. both NO E2 and male subjects. Pancreatic polypeptide was significantly lower (P < 0.05) in both the E2 and NO E2 groups compared with the male subjects (136 +/- 20 and 136 +/- 23 vs. 194 +/- 16 pmol/l). Last, glycerol (36 +/- 3 vs. 47 +/- 5 micro mol/l; P < 0.05), lactate (1.4 +/- 0.1 vs. 1.8 +/- 0.2 mmol/l; P < 0.05), and muscle sympathetic nerve activity (19 +/- 4 to 27 +/- 4 vs. 27 +/- 5 to 42 +/- 6 bursts/min; P < 0.05) responses to hypoglycemia were all significantly lower in E2 vs. NO E2 subjects. We conclude that estrogen appears to play a major role in the sexual dimorphism present in counterregulatory responses to hypoglycemia in healthy humans.

Epinephrine↗
PubMed2003

Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes.

Exercise-related hypoglycemia is common in intensively treated patients with type 1 diabetes. The underlying mechanisms are not clearly defined. In nondiabetic subjects, hypoglycemia blunts counterregulatory responses to subsequent exercise. It is unknown whether this also occurs in type 1 diabetes. Therefore, the goal of this study was to test the hypothesis that prior hypoglycemia could result in acute counterregulatory failure during subsequent exercise in type 1 diabetes. A total of 16 type 1 diabetic patients (8 men and 8 women, HbA(1c) 7.8 +/- 0.3%) were investigated during 90 min of euglycemic cycling exercise, following either two 2-h periods of previous-day hypoglycemia (2.9 mmol/l) or previous-day euglycemia. Patients' counterregulatory responses (circulating levels of counterregulatory hormones, intermediary metabolites, substrate flux via indirect calorimetry, tracer-determined glucose kinetics, and cardiovascular measurements) were comprehensively assessed during exercise. Identical euglycemia and basal insulin levels were successfully maintained during all exercise studies, regardless of blood glucose levels during the previous day. After resting euglycemia, patients displayed normal counterregulatory responses to exercise. Conversely, when identical exercise was repeated after hypoglycemia, the glucagon response to exercise was abolished, and the epinephrine, norepinephrine, cortisol, endogenous glucose production, and lipolytic responses were reduced by 40-80%. This resulted in a threefold increase in the amount of exogenous glucose needed to maintain euglycemia during exercise. Our results demonstrate that antecedent hypoglycemia, in type 1 diabetes, can produce acute counterregulatory failure during a subsequent episode of prolonged moderate-intensity exercise. The metabolic consequence of the blunted neuroendocrine and autonomic nervous system counterregulatory responses was an acute failure of endogenous glucose production to match the increased glucose requirements during exercise. These data indicate that counterregulatory failure may be a significant in vivo mechanism responsible for exercise-associated hypoglycemia in type 1 diabetes.

Adult↗
PubMed2003

Cortisol acts through central mechanisms to blunt counterregulatory responses to hypoglycemia in conscious rats.

Physiological levels of cortisol have been found to blunt neuroendocrine and metabolic responses to subsequent hypoglycemia in humans. The aim of this study was to determine whether cortisol acts directly on the brain to elicit this effect. A total of 41 conscious unrestrained Sprague-Dawley rats were studied during 2-day experiments. Day 1 consisted of two episodes of clamped 2-h hyperinsulinemic (30 pmol. kg(-1) x min(-1)) hypoglycemia (2.8 +/- 0.1 mmol/l; n = 12; ANTE HYPO), euglycemia (6.2 +/- 0.1 mmol/l; n = 12; ANTE EUG), or euglycemia (6.2 +/- 0.1 mmol/l) plus simultaneous intracerebroventricular (ICV) infusion of cortisol (25 microg/h; n = 9; ANTE EUG+Cort) or saline (24 microl/h; n = 8; ANTE EUG+Sal). For all groups, day 2 consisted of a 2-h hyperinsulinemic (30 pmol x kg(-1) x min(-1)) hypoglycemic (2.9 +/- 0.2 mmol/l) clamp. Plasma epinephrine and glucagon incremental area under the curve (Delta AUC) responses were significantly less in ANTE EUG+Cort and ANTE HYPO versus both ANTE EUG and ANTE EUG+Sal (P < 0.05). The Delta AUC responses of plasma norepinephrine were significantly lower in ANTE EUG+Cort versus both ANTE EUG and ANTE EUG+Sal (P < 0.05). Endogenous glucose production was significantly less in ANTE HYPO and ANTE EUG+Cort versus the other groups (P < 0.05). Lastly, the glucose infusion rate to maintain the desired hypoglycemia was significantly greater in ANTE EUG+Cort and ANTE HYPO versus the other two groups (P < 0.05). In summary, ICV infusion of cortisol significantly blunted norepinephrine, epinephrine, glucagon, and endogenous glucose production responses to next-day hypoglycemia. We conclude that cortisol can act directly on the central nervous system to blunt counterregulatory responses to subsequent hypoglycemia in the conscious rat.

Animals↗
PubMed2003

Hypoglycemia in diabetes.

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

Blood Glucose↗
PubMed2002

Hypoglycemia associated autonomic failure.

Intensively treated patients with diabetes have a three-fold increased risk of severe hypoglycemic episodes with an attendant four percent mortality. These findings, unfortunately undermine attempts to achieve normoglycemia in diabetic patients. It has been proven that antecedent hypoglycemia is a major factor responsible for blunting metabolic, neuroendocrine and also autonomic responses to subsequent hypoglycemia. Diabetic patients with good glycemic control become unable to recognize symptoms of hypoglycemia. Lack of symptoms, or hypoglycemia unawareness, is part of the syndrome called hypoglycemia associated autonomic failure. This syndrome also includes inadequate neuroendocrine hormonal responses and reduced glycemic thresholds for counterregulatory hormonal secretion. Factors regulating the magnitude of hypoglycemia associated autonomic failure include antecedent duration and frequency of hypoglycemia, prior episodes of exercise, and autonomic neuropathy. Understanding the pathophysiology of this syndrome will provide a foundation for therapy aimed at preventing severe hypoglycemia during intensive metabolic control. This article will review our current understanding of the mechanisms responsible for hypoglycemia associated autonomic failure.

Autonomic Nervous System Diseases↗
PubMed2002

Prior exercise and the response to insulin-induced hypoglycemia in the dog.

To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU.kg(-1).min(-1)) euglycemic (n = 5 exercised and n = 9 sedentary) or hypoglycemic (65 mg/dl; n = 8 exercised and n = 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (R(a)) and utilization (R(d)) were assessed with arteriovenous and isotopic ([3-(3)H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) R(d) was greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not R(a), was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in R(a) but to a reduction in insulin-stimulated R(d). The primary site of this reduction is the liver.

Animals↗
PubMed2002

Effect of gender on counterregulatory responses to euglycemic exercise in type 1 diabetes.

A marked sexual dimorphism in neuroendocrine and metabolic responses to moderate, prolonged exercise occurs in healthy humans. It is unknown whether similar differences occur in type 1 diabetes mellitus (T1DM). Fifteen patients with T1DM (7 women and 8 men) were studied during 90 min of euglycemic exercise at 50% of the maximum rate of O(2) consumption. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness, and had no history or evidence of autonomic neuropathy. Hypoglycemia was scrupulously avoided during the week preceding tests. Exercise was performed under constant infusion of regular insulin (1 U/h) and a variable 20% dextrose infusion, as needed to maintain euglycemia. At 15-min intervals, neuroendocrine, metabolic (glucose kinetics, intermediate metabolism, lipolysis), and cardiovascular responses were assessed. Indirect calorimetry was performed during the last 10 min of exercise. Plasma glucose and insulin did not differ between genders at baseline or during exercise. Key neuroendocrine responses were significantly reduced in women, compared with men, during exercise (epinephrine, 360 +/- 104 vs. 666 +/- 126 pM; norepinephrine, 2.3 +/- 0.8 vs. 4.1 +/- 1.0 nM; GH, 10 +/- 5 vs. 22 +/- 8 micro g/liter). Glucagon, cortisol, and pancreatic polypeptide responses were similar between genders. Despite reduced catecholamine responses in women, no gender differences were observed in endogenous glucose production (EGP) or exogenous glucose infusion rate during exercise. The lipolytic response to exercise (blood glycerol), on the other hand, was greater in women than in men. In conclusion, a marked sexual dimorphism exists in counterregulatory responses to exercise in T1DM, including key neuroendocrine (catecholamine, GH) and metabolic (lipolysis) responses. Other responses, including glucagon and EGP, were similar between genders, suggesting that the glucagon to insulin ratio may be the primary determinant of EGP during moderate intensity exercise in T1DM.

Adult↗
PubMedDate not supplied

The role of glimepiride in the effective management of Type 2 diabetes.

Type 2 diabetes mellitus, a disorder of impaired insulin secretion and insulin resistance, has reached epidemic proportions. The effective management of Type 2 diabetes is of vital concern to clinicians. The identification of high-risk individuals and lifestyle management can help control diabetes; however, most patients require pharmacologic intervention. The goals of pharmacologic therapy are to achieve adequate glycemic control while avoiding hypoglycemia and weight gain and to minimize the risk of future micro- and macrovascular complications. There are a number of available glucose-lowering agents from which to choose. This review focuses on the sulfonylureas, the first oral agents introduced for the management of Type 2 diabetes, which are effective, well-tolerated, and well-established drugs, Second-generation sulfonylureas are now widely used in the management of Type 2 diabetes. The most recent addition, glimepiride, can be used in combination with metformin, the thiazolidinediones, alpha-glucosidase inhibitors, and insulin. The unique properties of glimepiride may provide advantages over other currently available insulin secretagogues.

Blood Glucose↗
PubMedDate not supplied

Leptin: metabolic control and regulation.

Leptin, a protein released from adipose tissue, is being recognized to play an integral role in endocrine regulation of metabolism. While it is clearly evident that leptin is decreased during caloric restriction, the response of leptin to other types of stress has been plagued by conflicting data. With hypoglycemia stress, the literature may conflict because experimentally hypoglycemia is induced with infusion of insulin, an endocrine factor that can increase leptin levels. With exercise, leptin's response may depend on duration and intensity of exercise. While it has been clearly shown that the sympathetic nervous system (SNS) inhibits leptin secretion in a variety of experimental modes, the hypothalamic-pituitary-adrenal (HPA) axis may stimulate leptin secretion. This creates a paradox of leptin regulation during stress since both systems are activated with stress. If the SNS inhibition overrides the HPA axis' activation of leptin secretion, leptin's role during stress may be to allow a shifting of fuel consumption towards carbohydrate utilization. In type 1 diabetes mellitus, autonomic dysfunction may prevent the fall in leptin during stress. Although obesity is associated with type 2 diabetes mellitus, patients may have decreased leptin levels, especially when glucose is poorly controlled. This may contribute to further obesity and worsening of the disease. The purpose of this review to is critically analyze the literature regarding the impact of different types of stress on leptin secretion, the function of leptin during stress, and the role of leptin in the pathophysiology of diabetes.

Animals↗
PubMedDate not supplied

Leptin responses to antecedent exercise and hypoglycemia in healthy and type 1 diabetes mellitus men and women.

These studies examined the effects of hypoglycemia or exercise on leptin levels in 47 (23 women, 24 men) healthy (age 26+/-2 years, body mass index 23+/-0.5 kg.m(-2)) and type 1 diabetes mellitus (T1DM) subjects (age 29+/-2 years, body mass index 27+/-2 kg.m(-2)). In Study 1, healthy and T1DM subjects were exposed to morning and afternoon 120-min hyperinsulinemic hypoglycemic ( approximately 50 mg/dl) or euglycemic ( approximately 90 mg/dl) clamps. In Study 2, healthy subjects were studied during morning and afternoon 90-min exercise bouts at 50% VO(2max). In Study 1, basal levels of leptin were significantly greater in T1DM vs. the healthy subjects (13.8+/-3 vs. 5.4+/-1 ng/dl; P<.05). However, during the last 30 min of morning hypoglycemia, plasma leptin levels significantly decreased from 5.4+/-1 to 4.0+/-1 ng/dl (P<.05) and remained low during afternoon hypoglycemia (4.3+/-1 ng/dl) in healthy but not T1DM subjects. In Study 2, plasma leptin levels did not significantly change during exercise the bout in healthy men, but significantly decreased 3 h after morning exercise, and continued to decrease during afternoon exercise in healthy women (P<.0001). Thus, plasma leptin levels decrease in response to hypoglycemia in healthy but not T1DM subjects. However, T1DM patients do have increased basal leptin levels compared to healthy man. Lastly, there is a marked sexual dimorphism in plasma leptin responses to repeated episodes of exercise.

Adaptation, Physiological↗