John Lindsay

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes

Aims  Glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half‐life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action.

Demonstration of Glycated Insulin in Human Diabetic Plasma and Decreased Biological Activity Assessed by Euglycemic-Hyperinsulinemic Clamp Technique in Humans

The presence and biological significance of circulating glycated insulin has been evaluated by high-pressure liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI-MS), radioimmunoassay (RIA), receptor binding, and hyperinsulinemic-euglycemic clamp techniques. ESI-MS analysis of an HPLC-purified plasma pool from four male type 2 diabetic subjects (HbA(1c) 8.1 +/- 0.2%, plasma glucose 8.7 +/- 1.3 mmol/l [means +/- SE]) revealed two major insulin-like peaks with retention times of 14-16 min. After spectral averaging, the peak with retention time of 14.32 min exhibited a prominent triply charged (M+3H)(3+) species at 1,991.1 m/z, representing monoglycated insulin with an intact M(r) of 5,970.3 Da. The second peak (retention time 15.70 min) corresponded to native insulin (M(r) 5,807.6 Da), with the difference between the two peptides (162.7 Da) representing a single glucitol adduct (theoretical 164 Da). Measurement of glycated insulin in plasma of type 2 diabetic subjects by specific RIA gave circulating levels of 10.1 +/- 2.3 pmol/l, corresponding to approximately 9% total insulin. Biological activity of pure synthetic monoglycated insulin (insulin B-chain Phe(1)-glucitol adduct) was evaluated in seven overnight-fasted healthy nonobese male volunteers using two-step euglycemic-hyperinsulinemic clamps (2 h at 16.6 micro g x kg(-1) x min(-1), followed by 2 h at 83.0 micro g x kg(-1) x min(-1); corresponding to 0.4 and 2.0 mU x kg(-1) x min(-1)). At the lower dose, the exogenous glucose infusion rates required to maintain euglycemia during steady state were significantly lower with glycated insulin (P < 0.01) and approximately 70% more glycated insulin was required to induce a similar rate of insulin-mediated glucose uptake. Maximal responses at the higher rates of infusion were similar for glycated and control insulin. Inhibitory effects on endogenous glucose production, insulin secretion, and lipolysis, as indicated by measurements of C-peptide, nonesterified free fatty acids, and glycerol, were also similar. Receptor binding to CHO-T cells transfected with human insulin receptor and in vivo metabolic clearance revealed no differences between glycated and native insulin, suggesting that impaired biological activity is due to a postreceptor effect. The present demonstration of glycated insulin in human plasma and related impairment of physiological insulin-mediated glucose uptake suggests a role for glycated insulin in glucose toxicity and impaired insulin action in type 2 diabetes.

The Postoperative Basal Cortisol and CRH Tests for Prediction of Long-Term Remission from Cushing's Disease after Transsphenoidal Surgery

CONTEXT Selective adenomectomy via transsphenoidal surgery induces remission of Cushings disease (CD) in most patients. Although an undetectable postoperative serum cortisol (<2 μg/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence. OBJECTIVE We hypothesized that patients with subnormal cortisol (2-4.9 μg/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence. DESIGN, SETTING, AND PARTICIPANTS We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery. INTERVENTION AND MAIN OUTCOME MEASURES Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10. RESULTS Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 μg/dl (87%) than below 5 μg/dl (98%), yet recurrence rates were similar (<2 μg/dl, 9.5%; <5 μg/dl, 10.4%; 2-4.9 μg/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred. CONCLUSIONS A postoperative cortisol below 2 μg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 μg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up.

The diagnosis and investigation of adrenal insufficiency in adults

There is considerable variation in the methods used to diagnose and investigate adrenal insufficiency in clinical practice. These include a range of adrenocorticotropin (ACTH) stimulation and other dynamic testing protocols, serum cortisol cut-off values for diagnosis and tests used for differential diagnosis. With the introduction of modern cortisol and ACTH assays, the interpretation of tests used for diagnosis and differential diagnosis has become more complex and requires local validation. This review examines the basis of normal hypothalamic–pituitary–adrenal axis function and adrenal insufficiency states based upon an evidence base accumulated over the past four decades. The role of the laboratory in the differential diagnosis and interpretation based upon assay methodology is discussed. The accurate identification of patients who may benefit from corticosteroid replacement in special settings such as critical illness is challenging and will be explored.

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

BACKGROUND Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36+/-1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design. RESULTS Plasma glucose reached 18.2+/-1.7 and 16.7+/-1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9+/-1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9+/-0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6+/-163.9 pmol/l (P<0.05) and 11.8+/-1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC(50) values of 17.1 and 2.1 microM respectively. CONCLUSIONS Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

Inadequate growth hormone suppression following an octreotide test dose predicts the need for adjuvant therapy to achieve ‘safe’ growth hormone levels

Because the available data on large population samples in Italy are limited, we would like to offer recent findings from our observational study, in which serum 25-hydroxyvitamin D3 concentrations [25(OH)D] were measured using an automated chemiluminescence immunoassay (DiaSorin LIAISON, Stillwater, MN, USA; withinand between-assay precision below 9% and 13%; analytical and functional sensitivity of 12·5 and 17·5 nmol/l, respectively) in a large sample of individuals with a wide range of age (6 months − 103 years). We studied 6403 (male/female = 1299/5104) medical inpatients and outpatients who consecutively attended the laboratory of the Hospital of Vicenza (a town in Northern Italy) for 25(OH)D measurements during the last 3 years. The mean ( ± SD) serum 25(OH)D concentration for the whole population was 45·0 ± 42 nmol/l (median 36; range 12·5–862). As shown in Table 1, there was a strong, inverse, association between serum 25(OH)D levels and age both in men and women. No significant seasonal differences in serum 25(OH)D measurements were found. Among these subjects, 52·5% ( n = 3359) had a serum 25(OH)D concentration ≤ 37·5 nmol/l with percentages steadily increasing with advancing age and ranging from 26·9% to 72·9% in men and from 39·1% to 74·8% in women. Approximately 20% ( n = 1299) of subjects had a very low 25(OH)D concentration ( ≤ 12·5 nmol/l) with percentages ranging from 11·1% to 40·2% in men and from 12·5% to 43·1% in women. Because this is not a population-based study, we stress that our results do not apply to non-institutionalized people, among whom vitamin D deficiency may be (much) lower. In conclusion, we found a high prevalence of vitamin D deficiency among unselected medical inpatients and outpatients, with a wide range of age, living in Northern Italy. Because of the potential adverse effects of vitamin D deficiency on the skeleton and other organ systems, widespread screening for vitamin D deficiency or routine vitamin D supplementation should be seriously considered. Massimo Cigolini*, Valentino Miconi*, Giuliano Soffiati†, Antonio Fortunato†, Maria Pina Iagulli*, Simonetta Lombardi* and Giovanni Targher‡ * Observatory of Clinical Epidemiology ‘Sen. D. Giacometti’, Department of Medicine, Hospital of Arzignano; † Laboratory of Clinical Chemistry, ‘San Bortolo’ Hospital, Vicenza; and ‡ Division of Internal Medicine, ‘Sacro Cuore’ Hospital, Negrar, Italy

Effects of nateglinide on the secretion of glycated insulin and glucose tolerance in type 2 diabetes

AIMS Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes. METHODS Ten patients (5 M/5 F, age 57.8+/-1.9 years, HbA(1c) 7.6+/-0.5%, fasting plasma glucose 9.4+/-1.2 mmol/l, creatinine 81.6+/-4.5 microM/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min. RESULTS Plasma glucose and glycated insulin responses were reduced by 9% (P=0.005) and 38% (P=0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P=0.005) and 25% (P=0.007) by nateglinide. CONCLUSIONS Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the antihyperglycaemic action of nateglinide.

Hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland

Tumours metastasizing to the pituitary gland are uncommon. Symptomatic patients with pituitary metastases can present with diabetes insipidus, headache, visual field defects and/or anterior pituitary hormonal dysfunction. Treatment options for pituitary metastases include, surgical resection, cranial or parasellar irradiation and/or chemotherapy, and hormonal replacement if indicated. The overall prognosis of pituitary metastases is poor. We present a case of hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.

Sustained improvement in vision in a recurrent growth hormone secreting macroadenoma during treatment with octreotide in the absence of marked tumour shrinkage.

Visual improvement following octreotide for growth hormone secreting pituitary macroadenomas is uncommon without tumour shrinkage. A 45-year old lady presented with blurred vision for 12 months. Visual assessment revealed a bitemporal hemianopia and CT scan demonstrated a large pituitary tumour with lateral and suprasellar extension. Acromegaly was confirmed by 75 g glucose tolerance testing. Primary transsphenoidal surgery was performed with normalisation of visual acuity and fields of vision. Post-operatively she had anterior pituitary hormone deficiency. As GH and IGF-1 levels remained elevated she underwent external pituitary irradiation. CT scanning demonstrated tumour shrinkage associated with a modest fall in GH levels. IGF-1 levels remained elevated falling to the age-related upper limit of normal after 5 years. At regular review she had stable visual acuity and fields of vision.She presented as an emergency 7 years from presentation with reduced vision and recurrence of bitemporal hemianopia. An MRI demonstrated a large pituitary adenoma. We therefore undertook a carefully monitored trial of octreotide with great caution with daily reassessment of acuity and fields. A decision was made to proceed to surgery in the event of deterioration or lack of improvement after a short trial over 5–7 days. We observed normalisation of visual acuity and perimetry within 3 days. She then commenced long-acting octreotide (Sandostatin LAR) 20 mg every 28 days. MRI after 1 week showed shrinkage of the tumour by a few millimetres. Five months later repeat MRI failed to show any further improvement in tumour size. However she remains well 29 months from treatment with normal vision and is being monitored carefully as her chosen form of therapy.Somatostatin analogues may be effective as therapy in a selected group of patients with acromegaly and visual loss who are not suitable for pituitary surgery. If used in this way the drug must be given cautiously with frequent detailed ongoing visual assessments. In this present case there has been a restoration of vision but the long-term outlook remains guarded without significant tumor shrinkage.