Metformin is the key factor for elevated plasma GDF-15 levels in type 2 diabetes:a nested, case-control study

Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case–control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin

Phosphodiesterases and cAMP pathway in pituitary diseases

© 2019 Bizzi, Bolger, Korbonits and Ribeiro-Oliveira. Human phosphodiesterases (PDEs) comprise a complex superfamily of enzymes derived from 24 genes separated into 11 PDE gene families (PDEs 1-11), expressed in different tissues and cells, including heart and brain. The isoforms PDE4, PDE7, and PDE8 are specific for the second messenger cAMP, which is responsible for mediating diverse physiological actions involving different hormones and neurotransmitters. The cAMP pathway plays an important role in the development and function of endocrine tissues while phosphodiesterases are responsible for ensuring the appropriate intensity of the actions of this pathway by hydrolyzing cAMP to its inactive form 5'-AMP. PDE1, PDE2, PDE4, and PDE11A are highly expressed in the pituitary, and overexpression of some PDE4 isoforms have been demonstrated in different pituitary adenoma subtypes. This observed over-expression in pituitary adenomas, although of unknown etiology, has been considered a compensatory response to tumorigenesis. PDE4A4/5 has a unique interaction with the co-chaperone aryl hydrocarbon receptor-interacting protein (AIP), a protein implicated in somatotroph tumorigenesis via germline loss-of-function mutations. Based on the association of low PDE4A4 expression with germline AIP-mutation-positive samples, the available data suggest that lack of AIP hinders the upregulation of PDE4A4 protein seen in sporadic somatotrophinomas. This unique disturbance of the cAMP-PDE pathway observed in the majority of AIP-mutation positive adenomas could contribute to their well-described poor response to somatostatin analogs and may support a role in tumorigenesis.We are grateful for the support by Fundação de Amparo à Pesquisa de Minas Gerais—Fapemig (AR-O), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (AR-O, MB) and the Medical Research Council UK (MK), and the NIH, USA (GB)

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms.

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis

Diabetes in the older patient : heterogeneity requires individualisation of therapeutic strategies

Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.(VLID)358448

Factors predicting long-term comorbidities in patients with Cushings syndrome in remission

Purpose In Cushings syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushings syndrome in remission. Methods In a retrospective cross-sectional study, 118 patients with Cushings syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 238) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis. Results In patients with manifest comorbidities at diagnosis, remission of Cushings syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushings cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids. Conclusions Long-term comorbidities after remission of Cushings syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushings syndrome.(VLID)363261

Characterization of GPR101 transcripts structure and expression patterns

We recently showed that Xq26.3 microduplications cause X-linked acrogigantism (X-LAG). X-LAG patients mainly present with growth hormone and prolactin-secreting adenomas and share a minimal duplicated region containing at least four genes. GPR101 was the only gene highly expressed in their pituitary lesions, but little is known about its expression patterns. GPR101 transcripts were characterized in human tissues by 5’-RACE and RNAseq, while the putative promoter was bioinformatically predicted. We investigated GPR101 mRNA and protein expression by RT-qPCR, whole-mount in situ hybridization, and immunostaining, in human, rhesus monkey, rat, and zebrafish. We identified four GPR101 isoforms characterized by different 5’ untranslated regions (UTRs) and a common 6.1 kb-long 3’UTR. GPR101 expression was very low or absent in almost all adult human tissues examined, except for specific brain regions. Strong GPR101 staining was observed in human fetal pituitary and during adolescence, whereas very weak/absent expression was detected during childhood and adult life. In contrast to humans, adult pituitaries of monkey and rat expressed GPR101, but in different cell types. Gpr101 is expressed in the brain and pituitary during rat and zebrafish development; in rat pituitary Gpr101 is expressed only after birth and showed sexual dimorphism. This study shows that different GPR101 transcripts exist and that the brain is the major site of GPR101 expression across different species, although divergent species- and temporal-specific expression patterns are evident. These findings suggest an important role for GPR101 in brain and pituitary development and likely reflect the very different growth, development and maturation patterns among species