Intensification patterns and the probability of HbA1c goal attainment in Type 2 diabetes mellitus: real-world evidence for the concept of 'intensification inertia'.

AIMS: To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS: Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (<53 mmol/mol). RESULTS: The probability of HbA1c goal attainment (Kaplan-Meier analysis) in the group with index HbA1c 53-63 mmol/mol (7.0-7.9%) was highest with the addition of oral antidiabetic drugs [57.3% (95% CI 52.1, 62.0)] or glucagon-like peptide-1 receptor agonists [56.7% (95% CI 40.4, 68.6)], in the 64-74 mmol/mol (8.0-8.9%) group with the addition of oral antidiabetic drugs [31.9% (95% CI 25.1, 38.1)] or insulin [30.6% (95% CI 18.3, 41.0)], and in the ≥75 mmol/mol (≥9.0%) group with the addition of glucagon-like peptide-1 receptor agonists [53.0% (95% CI 31.8, 67.6)] or insulin [43.5% (95% CI 36.4, 49.8)]. CONCLUSIONS: Numerical, but not statistically significant, differences in HbA1c goal attainment probability by type of intensification were most marked in people with the highest index HbA1c [≥75 mmol/mol (≥9.0%)]; in this group, injectable therapy showed trends toward greater glycaemic control benefits. Additional research into the phenomenon of intensification inertia is warranted.

How safe is metabolic/diabetes surgery?

Although recent studies have shown the impressive antidiabetic effects of laparoscopic Roux-en-Y gastric bypass (LRYGB), the safety profile of metabolic/diabetes surgery has been a matter of concern among patients and physicians. Data on patients with type 2 diabetes who underwent LRYGB or one of seven other procedures between January 2007 and December 2012 were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database and compared. Of the 66 678 patients included, 16 509 underwent LRYGB. The composite complication rate of 3.4% after LRYGB was similar to those of laparoscopic cholecystectomy and hysterectomy. The mortality rate for LRYGB (0.3%) was similar to that of knee arthroplasty. Patients who underwent LRYGB had significantly better short-term outcomes in all examined variables than patients who underwent coronary bypass, infra-inguinal revascularization and laparoscopic colectomy. In conclusion, LRYGB can be considered a safe procedure in people with diabetes, with similar short-term morbidity to that of common procedures such as cholecystectomy and appendectomy and a mortality rate similar to that of knee arthroplasty. The mortality risk for LRYGB is one-tenth that of cardiovascular surgery and earlier intervention with metabolic surgery to treat diabetes may eliminate the need for some later higher-risk procedures to treat diabetes complications.

White fish reduces cardiovascular risk factors in patients with metabolic syndrome: the WISH-CARE study, a multicenter randomized clinical trial.

BACKGROUND AND AIMS: Reduction of cardiovascular risk with high consumption of fish in diet is still a matter of debate, and concerns about heavy metal contamination have limited consumption of oily fish. We aimed to evaluate the effect of regular ingestion of white fish on cardiovascular risk factors in patients with metabolic syndrome. METHODS AND RESULTS: Multicenter randomized crossover clinical trial including 273 individuals with metabolic syndrome. An 8-week only-one dietary intervention: 100 g/d of white fish (Namibia hake) with advice on a healthy diet, compared with no fish or seafood with advice on a healthy diet. Outcomes were lipid profile, individual components of the metabolic syndrome, serum insulin concentrations, homeostasis model of insulin resistance, serum C-reactive protein and serum fatty acid levels. We found a significant lowering effect of the intervention with white fish on waist circumference (P < 0.001) and diastolic blood pressure (P = 0.014). A significant lowering effect was also shown after the dietary intervention with fish on serum LDL concentrations (P = 0.048), whereas no significant effects were found on serum HDL or triglyceride concentrations. A significant rise (P < 0.001) in serum EPA and DHA fatty acids was observed following white fish consumption. Overall adherence to the intervention was good and no adverse events were found. CONCLUSION: In individuals with metabolic syndrome, regular consumption of hake reduces LDL cholesterol concentrations, waist circumference and blood pressure components of the metabolic syndrome. CLINICAL TRIAL REGISTRY: White Fish for Cardiovascular Risk Factors in Patients with Metabolic Syndrome Study, Registered under ClinicalTrials.gov Identifier: NCT01758601.

Correlation between brain interstitial and total serum cortisol levels in traumatic brain injury. A preliminary study.

INTRODUCTION: Brain cortisol availability has never been evaluated in patients with traumatic brain injury (TBI). Cerebral microdialysis is a well-established technique for monitoring brain metabolism in neurocritically ill patients, which may be used to measure interstitial cortisol. The objective of this preliminary study was to measure brain interstitial cortisol and its correlation with total serum cortisol in patients with TBI. METHODS: We prospectively studied 6 patients with severe TBI admitted to the Intensive Care Unit of our tertiary University Hospital in which multimodal neuromonitoring including cerebral microdialysis with a high cut-off of 100 k-Da and 20-mm long membrane was used. Serum and brain interstitial cortisol microdialysis samples were obtained every 8 h and analyzed afterwards. RESULTS: Linear regression analysis of total serum cortisol and brain interstitial cortisol in the whole population showed a moderate correlation (R2=0.538, p<0.001, no.=118). However, intra-individual correlation showed a great variability, with correlation coefficients ranging from a R2=0.091 to R2=0.680. CONCLUSION: Our prospective and preliminary study showed a moderate correlation of brain interstitial cortisol and total serum cortisol values in patients with diffuse TBI. However, intra-individual analysis showed a great variability. These results suggest that total serum cortisol may not reflect brain cortisol availability in half of TBI patients.

Effect of barbiturate coma on adrenal response in patients with traumatic brain injury.

INTRODUCTION: Barbiturate coma is the second tier measure recommended by guidelines to treat post-traumatic refractory intracranial pressure. Systemic hypotension is its most important side effect. Recent evidence suggests that low-dose corticosteroid therapy may be used in a subset of patients with traumatic brain injury (TBI) to avoid hypotension. We evaluated adrenal function in TBI patients undergoing barbiturate coma, as treatment of their refractory intracranial hypertension. MATERIALS AND METHODS: We prospectively studied 40 patients with moderate to severe TBI. Group A (17 patients) were treated with barbiturate coma. Group B (23 patients) presented intracranial hypertension controlled with first tier measures, and acted as a control. Adrenal function was evaluated by using the high-dose corticotropin stimulation test within 24 h after brain injury and after barbiturate coma induction. RESULTS: Within 24 h after TBI, adrenal function was similar in both groups. Once barbiturate coma was induced, patients in group A treated with barbiturate coma presented a higher incidence of adrenal insufficiency compared with the control group B (53% vs 22%, p=0.03). Patients treated with barbiturates, who developed adrenal impairment, required higher doses of norepinephrine to maintain cerebral perfusion pressure than patients treated with barbiturates without adrenal impairment (1.07+/-1.04 microg/kg/min vs 0.31+/-0.32 mug/kg/min, p=0.03). CONCLUSIONS: Patients with TBI treated with barbiturate coma are at higher risk of developing adrenal insufficiency. This subset of patients presented higher requirements of vasoactive support to avoid hypotension. In these patients corticosteroid therapy may have potential therapeutic implications to treat hemodynamic instability.

Critical assessment of the current guidelines for the management and treatment of morbidly obese patients.

An interdisciplinary panel of specialists met in Mallorca in the first European Symposium on Morbid Obesity entitled; "Morbid Obesity, an Interdisciplinary Approach". During the two and half days of the meeting, the participants discussed several aspects related to pathogenesis, evaluation, and treatment of morbid obesity. The expert panel included basic research scientists, dietitians and nutritionists, exercise physiologists, endocrinologists, psychiatrists, cardiologists, pneumonologists, anesthesiologists, and bariatric surgeons with expertise in the different weight loss surgeries. The symposium was sponsored by the Balearic Islands Health Department; however, this statement is an independent report of the panel and is not a policy statement of any of the sponsors or endorsers of the Symposium. The prevalence of morbid obesity, the most severe state of the disease, has become epidemic. The current recommendations for the therapy of the morbidly obese comes as a result of a National Institutes of Health (NIH) Consensus Conference held in 1991 and subsequently reviewed in 2004 by the American Society for Bariatric Surgery. This document reviews the work-up evaluation of the morbidly obese patient, the current status of the indications for bariatric surgery and which type of procedure should be recommended; it also brings up for discussion some important real-life clinical practice issues, which should be taken into consideration when evaluating and treating morbidly obese patients. Finally, it also goes through current scientific evidence supporting the potential effectiveness of medical therapy as treatment of patients with morbid obesity.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

UNLABELLED: Brackground:The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. OBJECTIVE: Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. METHODS: Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m(-)(2) participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. RESULTS: No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. CONCLUSIONS: The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients.

Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene expression in kidney.

Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney, which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy, one of the major complications of diabetes mellitus, we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney, which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor, there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly, IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain, we hypothesize that, among other factors, high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes, although a role for this receptor in signal transduction cannot be excluded. Finally, the possible role of IGF-binding proteins requires further study.

Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats.

Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a highfat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (Vp) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (125I and 131I) to separately determine the PS and Vp values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml x g(-1) x ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The Vp values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study.

Liver regeneration is associated with increased expression of the insulin-like growth factor-II/mannose-6-phosphate receptor.

The process of liver regeneration involves the concerted action of certain growth factors, which stimulate hepatocyte proliferation, and other antiproliferative factors, which prevent uncontrolled growth of this organ. Some of the biological actions of insulin-like growth factor-II (IGF-II), a mitogenic polypeptide closely related to insulin, may be mediated by the IGF-II receptor. This receptor consists of a single chain extracellular domain and a very small cytoplasmic domain, and can bind lysosomal enzymes that contain mannose-6-phosphate (M-6-P) residues. Since these enzymes may be involved in remodelling processes in certain tissues, we measured the expression of the IGF-II/M-6-P receptor in the liver after subtotal hepatectomy. Binding of [125I]IGF-II to crude plasma membranes from regenerating liver was maximal 2 days after hepatectomy (4.9% specific binding/60 micrograms protein) and subsequently decreased. Both control livers (livers removed at the time of operation) and sham-operated control livers demonstrated specific [125I]IGF-II binding of 1.1% throughout the experimental period. This increase in binding in regenerating liver was shown to be associated with an increase in the concentration of IGF-II receptor protein by means of Western blot analysis using a polyclonal anti-IGF-II/M-6-P receptor antiserum (3637). Similarly, steady state levels of IGF-II/M-6-P receptor mRNA, measured by solution hybridization/RNase protection assays, were significantly increased in the regenerating liver (2.0-fold over the control value 2 days after hepatectomy). Five and 10 days postsurgery, the levels of IGF-II receptor mRNA were markedly reduced, and they were even lower than the levels in control livers.(ABSTRACT TRUNCATED AT 250 WORDS)

Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes.

Both bone mass and serum leptin levels are increased in obesity. Because osteoblasts and adipocytes arise from a common precursor in bone marrow, we assessed the effects of human recombinant leptin on a conditionally immortalized human marrow stromal cell line, hMS2-12, with the potential to differentiate to either the osteoblast or adipocyte phenotypes. By RT-PCR and Western immunoblot analysis, the hMS2-12 cells expressed messenger RNA (mRNA) and protein for the leptin receptor. Leptin did not affect hMS2-12 cell proliferation, but resulted in dose- and time-dependent increases in mRNA and protein levels of alkaline phosphatase, type I collagen, and osteocalcin, and in a 59% increase in mineralized matrix. Leptin increased mRNA levels of lipoprotein lipase at 3 days, but decreased mRNA levels of adipsin and leptin at 9 days and decreased lipid droplet formation by 50%. Leptin did not affect the expression of Cbfa1 or peroxisome proliferator-activated receptor-gamma2, transcription factors involved in commitment to the osteoblast and adipocyte pathways, respectively. Thus, leptin acts on human marrow stromal cells to enhance osteoblast differentiation and to inhibit adipocyte differentiation. Our data support the hypothesis that leptin is a previously unrecognized, physiological regulator of these two differentiation pathways, acting primarily on maturation of stromal cells into both lineages.

Leptin and leptin receptor expression in rat and mouse pituitary cells.

Leptin is a circulating hormone secreted mainly by adipose tissue. Recent studies have shown leptin production by other tissues, including the placenta, stomach, and mammary tissues. Various reports have suggested that the anterior pituitary may have a role in the regulatory effects of leptin. We recently localized leptin in the human anterior pituitary, but analysis of leptin in rodent pituitary has not been previously reported. In this study we examined rat and mouse pituitary tissues and various cell lines for leptin by RT-PCR, immunohistochemistry, and Western blotting. Leptin receptor messenger RNA was also examined in these tissues by RT-PCR. Leptin was present in a small percentage of rat (4.8 +/- 0.7%) and mouse (7 +/- 2%) pituitary cells. Colocalization studies with leptin and pituitary hormones showed leptin expression mainly in TSH cells (24 +/- 2% of TSH cells in the rat pituitary and 31 +/- 1% of TSH cells in the mouse pituitary). A folliculo-stellate (FS) cell line, TtT/GF, also expressed leptin. The long isoform of leptin receptor (OB-Rb) was present in normal pituitary and in various pituitary cell lines, including FS, GH3, and alphaT3-1 cells. Treatment of GH3 and FS cells with leptin (1 x 10(-8) M) inhibited cell proliferation assessed by [3H]thymidine incorporation in GH3, but not in FS, cells. These findings show for the first time that leptin is expressed in rat and mouse anterior pituitaries mainly by TSH cells and by a mouse FS cell line. The finding of leptin and of the long isoform of leptin receptor in normal rat and mouse pituitaries and in various cell lines implicates an autocrine/paracrine loop in the production and regulation of leptin and leptin receptor in the rodent pituitary.

Leptin reduces ovariectomy-induced bone loss in rats.

Bone mineral density increases with fat body mass, and obesity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and directly related to fat body mass. We report here the effects of leptin administration compared with estrogen therapy on ovariectomy-induced bone loss in rats. Leptin was effective at reducing trabecular bone loss, trabecular architectural changes, and periosteal bone formation. Interestingly, the combination of estrogen and leptin further decreased bone turnover compared with that in estrogen-treated ovariectomized rats. Leptin also significantly increased osteoprotegerin mRNA steady state levels and protein secretion and decreased RANK ligand mRNA levels in human marrow stromal cells in vitro. Our findings suggest that leptin could modulate bone remodeling in favor of a better bone balance in rats. This study is the first evidence that leptin therapy has a significant effect in preventing ovariectomy-induced bone loss, and this effect may at least in part be mediated by the osteoprotegerin/RANK ligand pathway.

Acute administration of corticoids: a new and peculiar stimulus of growth hormone secretion in man.

It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.

The interaction of proinsulin with the insulin-like growth factor-I receptor in human liver, muscle, and adipose tissue.

Because of the sequence homology and tertiary structure similarities between proinsulin (PI) and insulin-like growth factor-I (IGF-I), it is possible that PI interacts with the IGF-I receptor with higher affinity than insulin. To test this hypothesis in man, we have partially purified IGF-I receptors from liver, muscle, and adipose tissue and studied their interaction with PI, insulin, IGF-I, and IGF-II. With some tissue to tissue variation, [125I]insulin binding was 4- to 8-fold greater than IGF-I binding. Unlabeled IGF-I at about 1 x 10(-9 M, IGF-II at about 1 x 10(-8) M, and insulin at about 1 x 10(-6) M displace 50% the binding of [125I]IGF-I to its receptor, whereas PI at 1 x 10(-6) M displaces less than 20% of the binding of [125I]IGF-I to its receptor. We conclude that in human liver, muscle, and adipose tissue, PI does not interact with the IGF-I receptor at a higher affinity than insulin, and the affinity of IGF-I receptors is several-fold lower than that of insulin receptors. It is, therefore, unlikely that if PI were to be administered to man any of its biological effects would be by interacting with the IGF-I receptor.

Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation.

Leptin is a circulating hormone secreted by adipose and a few other tissues. The leptin receptor consists of a single transmembrane-spanning polypeptide that is present as a long physiologically important form as well as in several short isoforms. Recent studies have suggested that the anterior pituitary may have a role in the regulatory effects of leptin in animal models. To test this possibility in human pituitaries, we examined the expression of leptin and OB-R in normal and neoplastic pituitaries, and the possible functions of leptin in the pituitary were also analyzed. Leptin was present in 20-25% of anterior pituitary cells and was expressed in most normal anterior pituitary cells, including ACTH (70% of ACTH cells), GH (21%), FSH (33%), LH (29%), TSH (32%), and folliculo-stellate cells (64%), but was colocalized with very few PRL cells (3%), as detected by double labeling immunohistochemistry with two different antileptin antibodies. In addition, leptin expression was detected by RT-PCR in some pituitary tumors, including ACTH (three of four), GH (one of four), null cells (two of four), and gonadotroph (one of four) tumors as well as in normal pituitary. Immunohistochemical staining showed greater immunoreactivity for leptin in normal pituitaries compared to adenomas. Treatment of an immortalized cultured anterior pituitary cell line, HP75, with leptin stimulated pancreastatin secretion in vitro. Leptin also inhibited cell growth in the human HP75 and in the rat pituitary GH3 cell lines. Both long (OB-Rb) and common (OB-Ra) forms of the leptin receptor messenger ribonucleic acid and leptin receptor protein were expressed in normal and neoplastic anterior pituitary cells. These findings show for the first time that leptin is expressed by most human anterior pituitary cell types and that there is decreased leptin protein immunoreactivity in pituitary adenomas compared to that in normal pituitary tissues. We also show that OB-Rb is widely expressed by normal and neoplastic anterior pituitary cells, implicating an autocrine/paracrine loop in the production and regulation of leptin in the pituitary.

High dose intravenous, but not low dose subcutaneous, insulin-like growth factor-I therapy induces sustained insulin sensitivity in severely resistant type I diabetes mellitus.

We have previously demonstrated weekly iv insulin-like growth factor-I (IGF-I; 500 micrograms/kg) bolus therapy to be effective in inducing sustained insulin sensitivity in a patient with type I diabetes mellitus and massive insulin resistance. The present study was undertaken to determine the efficacy of daily sc IGF-I in the treatment of two severely insulin-resistant type I diabetic patients (requiring in excess of 3500 U insulin/day) compared to weekly iv IGF-I therapy. Prolonged insulin sensitivity was achieved in both patients after weekly 500 micrograms/kg iv bolus infusions of IGF-I, with sc insulin requirements falling to approximately 1 U/kg.day. Smaller iv doses (250 micrograms/kg) of IGF-I were ineffective in acutely lowering serum glucose or inducing sustained insulin sensitivity. However, even this smaller IGF-I dose resulted in acute symptomatic hypophosphatemia, which could be prevented by coadministration of potassium phosphate. With sc administered IGF-I (up to 10 mg twice daily), insulin appeared to control patient glucose concentrations, but severe insulin resistance returned within 72 h of discontinuing IGF-I therapy. IGF-I dosing was decreased to the lowest concentration that maintained euglycemia (7.5 mg in the morning and 2.5 mg in the evening). However, severe arthropathy in both patients and neurological symptoms including multiple cranial nerve palsies in one patient were associated with chronic therapy. We conclude that both iv and sc administered IGF-I can precipitate acute symptomatic hypophosphatemia. Chronic low dose sc therapy may be associated with severe neuropathy and arthropathy, and does not induce the sustained insulin sensitivity associated with high dose intermittent bolus IGF-I therapy.

Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E2) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E2 having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.

Thyroid incidentalomas. Prevalence, diagnosis, significance, and management.

Thyroid incidentalomas are common, always impalpable, often less than 1.5 cm in size, and frequently benign. The authors recommend that low-risk patients with incidentalomas be followed up with clinical palpation in 6 to 12 months and not be subjected to routine testing with US-FNA. In the authors' strategy, fine-needle aspiration is reserved for an impalpable nodule and is performed under ultrasonographic guidance in the high-risk group of patients in whom either the imaging features or the clinical history is worrisome for malignancy. It does not seem necessary, practical, or cost-effective to perform biopsy or to excise surgically all impalpable nodules. Because of the high prevalence of thyroid incidentalomas, most of which are benign, a nonsurgical approach is logical.

Subcellular localization of leptin in non-tumorous and adenomatous human pituitaries: an immuno-ultrastructural study.

Leptin is a key mediator in the maintenance of neuroendocrine homeostasis. Recently, leptin and leptin receptor expression were demonstrated in non-tumorous and adenomatous human pituitaries. This study was performed to determine the subcellular localization of leptin in human adenohypophyses (n = 3) and in various types of pituitary adenoma (n = 16). Immunoelectron microscopy showed leptin immunolabeling in most hormone-producing cells of the human non-tumorous adenohypophysis, but not in stellate cells. Labeling was noted over secretory granules. Immunocytochemistry using double labeling revealed leptin expression in GH-, ACTH-, TSH-, and FSH/LH-containing cells but not in PRL cells. The percentage of immunopositive cells and the intensity of immunostaining varied considerably among the various cell types. Immunoelectron microscopy with double gold labeling showed co-localization of leptin and adenohypophysial hormones in the same secretory granules. Among pituitary tumors, leptin immunolabeling was evident only in corticotroph adenomas. Compared to non-tumorous corticotrophs, leptin immunoexpression was less abundant in corticotroph adenomas. The presence of leptin and adenohypophysial hormones in the same secretory granules suggests that leptin is secreted concomitantly with various adenohypophysial hormones and that its release is under the control of hypothalamic stimulating and inhibiting hormones.