Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Corneal confocal microscopy as a non-invasive test to assess diabetic peripheral neuropathy.

OBJECTIVE: To evaluate the efficacy of corneal confocal microscopy (CCM) as a non-invasive test to assess diabetic peripheral neuropathy in Chinese patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Diabetic distal symmetric polyneuropathy (DSPN) and its severity degrees were assessed based on the modified Toronto diagnostic criteria in 128 patients with type 2 diabetes (No DSPN [n = 49], mild DSPN [n = 43], moderate-to-severe DSPN [n = 36]) and 24 age-matched controls. CCM was also examined in all enrolled subjects. Corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD) and corneal nerve fiber density (CNFD) were analyzed by Fiji imaging analysis software. The efficacy of CCM as a non-invasive test to assess diabetic peripheral neuropathy was determined. RESULTS: CNFL was 17.99 ±â€¯0.66, 15.82 ±â€¯0.64, 14.98 ±â€¯0.63, and 12.49 ±â€¯0.93 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNFL in type 2 diabetes patients with no, mild, and moderate-to-severe DSPN demonstrated a significant reduction than in healthy controls (P = .012, .003 and <.001, respectively). CNFL in patients with moderate-to-severe DSPN was significantly shorter than in patients with no or mild DSPN (P < .001 and .004, respectively). CNBD was 41.48 ±â€¯3.35, 33.02 ±â€¯2.50, 30.91 ±â€¯2.33, and 18.00 ±â€¯2.33 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNBD in healthy control was significantly higher than in type 2 diabetes patients with no, mild, and moderate-to-severe DSPN (P = .036, 0.016 and < .001, respectively). CNBD in patients with moderate-to-severe DSPN was significantly lower than in patients with no or mild DSPN (P < .001 for both). CNFD was 35.32 ±â€¯1.18, 35.68 ±â€¯1.10, 34.54 ±â€¯1.12, and 32.28 ±â€¯1.76 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNFD did not differ among the four groups. In an analysis that divided CNFL, CNFD and CNBD into quartiles, there were no significant differences in electromyography findings and vibration perception threshold among the 4 groups; however, significant differences were seen in the positive distribution of temperature perception measurements following CNFL and CNBD stratification (P = .001 and < .001, respectively). CONCLUSION: CCM might be a non-invasive method for detecting DSPN and its severity degree in Chinese patients diagnosed with type 2 diabetes.

Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.

RATIONALE: Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS: A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES: Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS: Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES: The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS: The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.

Recurrent gain-of-function USP8 mutations in Cushing's disease.

Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

Hyperglycemia induced by glucocorticoids in nondiabetic patients: a meta-analysis.

BACKGROUND/AIMS: Glucocorticoids are associated with a number of side effects including the development of new-onset hyperglycemia or diabetes. The diagnosis and treatment of glucocorticoid-induced hyperglycemia are surprisingly undervalued by many health-care professionals, probably due to the lack of quality studies that assess specific reasons for and prevention of hyperglycemia. The aim of this meta-analysis was to evaluate the long-term incidence of glucocorticoid-induced hyperglycemia and diabetes in nondiabetic patients who received glucocorticoid treatment. METHODS: We searched Medline, Embase, and the Cochrane Library (Central) until January 2014 for studies in which subjects received systematic glucocorticoid treatment and which evaluated whether subjects developed hyperglycemia or were diagnosed with diabetes following treatment. The primary outcome for this analysis was the incidence of hyperglycemia and the secondary outcome was the frequency of diabetes. RESULTS: We identified 13 studies that met our inclusion criteria; 12 of the studies were retrospective or observational in design. We found that the rate at which patients developed glucocorticoid-induced hyperglycemia or diabetes was 32.3% (p = 0.003) and 18.6% (p = 0.002), respectively. CONCLUSIONS: Our meta-analysis indicated that glucocorticoid-induced hyperglycemia occurs fairly frequently and points to the need for the design of prospective, randomized, controlled studies to further investigate and better understand this medical problem.

Improvement of myocardial glycolipid metabolic disorder in diabetic hamster with Astragalus polysaccharides treatment.

The objective of the present study is to observe the effect of Astragalus polysaccharide (APS) on myocardial glucose and lipid metabolism in diabetes (DM) hamster and to explore its mechanism in intervention of DM cardiomyopathy. Low-dose- streptozotocin-induced hamsters (STZ, 40 mg/kg × 3 days, i.p.) with blood glucose >13.9 mmo/L were considered as type 2 diabetic models. We measure blood glucose, serum lipid, insulin, C-peptide, myocardial enzyme levels, myocardial glycogen staining, myocardial ultrastructure, fluorescence quantitative RT-PCR detection of myocardial PPAR-α and the target genes (FATP, ACS) and GLUT4 mRNA expression in normal control group, DM group and APS treatment group hamsters. There was significant glycolipid metabolic disorders in DM group compared with normal group. Glucose, glycosylated serum protein, myocardial enzymes and lipid levels in APS treatment group decreased significantly than DM group, but insulin and C-peptide levels was no difference. Myocardial glycogen staining and abnormal myocardial ultrastructure in APS treatment group were significantly improved than in DM group. Gene expression of myocardial PPAR-α and its target genes (FATP, ACS) in APS group were significantly lower than in DM group, while gene expression of GLUT4 in APS group was higher than DM group. APS can partially improve myocardial glucose and lipid metabolism disorders in diabetic hamsters and protect myocardium in some extent.

Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes.

Fibroblast growth factor (FGF) 21 and growth hormone (GH) are metabolic hormones that play important roles in regulating glucose and lipid metabolism. Both hormones are induced in response to fasting and exert their actions on adipocytes to regulate lipolysis. However, the molecular interaction between these two hormones remains unclear. Here we demonstrate the existence of a feedback loop between GH and FGF21 on the regulation of lipolysis in adipocytes. A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. In FGF21-null mice, both the magnitude and duration of GH-induced lipolysis are significantly higher than those in their wild type littermates. Taken together, these findings suggest that GH-induced hepatic FGF21 production is mediated by FFA released from adipose tissues, and elevated FGF21 in turn acts as a negative feedback signal to terminate GH-stimulated lipolysis in adipocytes.

[An epidemiological study on diabetic retinopathy among type 2 diabetic patients in Shanghai].

OBJECTIVE: To investigate the prevalence and risk factors of diabetic retinopathy (DR) among type 2 diabetic patients aged over 30 in Shanghai central area. METHODS: 1039 patients diagnosed with type 2 diabetes mellitus (DM) aged over 30 were investigated by randomized cluster sampling in Shanghai central area and data from 767 of those patients were analyzed. RESULTS: (1) Among all of the 1534 digital ocular fundus images from 767 patients, 87.6% of the images from 672 patients were gradable. (2) Among all of the 672 patients with gradable ocular fundus images, the prevalence of non-proliferative diabetic retinopathy (NPDR) was 21.6%, while proliferative diabetic retinopathy (PDR) was 1.3%. The rates of mild, moderate and severe NPDR were 8.8%, 11.2% and 1.6% respectively. (3) DR patients were characterized with elder age, higher HbA1c, urea nitrogen and serum creatinine. DM duration and the level of fasting plasma glucose were risk factors for DR. CONCLUSION: The overall prevalence of DR in type 2 diabetic patients aged over 30 in Shanghai central area was 22.9% and the DR risk factors were found to include duration of diabetes and fasting plasma glucose level.