Context: Fasting is associated with suppressed insulin and augmented GH secretion. The involvement of each mechanism in the regulation of fuel mobilization during fasting is unknown.
Objective: To ...ascertain the role of GH in the regulation of the rates of lipolysis, proteolysis, and hepatic glucose production (HGP) during the physiological daily feed/fast cycle and after 2 d of complete fasting, we used a model of selective GH suppression by the administration of GHRH receptor antagonist (GHRH-A).
Design and Setting: We conducted an open label in-patient study in the General Clinical Research Center at the University of Michigan.
Participants: Six healthy, nonobese volunteers participated.
Main Outcome Measures: We assessed 24-h plasma GH concentration and rates of lipolysis, proteolysis, and HGP using stable isotope techniques after an overnight fast and after 2 d of fasting.
Results: GHRH-A suppressed plasma GH by about 65% during the fed state (P = 0.015) but did not alter the rates of lipolysis, proteolysis, or HGP. Fasting for 2 d suppressed plasma insulin concentration by about 80% and elevated plasma GH about 4-fold (both P < 0.01). This was accompanied by a doubling in the rate of lipolysis, an approximately 40% increase in proteolysis, and an approximately 30% decline in HGP (all P < 0.05). Preventing the fasting-induced increase in GH with GHRH-A largely abolished the increase in the rate of lipolysis. GHRH-A also augmented the fasting-induced reduction in HGP but did not alter proteolysis.
Conclusions: Endogenous GH plays a very limited metabolic role during the daily feed/fast cycle but is essential for the increased lipolytic rate found with more prolonged fasting.
Pheochromocytoma is a rare adrenal gland tumor that is often difficult for physicians to diagnose because of its general, nonspecific complaints. Diagnosis is particularly difficult in patients with ...neurofibromatosis 1, because pheochromocytoma in these patients will mimic other cardiovascular abnormalities. The authors report the case of a 60-year-old woman with an extensive history of hyperlipidemia, malignant hypertension, coronary artery disease, and neurofibromatosis 1 who was referred for an elective cardiac catheterization as a result of an abnormal stress test. The patient returned to the hospital 3 days after the procedure complaining of increased angina and palpitations. While hospitalized, she developed severe episodic hypertension. A computed tomographic scan revealed bilateral adrenal masses. Findings of biochemical and imaging evaluation confirmed the diagnosis of bilateral pheochromocytoma. Early screening of pheochromocytomas in high-risk populations is essential for prompt diagnosis and successful management.
Abstract Study Objective To evaluate three evening insulin glargine dosing strategies for achievement of target (100–179 mg/dL; 5.5 - 9.8 mmol/L) and widened (80–249 mg/dL; 4.4 - 13.7 mmol/L) ...preoperative fasting blood glucose (FBG) ranges on the day of surgery. Design Prospective, randomized, open trial. Setting Preoperative units at two sites of a suburban hospital system. Patients 401 adult, ASA physical status 3 and 4 patients with type 1 and type 2 diabetes, undergoing elective noncardiac surgery. Interventions Patients were divided into two groups according to absence of daily rapid-acting/short-acting insulin (insulin glargine-only group) or presence of daily rapid-acting/short-acting insulin (insulin glargine plus bolus group). Subjects were then randomized to three evening insulin glargine dosing strategies: (a) take 80% of usual dose, (b) call physician for dose, or (c) refer to dosing table, based on self-reported usual FBG and insulin regimen. In the prehospital setting, patients administered the instructed insulin glargine dose on the evening before surgery. Measurements Venous blood glucose values were recorded in the preoperative holding area on the day of surgery. Main Results No significant differences in target preoperative FBG achievement were detected among strategies in the insulin glargine-only group (n = 174) or the insulin glargine plus bolus group (n = 227). In widened preoperative FBG achievement, no significant difference was noted among strategies in the insulin glargine-only group. In the insulin glargine plus bolus group, fewer subjects following the dosing table had FBG > 249 mg/dL (> 13.7 mmol/L; P = 0.031). Conclusions Target preoperative FBG achievement was similar among strategies in both insulin glargine groups. An insulin glargine adjustment strategy based on usual glycemic control may better prevent severe preoperative hyperglycemia in patients receiving basal/bolus regimens.
The diagnosis of acromegaly is suspected based on the typical clinical presentation and is subsequently confirmed biochemically by elevated GH and IGF-I concentrations.
We report three female ...patients with pituitary tumors who presented without any signs or symptoms of acromegaly but with elevated IGF-I levels. Plasma GH was measured every 10 min for 24 h, and an oral glucose tolerance test was performed. All patients had abnormally elevated mean and trough plasma GH levels as well as post-glucose nadir GH concentrations. All patients had magnetic resonance imaging scans revealing pituitary tumors and underwent transsphenoidal surgery. Histologically, they had GH-producing pituitary tumors. Plasma IGF-I levels returned to normal in two patients after surgery.
Some pituitary adenomas are true GH-secreting tumors despite not being accompanied by obvious clinical stigmata of acromegaly. Natural history of this disease is unknown because of the small number of reported patients and inconsistent results of biochemical testing. Based on the results of this and previous reports, we propose that all patients with known pituitary tumors, especially younger women with normal or mildly elevated prolactin level, be evaluated for GH excess.
BACKGROUND:Transsphenoidal surgery is the standard approach for treating Cushing disease. Evidence is needed to document effectiveness.
OBJECTIVE:To analyze results of transsphenoidal surgery in 276 ...consecutive patients, including 19 children.
METHODS:Medical records were reviewed for patients treated initially with surgery for Cushing disease from 1980 to 2012. Radiographic features, pathology, remissions, recurrences, and complications were recorded. Patients were categorized for statistical analysis based on tumor size (microadenomas, macroadenomas, and negative imaging) and remission type (type 1 = morning cortisol ≤3 μg/dL; type 2 = morning cortisol normal).
RESULTS:Females comprised 78% of patients and were older than men. Imaging showed 50% microadenomas, 13% macroadenomas, and 37% negative for tumor. Remission rates for microadenomas, macroadenomas, and negative imaging were 89%, 66%, and 71%, respectively. Patients with microadenomas were more likely to have type 1 remission. Pathology showed adrenocorticotropic hormone-secreting adenomas in 82% of microadenomas, in 100% of macroadenomas, and in 43% of negative imaging. The incidence of hyperplasia was 8%. The finding of hyperplasia or no tumor on pathology predicted treatment failure. The recurrence rate was 17%, with an average time to recurrence of 4.0 years. Patients with type 1 remission had a lower rate of recurrence (13% type 1 vs 50% type 2) and a longer time to recurrence. Children had similar imaging findings, remission rates, and pathology. There were no operative deaths.
CONCLUSION:Transsphenoidal surgery provides a safe and effective treatment for Cushing disease. For both adults and children, the best outcomes occurred in patients with microadenomas and/or those with type 1 remission.
ABBREVIATIONS:ACTH, adrenocorticotropic hormoneIPSS, inferior petrosal sinus sampling
Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in ...the Notch3 gene altering the number of cysteine residues. Methods We directly sequenced exons 2–23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls. Results We identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations. Conclusions In our sample, 60% of Russian patients with ‘clinically suspected’ CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening.
Many medical specialists investigated the role of NO and NO-synthases in biological systems. To our mind, many incomprehensible phenomena and facts that are contradictory at the first sight could be ...explained based on the concepts of the nitric oxide and superoxide anion radical cycles 1,2. Relevance histochemical research on the dynamics NO-synthase/NADPH-diaphorase in biopsies of peripheral nerve due to the fact that they can give an answer to the question: how Schwann cells using intracellular “nanotechnology” with NO, solve problems repair nerve conductive paths in normal conditions and pathology 3.
We examined the NADPH-diaphorase histochemistry in Guillain–Barre syndrome in the six peripheral nerve biopsies in the period from 11 to 52days. Tissue samples were examined by electron microscopy and light and electron microscopy NADPH-diaphorase histochemistry, using the tetrazolium method in our modification 3,4. This modification allowed the visualization of one the same object on adjacent sections at the level of light and electron histochemistry.
We have investigated the localization of marker NO-synthase/NADPH-diaphorase in peripheral nerve biopsy of the skin (nerve suralis), taken at different stages of the flow of severe Guillain–Barre syndrome-an inflammatory demyelinating disease. It has been shown that, depending on the stage of the disease, changes in the distribution of NO-synthase/NADPH-diaphorase in Schwann and immune cells. The dynamics of growth and decline NO-synthase/NADPH-diaphorase activity in these cells was different. These data suggest that the activation of the mechanism of demyelination in Schwann cells surrounding the peripheral nerves of the skin, changes NO-synthase/NADPH-diaphorase distribution, which may indicate the important role of NO and products of metabolism in the development of Guillain–Barre syndrome.
Comparison of the results of light and electron histochemistry, with survey data obtained by electron microscopy and ultrastructural pathology allowed to associate with the cellular and sub-cellular parameters reflecting NO-synthase/NADPH-diaphorase localization and activity of this enzyme. Histochemical analysis of data on changes in NO-synthase/NADPH-diaphorase Schwann and immune cells in the development of Guillain–Barre syndrome-a demyelinating disease conducted from the standpoint of normal physiological disorders of regulatory mechanisms that operate in a cyclic or periodic mode 1–4.
Supported by a research grant from RFFI.
Patients with diabetes who use insulin pumps continuous subcutaneous insulin infusion (CSII) undergo surgeries that require postoperative hospital admission. There are no defined guidelines for CSII ...perioperative use.
This retrospective single-institution study identified type 1 and type 2 diabetes subjects by electronically searching 2005-2010 anesthesia preoperative assessments for "pump." Surgical cases (n = 92) were grouped according to intraoperative insulin delivery method: (a) CSII continuation of basal rate with/without correctional insulin bolus(es) (n = 53); (b) conversion to intravenous insulin infusion (n = 20); and (c) CSII suspension with/without correctional insulin bolus(es) (n = 19). These groups were compared on mean intraoperative blood glucose (BG) and category of most extreme intraoperative BG.
Differences were found on baseline characteristics of diabetes duration (p = .010), anesthesia time (p = .011), proportions receiving general anesthesia (p = .013), and preoperative BG (p = .033). The conversion group had the longest diabetes duration and anesthesia time; it had a higher proportion of general anesthesia recipients and a higher mean preoperative BG than the continuation group. There was no significant difference in mean BG/surgical case between continuation (163.5 ± 58.5 mg/dl), conversion (152.3 ± 28.9 mg/dl), and suspension groups (188.3 ± 44.9 mg/dl; p = .128). The suspension group experienced a greater percentage of cases (84.2%) with one or more intraoperative BG > 179 mg/dl than continuation (45.3%) and conversion (40%) groups Figure 1 groupings (p = .034).
In this limited sample, preliminary findings are consistent with similar intraoperative glycemic control between CSII continuation and CSII conversion to intravenous insulin infusions. Continuous subcutaneous insulin infusion suspension had a greater rate of hyperglycemia. Preoperative differences between insulin delivery groups complicate interpretations of findings.
Context: It is unclear whether the pattern of GH delivery to peripheral tissues has important effects.
Objective: The aim of the study was to compare the effects of pulsatile vs. continuous ...administration of GH upon metabolic and IGF-I parameters in obese subjects.
Setting: The study was conducted at the General Clinical Research Center at the University of Michigan Medical Center.
Participants: Four men and five women with abdominal obesity (body mass index, 33 ± 3 kg/m2; body fat, 40 ± 3%) participated in the study.
Intervention: GH (0.5 mg/m2 · d) was given iv for 3 d as: 1) continuous infusion (C); and 2) pulsatile boluses (P) (15% of the dose at 0700, 1300, and 1800 h and 55% at 2400 h). These trials were preceded by a basal period (B) when subjects received normal saline.
Main Outcome Measures: Rate of lipolysis and hepatic glucose production were evaluated using stable isotope tracer techniques. The composite index of insulin sensitivity (Matsuda index) was assessed using oral glucose tolerance test.
Results: The increase in plasma IGF-I concentrations was greater (P < 0.05) with continuous GH infusion (211 ± 31, 423 ± 38, and 309 ± 34 μg/liter for B, C, and P, respectively). Muscle IGF-I mRNA was significantly increased (P < 0.05) only after the continuous GH infusion (1.2 ± 0.4, 4.4 ± 1.3, and 2.3 ± 0.6 arbitrary units, for B, C, and P, respectively). Only pulsatile GH augmented the rate of lipolysis (4.1 ± 0.3, 4.8 ± 0.7, and 7.1 ± 1.1 μmol/kg · min for B, C, and P, respectively). GH had no effect on hepatic glucose production, but both modes of GH administration were equally effective in impairing insulin sensitivity.
Conclusion: These findings indicate that, in obese subjects, discrete components of GH secretory pattern may differentially affect IGF-I generation and lipolytic responses.
In obese subjects, GH regulated different physiological parameters (e.g., lipolytic rate, IGF-1 production) in a tissue- and pattern-specific manner.
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