Reduction in insulin sensitivity following administration of the clinically used low-dose pressor, norepinephrine.

BACKGROUND: Hyperglycaemia in acutely ill patients is well described and correcting this hyperglycaemia improves outcomes. It has been generally attributed to endogenous factors, specifically decreased secretion of insulin or increased secretion of anti-insulin hormones, and cytokines, or both. Norepinephrine is the most commonly used vasopressor in critically ill patients. When titrated, it has anecdotally been found to cause wide swings in blood glucose levels. We tested the hypothesis that norepinephrine, a plausible exogenous, iatrogenic cause of hyperglycaemia, causes resistance to insulin action with the hyperinsulinaemic-euglycaemic clamp method. METHODS: Hyperinsulinaemic-euglycaemic (about 100 mg dL(-1) ) clamps were performed before and during infusion of norepinephrine, in doses of 110 ng kg(-1) min(-1) , which raised mean arterial pressure from 82 ± 7 to 94 ± 8 mmHg (p < 0.01) in 11 healthy adults. RESULTS: The glucose infusion rate required to maintain euglycaemia during the clamps, a marker of whole-body insulin sensitivity, decreased from 11.2 ± 3.7 mg kg(-1) min(-1) at baseline to 9.0 ± 2.6 mg kg(-1) min(-1) (p = 0.015) during the norepinephrine infusion. Steady-state insulin and C-peptide levels did not significantly change. Cortisol levels showed diurnal variation in the beginning and were also different at steady state. CONCLUSIONS: Infusion of pressor doses of norepinephrine causes resistance to insulin action in humans.

The use of fibric Acid derivatives in cardiovascular prevention.

OPINION STATEMENT: Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol-lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.

Evaluation and therapy of hypercalcemia.

Hypercalcemia is a common but challenging disorder. It results from PTH-dependent or independent increased bone resorption, increased vitamin D-dependent absorption, or as a result of various drugs and substances. Outpatient hypercalcemia is most commonly caused by primary hyperparathyroidism while malignancy accounts for most inpatient disease. Treatment includes adequate hydration, intravenous bisphosphonates, and occasionally calcitonin as a temporizing measure. Treating the underlying cause, such as employing chemotherapy for malignancy or parathyroidectomy for hyperparathyroidism, is also essential.

Dissociation Between Hormonal Counterregulatory Responses and Cerebral Glucose Metabolism During Hypoglycemia.

Hypoglycemia is the most common complication of diabetes, causing morbidity and death. Recurrent hypoglycemia alters the cascade of physiological and behavioral responses that maintain euglycemia. The extent to which these responses are normally triggered by decreased whole-brain cerebral glucose metabolism (CMRglc) has not been resolved by previous studies. We measured plasma counterregulatory hormonal responses and whole-brain CMRglc (along with blood-to-brain glucose transport rates and brain glucose concentrations) with 1-[11C]-d-glucose positron emission tomography during hyperinsulinemic glucose clamps at nominal plasma glucose concentrations of 90, 75, 60, and 45 mg/dL (5.0, 4.2, 3.3, and 2.5 mmol/L) in 18 healthy young adults. Clear evidence of hypoglycemic physiological counterregulation was first demonstrated between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L) with increases in both plasma epinephrine (P = 0.01) and glucagon (P = 0.01). In contrast, there was no statistically significant change in CMRglc (P = 1.0) between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L), whereas CMRglc significantly decreased (P = 0.02) between 60 mg/dL (3.3 mmol/L) and 45 mg/dL (2.5 mmol/L). Therefore, the increased epinephrine and glucagon secretion with declining plasma glucose concentrations is not in response to a decrease in whole-brain CMRglc.

Hypoglycemia during moderate intensity exercise reduces counterregulatory responses to subsequent hypoglycemia.

Hypoglycemia, which occurs commonly during and following exercise in people with diabetes, is thought to be due to attenuated counterregulation in the setting of therapeutic insulin excess. To better understand the pathophysiology of counterregulation, we aimed to determine if dextrose administration to maintain euglycemia during moderate intensity exercise alters the attenuation of counterregulatory responses to subsequent hypoglycemia in healthy adults : Counterregulatory responses to hypoglycemia were assessed in 18 healthy adults after bed rest and following exercise with (n = 9) and without (n = 9) dextrose infusion. Responses were measured during a stepped euglycemic-hypoglycemic clamp 24 h after either bed rest or two 90-min bouts of exercise at 70% peak oxygen uptake : Hypoglycemia occurred during the second bout of exercise without dextrose infusion. Plasma glucagon and epinephrine responses to stepped hypoglycemia after antecedent exercise without dextrose infusion were significantly lower at the 45 mg/dL glycemic level compared to after bed rest. However, no attenuation of the counterregulatory responses to hypoglycemia was evident after antecedent exercise when dextrose was infused. This study suggests that the attenuation of the counterregulatory responses during hypoglycemia after exercise is likely due to the hypoglycemia that occurs during moderate prolonged exercise and not solely due to exercise or its intensity.

Resorptive hypercalcemia in post-essential thrombocythemia myelofibrosis: treatment with denosumab.

CONTEXT: Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. OBJECTIVE: We report a unique case of hypercalcemia associated with post-essential thrombocythemia myelofibrosis and review the clinical and laboratory features, pathogenesis, and responsiveness to treatment with the bone antiresorptive agent, denosumab. RESULTS: A 62-yr-old woman with essential thrombocythemia presented with progression to myelofibrosis with lytic skull lesions and symptomatic hypercalcemia. Other causes of hypercalcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hypercalcemia with the related entity of primary myelofibrosis. Her hypercalcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg sc dose of the anti-receptor activator of nuclear factor κB (RANK) ligand monoclonal antibody, denosumab, with sustained normocalcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. CONCLUSION: The pathogenesis of myelofibrosis-related hypercalcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although we did not measure these factors, denosumab holds promise in the treatment of malignancy-associated hypercalcemia and specifically that related to myelofibrosis. Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known.