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Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients.

ABSTRACT: Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2^-/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2^-/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2^-/- mice lack this compensatory mechanism. Contrary, BP fed STC2^-/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2^-/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2^-/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus.

SUBMITTER: Lopez JJ

PROVIDER: S-EPMC5742690 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To address the possible involvement of VGF peptides in obesity and diabetes, we studied type 2 diabetes (T2D) and obese patients, and high-fat diet induced obese mice. Two VGF peptides (NAPP-19 and QQET-30) were identified in human plasma by HPLC-ESI-MS. The VGF C-terminus, the above two cleaved peptides, and the TLQP-21 related peptide/s were studied using ELISA and immunohistochemistry. In euglycemic patients, plasma NAPPE and TLQP like peptides were significantly reduced with obesity (74±10 vs. 167±28, and 92±10 vs. 191±19 pmol/ml, mean+SEM, n = 10 and 6, obese vs. normal BMI, respectively, p<0.03). Upon a standard glucose load, a distinct response was shown for VGF C-terminus, TLQP and QQET-like (ERVW immunoreactive) peptides in euglycemic normal BMI patients, but was virtually abolished in euglycemic obese, and in T2D patients independently of BMI. High-fat diet induced obese mice showed reduced plasma VGF C-terminus, NAPPE and QQET-like (ERVW) peptide/s (3±0.2 vs. 4.6±0.3, 22±3.5 vs. 34±1.3, and 48±7 vs. 100±7 pmol/ml, mean+SEM, n = 8/group, obese vs. slim, respectively, p<0.03), with a loss of the response to glucose for all VGF peptides studied. In immunohistochemistry, TLQP and/or VGF C-terminus antibodies labelled VGF containing perikarya in mouse celiac ganglia, pancreatic islet cells and thin beaded nerve fibres in brown adipose tissues, with fewer in white adipose tissue. Upon the glucose load, tyrosine hydroxylase and VGF C-terminus immunoreactive axons became apparent in pancreatic islets of slim animals, but not in obese animals. Alltogether, a significant loss of VGF peptide immunoreactivity and/or their response to glucose was demonstrated in obese patients, with or without T2D, in parallel with a similar loss in high-fat diet induced obese mice. An involvement of VGF in metabolic regulations, including those of brown and/or white adipose tissues is underlined, and may point out specific VGF peptides as potential targets for diagnosis and/or treatment.

Project description:BackgroundInfection with, and treatment of HIV is associated with effects on glycaemia and renal function. The purpose of this study was therefore to compare glycaemic control and albuminuria in HIV-positive and HIV-negative type 2 diabetic patients.Materials and methodsDiabetic patients with and without HIV infection were recruited from a diabetic clinic at Chris Hani Baragwanath Hospital in Soweto, South Africa. Data was collected on weight, height, HbA1c, fasting glucose, urine albumin:creatinine ratio, HIV status, CD4 counts, viral load and concomitant therapies. Multivariable regression analysis was used to isolate the determinants of fasting glucose and HbA1c levels and risk factors for albuminuria.ResultsData were collected from 106 HIV-positive and 214 HIV-negative diabetics. All HIV infected subjects were receiving anti-retroviral therapy. The determinants of fasting glucose levels (log) were HIV infection (β = 0.04, p = 0.01) and use of anti-hypertensive agents (β = 0.07, p = 0.0006), whilst for HbA1c levels (log) they were HIV infection (β = -0.03, p = 0.03), BMI (β = 0.004, p = 0.0005), statin use (β = 0.04, p = 0.002) and glucose levels (β = 0.01, p<0.0005). In HIV-positive subjects, CD4 counts were negatively associated with glucose levels (β = -0.0002, p = 0.03). The risk factors for albuminuria were (odds ratio [95% CIs]) dyslipidaemia (1.94 [1.09, 3.44], p = 0.02) and HbA1c levels (1.24 [1.12, 1.38], p<0.0001).DiscussionThese data suggest that glycaemic control is worse in type 2 diabetic subjects with HIV infection and that HbA1c underestimates glycaemia in these patients. Albuminuria was not associated with HIV-positivity. The negative relationship of CD4 counts with glucose levels may reflect viral removal and easing of the associated inflammatory response. It is possible that the association of statin and anti-hypertensive therapies with high HbA1c and glucose levels, respectively, is due to such therapies being given largely to subjects with poor glycaemic control.

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Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients.

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