Metabolic alterations in adipose tissue during the early phase of experimental endotoxemia in humans.

Adipose tissue plays an important role in energy homeostasis; however, there is only little knowledge about its metabolic activity during critical illness or sepsis. We assessed adipose tissue metabolic activity and local blood flow during experimental endotoxemia in otherwise healthy humans. In a prospective, placebo controlled and randomized experiment we measured changes in lactate, glycerol, and pyruvate concentrations in microdialysate samples of femoral adipose tissue after an intravenous bolus of lipopolysaccharide (LPS, 4 ng/kg). Intravenous endotoxin caused an early and constant increase in interstitial pyruvate, while formation of lactate in adipose tissue was not affected. In contrast, lactate levels in serum were elevated significantly after 90 min (p<0.05) and likewise, serum glycerol concentrations rose 90 min after LPS treatment (p<0.05) and 60 min earlier than in adipose tissue. Subcutaneous adipose tissue blood perfusion increased 2-fold while there was a strong decline in skin blood flow. Pyruvate accumulation in subcutaneous adipose tissue is an early marker of endotoxemia. While adipose tissue is a major source of serum glycerol and lactate in humans during physiological conditions, it contributes only little to increased serum lactate and glycerol levels during endotoxemia.

Relationship between metabolic parameters, blood pressure, and sympathoendocrine function in healthy young adults with low birth weight.

The association between low birth weight (LBW) and elevated blood pressure has been attributed to disturbances in the endocrine and sympathetic nervous system. The present study focussed on parameters of cardiovascular and sympathetic function and on adrenocortical activity in 24 healthy subjects aged 20 - 30 years with a birth weight of less than 2500 g at term and a control group of 24 subjects with a normal birth weight (NBW; 3200 - 3700 g) who were thoroughly matched for gender, body mass index (BMI), and age. Blood pressure, heart rate, and insulin resistance (calculated according to the homeostasis model assessment) were determined. Additionally, free salivary cortisol was measured at 08 : 00 am and 11 : 00 pm. In 13 subjects of each group, muscle sympathetic nerve activity (MSNA) was measured microneurographically at rest and after baroreflex stimulation by nitroprusside (12 NBW and 9 LBW subjects). Metabolic parameters, blood pressure, and salivary cortisol did not differ between LBW and NBW subjects. MSNA was significantly lower in the LBW group. In both groups insulin resistance correlated positively with BMI and negatively with morning cortisol. In the LBW group, but not the NBW group, systolic and diastolic blood pressure correlated positively with BMI and insulin resistance, and negatively with morning salivary cortisol. A correlation between morning salivary cortisol and the MSNA was only found in NBW subjects. This positive correlation strengthened when MSNA was stimulated by nitroprusside administration. However, in the same maneuvre a negative correlation between morning salivary cortisol and MSNA was observed in the LBW group. The data indicate that insulin resistance depends on the same factors in LBW and NBW subjects. In LBW subjects the interplay between adrenocortical and sympathetic activity is altered. Furthermore, LBW subjects differ from the NBW group in their significant interrelationship between blood pressure and metabolic factors.

Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans.

OBJECTIVE: Reduced awareness of hypoglycemic symptoms and compromised hormonal counterregulation increase the risk of severe hypoglycemia in people with diabetes mellitus. Up to the present, angiotensin 1 receptor blockers, which play an important role in controlling diabetic complications, have not been known to increase the risk of hypoglycemia. Nevertheless, we observed 3 cases of diabetic patients complaining of reduced awareness of hypoglycemic symptoms while they were under treatment with losartan in our outpatients clinic. We therefore investigated the effects of losartan on symptomatic and hormonal responses to hypoglycemia in humans. RESEARCH DESIGN AND METHODS: We carried out a randomized, double-blind, crossover study including 16 healthy men. The subjects received losartan 50 mg/d versus placebo. Treatment periods lasted for 7 days and were followed by a stepwise hypoglycemic clamp session (4.5 to 3.8 to 3.1 to 2.4 mmol/L) with measurement of counterregulatory hormones (epinephrine, norepinephrine, adrenocorticotropin, cortisol, glucagon), symptoms, and hemodynamic parameters (blood pressure, heart rate). RESULTS: Losartan attenuated the hypoglycemia-induced rise in plasma epinephrine (6480 +/- 490 pmol/L versus placebo 8970 +/- 790 pmol/L; P <.001) and the rise in plasma adrenocorticotropin (21 +/- 2 pmol/L versus 26 +/- 3 pmol/L; P <.01). Losartan also reduced symptom scores during hypoglycemia (P <.05). CONCLUSION: We conclude that short-term treatment with losartan slightly attenuates symptomatic and hormonal responses to hypoglycemia. At present, for patients who are unaware of hypoglycemia and who require antihypertensive or nephroprotective treatment, we would recommend caution concerning treatment with losartan.

Excess triiodothyronine as a risk factor of coronary events.

BACKGROUND: Abnormalities in cardiac function, eg, arrhythmias and congestive heart failure, often accompany thyrotoxicosis. A relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction (MI) remains largely speculative. METHODS: The results of thyroid function studies on blood samples drawn from a total of 1049 patients (aged 40 years or older) immediately on emergency medical admission were related to frequencies of angina pectoris and myocardial infarction as determined according to current diagnostic algorithms. After 3 years, those patients who had initially presented with angina pectoris or acute MI were observed for subsequent coronary events; of these (n=185), 98% of the subjects (n=181) could be reevaluated. RESULTS: On hospital admission, the relative rate of angina pectoris and MI was markedly high (odds ratio, 2.6; 95% confidence interval, 1.3-5.2; P=.007) in patients with elevated serum free and total triiodothyronine (T(3)) levels. An initially elevated free T(3) level was a risk factor for subsequent coronary events during the 3-year follow-up (adjusted odds ratio, 4.8; 95% confidence interval, 1.3-17.4; P=.02). CONCLUSIONS: An elevation of serum free T(3) levels at hospital admission is associated with a 2.6-fold greater likelihood of the presence of a coronary event. Moreover, an initially elevated T(3) level is associated with a 3-fold higher risk of developing a subsequent coronary event during the next 3 years. Excess T(3) seemed to be a factor associated with the development and progression of acute myocardial ischemia.

Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans.

Circulating plasma insulin and glucose levels are thought to be major regulators of leptin secretion. There is evidence from in vitro and animal experiments that glucose metabolism rather than insulin alone is a main determinant of leptin expression. Here, we tested the hypothesis that in humans also leptin secretion is primarily regulated by glucose uptake and only secondarily by plasma insulin and glucose. In 30 lean and healthy men we induced 4 experimental conditions by using the blood glucose clamp technique. A total of 60 hypoglycemic and euglycemic clamps, lasting 6 h each, were performed. During these clamps insulin was infused at either high (15.0 mU/min x kg) or low (1.5 mU/min x kg) rates, resulting in low-insulin-hypo, high-insulin-hypo, low-insulin-eu, and high-insulin-eu conditions. Serum leptin increased from 0-360 min by 20.5 +/- 4.1% in the low-insulin-hypo, 33.6 +/- 7.6% in the high-insulin-hypo, 39.6 +/- 6.0% in the low-insulin-eu, and 60.4 +/- 7.6% in the high-insulin-eu condition. Multiple regression analysis revealed a significant effect of circulating insulin (low vs. high insulin; P = 0.001) and blood glucose (hypoglycemia vs. euglycemia; P = 0.001) on the rise of serum leptin. However, when the total amount of dextrose infused during the clamp (grams of dextrose per kg BW) was included into the regression model, this variable was significantly related to the changes in serum leptin (P = 0.001), whereas circulating insulin and glucose had no additional effect. These findings in humans support previous in vitro data that leptin secretion is mainly related to glucose metabolism.

Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in association with hyperinsulinemia is frequently found in patients with type 1 and type 2 diabetes mellitus and in subjects with abdominal adiposity. We questioned whether insulin could cause HPA axis activation and, if so, whether this insulin action may arise at the adrenal level or at a central (i.e. hypothalamic-pituitary) level. Experiments lasting for 6 h each were done in 30 lean healthy men. In 15 men, insulin was infused at a rate of 1.5 mU min(-1) kg(-1). Plasma glucose concentration was held constant during an euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session. The sequence of the 2 clamp sessions was random, and a 4-weeks recovery period was allowed between the two sessions. The protocol was essentially the same in another 15 men, with the exception that insulin was infused at a rate of 15.0 mU min(-1) kg(-1). During the euglycemic clamp sessions, we found plasma ACTH levels to increase only in the high-, but not in the low-insulin group (group by time interaction, P < 0.01); serum cortisol levels were greater in the high than in the low-insulin group (P < 0.02). In the hypoglycemic clamp sessions, plasma ACTH levels increased in the same pattern in the 2 groups; serum cortisol was greater in the high than in the low-insulin group at the beginning of the clamp (plasma glucose approximately 4.1 mmol/L; P < 0.05). Our results demonstrate that insulin acutely stimulates the HPA secretory activity in humans. The pattern suggests an effect of insulin at both peripheral and central levels of the HPA axis.

Protective effect of insulin against hypoglycemia-associated counterregulatory failure.

Antecedent hypoglycemic episodes reduce the counterregulatory neuroendocrine response to hypoglycemia. The role of insulin in the mechanism responsible for the antecedent hypoglycemia causing subsequent counterregulatory failure has not been elucidated. We performed antecedent hypoglycemic clamps (56 mg/dL) lasting 2 h with differing degrees of hyperinsulinemia, which were followed by 6-h stepwise hypoglycemic clamps (76-66-56-46 mg/dL) on the next day. Experiments were carried out in 30 young, healthy men. Fifteen of these subjects were tested on 2 occasions. On 1 occasion the antecedent hypoglycemia was induced by insulin infusion at a rate of 1.5 mU/min x kg (low insulin-ante-hypo); on the other occasion the insulin infusion rate was 15.0 mU/min x kg (high insulin-ante-hypo). Both sessions were separated by at least 4 weeks, and their order was balanced across subjects. The remaining 15 subjects (control group) received the same stepwise hypoglycemic clamp as the other subjects, but without antecedent hypoglycemia. During the stepwise hypoglycemic clamp, the counterregulatory increases in ACTH, cortisol, and norepinephrine were significantly blunted after the low insulin-ante-hypo (P < 0.01, P < 0.05, and P < 0.05, respectively) but not after the high insulin-ante-hypo (P = 0.12, P = 0.92, and P = 0.19, respectively) compared to that in the control group. The cortisol, norepinephrine, and glucagon responses were greater after the high than after the low insulin-ante-hypo (all P < 0.05). In conclusion, the present study clearly demonstrates that even a single episode of mild hypoglycemia reduces neuroendocrine counterregulation 18-24 h later. Insulin has a moderate protective effect on subsequent counterregulation.