Lloyd Axelrod

Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. EVIDENCE Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle). CONCLUSIONS We recommend evaluation and management of hypoglycemia only in patients in whom Whipples triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.

Improved Contemporary Surgical Management of Insulinomas: A 25-year Experience at the Massachusetts General Hospital

Objective:To determine changes in the management strategy of patients with insulinomas and identify critical factors in patient outcome. Background:Pancreatic insulinomas are rare neoplasms that are present in various ways. The optimal approach to localization, operative management, and follow-up of insulinomas is undetermined. Methods:Sixty-one patients with a diagnosis of insulinoma requiring surgery at a tertiary care center between 1983 and 2007 were reviewed. Demographic details, mode of presentation, preoperative localization, operative procedures, and pathology data were assessed. The effect of different factors on survival was determined. Results:Seven of 61 (11%) patients had a diagnosis of multiple endocrine neoplasia-type 1 (MEN-1). Multiple insulinomas were noted in 8% of cases and were more common in MEN-1 patients. The overall rate of malignancy was 8%. Confusion (67%), visual disturbances (42%), and diaphoresis (30%) were the most common presenting symptoms. Weight gain was noted in 44% of patients. The median duration of symptoms before diagnosis was 18 (1–240) months. The sensitivity of preoperative imaging of tumors before 1994 was 75%, compared with 98% after this period, which included use of endoscopic ultrasound scanning (P = 0.012). A combination of palpation and intraoperative ultrasound detected 92% of tumors. Distal pancreatectomy (40%), enucleation (34%), and pancreaticoduodenectomy (16%) were the most common procedures and pancreatic fistula occurred in 18% of patients. Three patients underwent noncurative distal pancreatectomy in the early period. The 10-year disease-specific and disease-free survival was 100% and 90% respectively. There were 5 patients with disease recurrence. Lymph node metastases (P < 0.001), lymphovascular invasion (P < 0.001), and the presence of MEN-1 (P = 0.035) were prognostically significant adverse factors in disease-free survival. Lymphovascular invasion was the only significant factor on multivariate analysis (P = 0.002). Conclusion:Pancreatic insulinomas can be readily localized preoperatively with modern imaging to avoid unsuccessful blind pancreatic resection. Surgical resection is associated with low morbidity and mortality and achieves long-term disease-free survival in the absence of lymphovascular invasion.

Studies of the control of plasma aldosterone concentration in normal man: II. Effect of dietary potassium and acute potassium infusion

The responses of plasma aldosterone, cortisol, and corticosterone to an infusion of 75 mEq of potassium chloride over 120 min were studied in 10 normal subjects. Five subjects were fed a 10 mEq and five a 200 mEq sodium diet, while all subjects ingested 40 mEq and 200 mEq potassium sequentially. Two potassium infusions were performed in each subject when in balance on a fixed sodium intake and low and then high potassium diets. Regardless of dietary intake, increases of serum potassium of 0.5-1.5 mEq/liter above preinfusion levels were usually associated with significant increments in plasma aldosterone concentration. Our data agree with previous evidence that the potassium ion stimulates the adrenal cortex directly to secrete aldosterone. Peripheral renin activity did not increase after the potassium infusion. Plasma cortisol and corticosterone levels generally followed the expected diurnal decline during the infusion, implying that ACTH secretion did not increase. The plasma aldosterone response to incremental changes in serum potassium was linear on each of the four diets. The slopes of these linear relationships increased significantly when the potassium intake was increased from 40 to 200 mEq. No increase in slope occurred on either potassium intake when dietary sodium was restricted from 200 to 10 mEq. Thus, identical increases in serum potassium were associated with greater increments in plasma aldosterone above preinfusion levels on either sodium intake when the 200 mEq potassium diet was compared with the 40 mEq potassium intake.

Invasive external otitis. Report of 21 cases and review of the literature.

We report 21 cases of invasive external otitis and review 130 cases from the English literature. Invasive external otitis is the term that most appropriately describes the locally invasive Pseudomonas infections that begins in the external ear canal, breaches the epithelial barrier and results in signs of local subcutaneous tissue invasion. Nineteen patients were diabetic. FIfteen of these 19 had preexistent, long-standing diabetes (average 15.8 years) and 10 had microvascular disease. Studies of the skin of the temporal bone in two patients provided evidence of diabetic microangiopathy of the dermal capillaries. Pseudomonas aeruginosa was isolated from the involved area in all cases. All patients without neurologic deficits survived, compared with six of nine with deficits of the central nervous system. All 13 patients in whom initial therapy was successful received a combination of an aminoglycoside and a semisynthetic penicillin, whereas all six episodes of recurrent disease occurred when only one antibiotic was used. The overall mortality was 15 percent (three of 20 in whom the long-term outcome is known). We propose that diabetic microangiopathy of the skin of the temporal bone results in poor local perfusion and creates an environment well suited for invasion by Pseudomonas aeruginosa. There is a good correlation between the extent of disease clinically and prognosis. Effective treatment requires early diagnosis and combination therapy with an aminoglycoside and a semisynthetic penicillin.

Perioperative management of patients treated with glucocorticoids.

HPA suppression is a common consequence of glucocorticoid therapy, whereas overt secondary adrenal insufficiency is a rare but life-threatening condition. Prolonged hypotension and a response to adequate doses of a glucocorticoid agent are not reliable ways to assess adrenocortical function. One must also demonstrate plasma cortisol levels that are inappropriately low for the clinical situation. Hypotension in patients previously treated with glucocorticoids is caused by loss of the permissive effect of glucocorticoids on vascular tone, which may be related in turn to enhanced PGI2 production in the absence of glucocorticoids. It is not caused by mineralocorticoid deficiency. Recurrent problems of study design and interpretation have plagued this area of investigation. Any patient who has received a glucocorticoid in doses equivalent to at least 20 mg a day of prednisone for more than 5 days is at risk for HPA suppression. If the doses are closer to but above the physiologic range, 1 month is probably the minimal interval. Recovery from prolonged exposure to high doses of glucocorticoids may take up to 1 year. Pituitary function returns before adrenocortical function. Recovery from short courses of treatment (e.g., 5 days) occurs more rapidly, in about 5 days. Recovery is time-dependent and spontaneous. The rate of recovery is a function of the dose and duration of therapy before tapering is started and while the dose is being reduced. ACTH therapy does not cause adrenocortical suppression but offers no advantage over glucocorticoids, has several disadvantages, and should no longer be used. Patients on alternate day glucocorticoid therapy have some suppression of basal cortisol levels but have normal or nearly normal responses to provocative tests of adrenocortical function. The standard short ACTH stimulation test is a reliable means of assessing adrenocortical function preoperatively. The low dose (1 microgram) short ACTH test is promising but has not been sufficiently well characterized, requires serial dilutions and cannot be recommended at this time. Studies of the physiologic adrenocortical response to surgical stress provide a basis for revised dose recommendations for perioperative coverage in the patient with known or suspected HPA suppression. Recommendations of a multidisciplinary group are presented.

INHIBITION OF PROSTACYCLIN PRODUCTION MEDIATES PERMISSIVE EFFECT OF GLUCOCORTICOIDS ON VASCULAR TONE: Perturbations of this Mechanism Contribute to Pathogenesis of Cushing's Syndrome and Addison's Disease

Glucocorticoids have a permissive effect on vascular tone and blood pressure; they enhance vascular responsiveness to vasopressors such as catecholamines without necessarily having an effect when administered alone. This effect does not require central or systemic mediation. Prostacyclin (prostaglandin I2; PGI2), a potent vasodilator, is produced by the vascular endothelium, vascular smooth muscle cells, adipocytes, and other cells. PGI2 production by vascular endothelium and other cells is decreased by glucocorticoids. The hypothesis is proposed that the effect of glucocorticoids on vascular tone is mediated by inhibition of PGI2 production by vascular endothelium (possibly other cells also). The inhibition of PGI2 production by glucocorticoids may contribute to the hypertension of Cushings syndrome. Loss of this inhibitory effect in glucocorticoid deficiency states (eg, Addisons disease) may cause enhanced PGI2 production, which may contribute to the haemodynamic and gastrointestinal manifestations of these disorders.

Plasma prostaglandin levels in rats with diabetes mellitus and diabetic ketoacidosis.

We studied by radioimmunoassay the plasma levels of 13,14-dihydro-15-keto-prostaglandin (PG)E2 (the stable metabolite of PGE2), 6-keto-PGFUt[the stable breakdown product of prostacyclin (PGI2)], and thromboxane (TX) B2 (the stable breakdown product of TXA2) in normal rats and rats with nonketotic diabetes mellitus (DM) or diabetic ketoacidosis (DKA). The plasma levels of the PGE2, PGI2, and TXA2 derivatives were markedly elevated in rats with DKA. The level of 13,14-dihydro-15-keto-PGE2 (0.298 ± 0.056 ng/ml, N = 34) was sixfold higher, the level of 6-keto-PGF1α (0.378 ± 0.049 ng/ml, n = 33) was twofold higher, and that of TXB2 (0.346 ± 0.046 ng/ml, n = 34) was 50% higher in rats with DKA than in normal rats. The plasma level of the PGI2 derivative was also elevated in rats with DM. The level of 6-keto-PGF1α (0.310 ± 0.050 ng/ml) was nearly as high in animals with DM as in those with DKA. The level of 13,14-dihydro-15-keto-PGE2 was not elevated and that of TXB2 was reduced in animals with DM. In response to insulin and to 5-methylpyrazole-3-carboxylic acid, two potent antilipolytic agents, the levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1α, decreased significantly in rats with DKA. Adipocytes produce large quantities of PGE2 and PGI2 during norepinephrine-induced lipolysis. DKA is a situation par excellence of high catecholamine and low insulin levels, just the circumstances required for accelerated lipolysis and maximal production of PGE2 and PGI2 by the adipocyte. The adipocyte may be an important source of the high plasma levels of the PGE2 and PGI2 derivatives present in rats with DKA and of the elevated levels of the PGI2 derivative present in animals with DM. The ability of both insulin and 5-methylpyrazole-3-carboxylic acid to decrease the levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1α supports this view. The high plasma levels of the PGE2, PGI2, and TXA2 derivatives in DKA and of the PGI2 derivative in DM raise the possibility that high levels of all three parent compounds may circulate in DKA and high levels of PGI2 may circulate in DM. The suppression of the elevated levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1α in DKA by two structurally unrelated antilipolytic agents suggests that the adipocyte may be a major source of the high plasma levels of both derivatives in this disorder.

Coordinate Control of Lipolysis by Prostaglandin E2 and Prostacyclin in Rat Adipose Tissue

PGE2 is a potent antilipolytic agent produced by adipose tissue, but its role as a physiological regulator of triglyceride lipolysis is controversial because inhibitors of prostaglandin synthesis have not enhanced hormone-stimulated lipolysis in adipose tissue consistently. Adipose tissue also produces PGI2, but this eicosanoid has not had a demonstrated effect on lipolysis under physiological conditions previously. We investigated both PGE2 and PGI2 production and their effects on lipolysis in rat adipose tissue. We found that 1) EPI-stimulated PGE2 production (like PGI2 production) requires the cooperation of adipocytes and endothellal cells, 2) adipose tissue produces PGE2 and PGI2 at comparable rates, 3) indomethacin inhibits EPI-induced PGE2 and PGI2 production and has no effect on EPI-stimulated lipolysis when added to a mixture of adipocytes and endothelial cells or to intact epididymal fat pads, 4) PGI2 is a potent lipolytic agent when added to isolated adipocytes in the absence of endothelial cells under physiological conditions, 5) the magnitudes and the ED50s of the antllipolytic effect of PGE2 and the lipolytic effect of PGI2 in isolated adipocytes in the absence of endothelial cells are comparable, 6) PGI2 antagonizes the antllipolytic effect of PGE2 in isolated adipocytes in the absence of endothelial cells in a dosage-related manner, and 7) the antllipolytic effect of added PGE2 in isolated adipocytes is greater in the absence of endothelial cells than in their presence, suggesting that endogenous eicosanoid production reduces the effectiveness of added PGE2. These studies demonstrate that catecholamine-induced lipolysis is under the coordinate control of PGE2, a potent antllipolytic agent, and PGI2, a potent lipolytic agent. The failure of PGH synthase inhibition to affect lipolysis can be explained by concurrent PGE2 and PGI2 inhibition. The existence of this mechanism for coordinate control of lipolysis may have broad implications for the function of adipose tissue in health and disease.

Prostacyclin Production by Isolated Adipocytes

Isolated rat adipocytes produce prostacyclin (PGI2) in relatively large quantities during norepinephrine (NE)-induced lipolysis. The endogenous NE-induced production rate of PGI2, calculated from the NE-induced production rate of PGI2 observed in our studies (2.2 ng/106 cells/2 h) and from the number of fat cells in the normal organism, is 1.46 ng/kg/min for rats, 4.46 ng/kg/min for men, and 11.86 ng/kg/min for women. These rates are comparable to the exogenous PGI2 infusion rate that alters platelet aggregation and blood pressure in rats and humans. Exogenous PGI2 failed to modify the rate of NE-induced lipolysis. Inhibition of endogenous PGI2 production by indomethacin had no effect on the rate of NE-induced lipolysis when either a maximal or submaximal lipolytic concentration of NE was used. PGI2 [rather than prostaglandin (PG) E2] may be the substance that accounts for the functional vasodilatation that accompanies hormone-induced lipolysis. PGI2 is produced in larger quantities than PGE2 during NE-induced lipolysis and is a more potent vasodilator than PGE2. Its instability can account for the inability of previous investigators to detect a vasodilator substance in the venous effluent of adipose tissue. The production of PGI2 by adipocytes may be an important modulator of the regulation of vascular tone and platelet aggregation by catecholamines in the vascular bed of adipose tissue and perhaps other tissues. PGI2 produced by adipocytes, by virtue of its ability to cause vasodilatation and inhibit platelet aggregation, may contribute to the maintenance of luminal patency in the vascular bed of adipose tissue and possibly other tissues as well.

The treatment of the hepatorenal syndrome with intra-renal administration of prostaglandin E1

Three patients with the hepatorenal syndrome were treated with prostaglandin E1 administered through a selective renal arterial catheter. Prostaglandin E1 was given in progressively increasing doses (2 to 100 ng/kg/min) over a 60-minute period. Control plasma prostaglandin E levels were elevated in all three patients, 0.98, 0.91, and 0.83 ng/ml, respectively. At the end of the infusion, plasma prostaglandin E levels had risen to 10.4, 2.63, and 10.3 ng/ml in the three patients respectively. Plasma renin activity increased during the course of the infusion in two of the patients. The plasma aldosterone concentration did not change during the prostaglandin E1 infusion. Intrarenal prostaglandin E1 failed to increase urine volume or urinary sodium concentration in three patients with the hepatorenal syndrome.