[Show abstract][Hide abstract] ABSTRACT: Circulating ANGPTL8 has recently been used as a marker of insulin action. We studied expression and insulin regulation of ANGPTL8 and ANGPTL3 in vivo and in vitro.
Expression of ANGPTL8 and ANGPTL3 was studied in 34 paired samples of human liver and adipose tissue. Effects of insulin on (i) plasma concentrations and adipose tissue expression of ANGPTL8 and ANGPTL3 (in vivo 6-hour euglycemic hyperinsulinemia, n=18), (ii) ANGPTL8 and ANGPTL3 gene and protein expression in immortalized human hepatocytes (IHH) and adipocytes were measured. Effect of ANGPTL3 on secretion of ANGPTL8 in cells stably overexpressing ANGPTL3 or -8 or both was determined.
ANGPTL3 was only expressed in the liver, while ANGPTL8 was expressed in both tissues. In vivo hyperinsulinemia significantly decreased both plasma ANGPTL8 and ANGPTL3 at 3 and 6 hours. Insulin increased ANGPTL8 expression in human adipose tissue 14- and 18-fold at 3 and 6 hours and ANGPTL8 was the most insulin-responsive transcript on microarray. Insulin also increased ANPGTL8 in cultured adipocytes and IHH but the protein mainly remained intracellular. In vitro in IHH, insulin decreased ANGPTL3 gene expression and secretion of ANGPTL3 into growth medium. Overexpression of ANGPTL8 in CHO cells did not result in its release into culture medium while abundant secretion occurred in cells co-expressing ANGPTL3 and -8.
Insulin decreases plasma ANGPTL3 by decreasing ANGPTL3 expression in the liver. Insulin markedly increases ANGPTL8 in adipose tissue and the liver but not in plasma. These data show that measurement of plasma ANGPTL3 but not -8 reflects insulin action in target tissues.
The Journal of Clinical Endocrinology and Metabolism 07/2015; DOI:10.1210/jc.2015-1254 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) with glargine 100 U/mL (Gla-100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs).
EDITION 2 (NCT01499095) was a randomised, 6-month, multicentre, open-label, two-arm, phase 3a study investigating once-daily Gla-300 versus Gla-100, plus OADs (excluding sulphonylurea), with a 6-month safety extension.
Similar numbers of participants in each group completed 12 months of treatment (Gla-300, 315 [78%]; Gla-100, 314 [77%]). Reduction in HbA1c was maintained through 12 months with both treatments (least squares (LS) mean [SE] change from baseline -0.55 [0.06] % for Gla-300 and -0.50 [0.06] % for Gla-100; LS mean difference -0.06 [95% CI: -0.22 to 0.10] %). A significant relative reduction of 37% in annualised rate of nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia was observed with Gla-300 vs Gla-100 (rate ratio 0.63 [95% CI: 0.42 to 0.96]; p = 0.031), and fewer participants experienced ≥1 event (relative risk 0.84 [0.71 to 0.99]). Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla-300 than Gla-100 (LS mean difference -0.7 [95% CI: -1.3 to -0.2] kg, p = 0.009). Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69% and 60% in the Gla-300 and Gla-100 groups).
In people with type 2 diabetes treated with Gla-300 or Gla-100, and non-sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla-300 group.
This article is protected by copyright. All rights reserved.
Diabetes Obesity and Metabolism 07/2015; DOI:10.1111/dom.12532 · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blood serum and plasma have intrinsic differences in their composition and the preprocessing, such as clotting temperature in serum, and storage at room temperature may have further effect on metabolite concentrations.
The influence of sampling preprocessing on the metabolic profiles in serum and different types of plasma was investigated using liquid chromatography and comprehensive 2D gas chromatography coupled to a mass spectrometer.
The profiles of polar metabolites were significantly dependent on the type of the sample, while lipid profiles were similar in serum and different types of plasma. Extended storage of plasma at room temperature resulted in degradation of lipids already after 1 day. Serum clotting at room temperature generally resulted in higher metabolite concentration compared with serum clotting on ice.
[Show abstract][Hide abstract] ABSTRACT: The EDITION 1, 2 and 3 studies compared the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) with insulin glargine 100 U/mL (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively.
The EDITION studies were multicentre, randomised, open-label, parallel-group, phase 3a studies with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large T2DM population (Gla-300, N = 1247; Gla-100, N = 1249).
No significant study-by-treatment interactions across studies were found, enabling them to be pooled. Mean change in HbA1c was comparable for Gla-300 and Gla-100 (each -1.02 [SE 0.03] %; LS mean difference 0.00 [95% CI: -0.08 to 0.07] %). Annualised rates of confirmed (≤3.9 mmol/L) or severe hypoglycaemia were lower with Gla-300 than Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with ≥1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low (<1 kg) in both groups, with less gain with Gla-300 (LS mean difference -0.28 kg [95% CI: -0.55 to -0.01], p = 0.039). Both treatments were well tolerated, with similar rates of adverse events.
Gla-300 provides comparable glycaemic control to Gla-100 in a large T2DM population with broad clinical spectrum, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.
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[Show abstract][Hide abstract] ABSTRACT: Objectives:
Patients with type 1 diabetes mellitus (T1DM) lack the portal/peripheral insulin gradient, which might diminish insulin stimulation of hepatic lipogenesis and protect against development of nonalcoholic fatty liver disease (NAFLD). We compared liver fat content and insulin sensitivity of hepatic glucose production and lipolysis between overweight T1DM patients and nondiabetic subjects.
Materials and methods:
We compared 32 overweight adult T1DM patients and 32 nondiabetic subjects matched for age, body mass index (BMI), and gender. Liver fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS), body composition by magnetic resonance imaging, and insulin sensitivity using the euglycemic-hyperinsulinemic clamp technique (insulin 0.4 mU/kg · min combined with infusion of D-[3-(3)H]glucose). We also hypothesized that low liver fat might protect from obesity-associated increases in insulin requirements and, therefore, determined insulin requirements across BMI categories in 3164 T1DM patients.
Liver fat content was significantly lower in T1DM patients than in nondiabetic subjects (0.6% [25th-75th quartiles, 0.3%-1.1%] vs 9.0% [3.0%-18.0%]; P < .001). The endogenous rate of glucose production (R(a)) during euglycemic hyperinsulinemia was significantly lower (0.4 [-0.7 to 0.8] mg/kg fat-free mass · min vs 0.9 [0.2-1.6] fat-free mass · min; P = .012) and the percent suppression of endogenous Ra by insulin was significantly greater (89% [78%-112%] vs 77% [50%-94%]; p = .009) in T1DM patients than in nondiabetic subjects. Serum nonesterified fatty acid concentrations during euglycemic hyperinsulinemia were significantly lower (78.5 [33.0-155.0] vs 306 [200.0-438.0] μmol/L; P < .001) and the percent suppression of nonesterified fatty acids significantly higher (89.1% [78.6%-93.3%] vs 51.4% [36.5%-71.1%]; P < .001) in T1DM patients than in nondiabetic subjects. Insulin doses were similar across BMI categories.
T1DM patients might be protected from steatosis and hepatic insulin resistance. Obesity may not increase insulin requirements in T1DM.
[Show abstract][Hide abstract] ABSTRACT: Aims
The Glu167Lys (E167K) variant in TM6SF2 was recently shown to influence liver fat (LFAT) content. We aimed at studying how the variant influences the circulating triacylglycerol (TAG) signature and whether it influences hepatic or adipose tissue insulin sensitivity.
We genotyped 300 Finnish subjects for E167K (rs58542926) in TM6SF2 and for I148M (rs738409) in PNPLA3 in whom LFAT was measured using 1H-MRS and circulating lipids by UPLC-MS. We compared plasma lipidome between E167K carriers (TM6SF2EK/KK) and non-carriers (TM6SF2EE), and between three groups of NAFLD: i) carriers of E167K but not the I148M variant in PNPLA3 (‘TM6SF2 NAFLD’), ii) carriers of the I148M but not the E167K variant (‘PNPLA3 NAFLD’) and iii) non-carriers of either risk allele (‘Non-risk NAFLD’). Hepatic and adipose tissue insulin sensitivities were measured using the euglycemic hyperinsulinemic clamp technique combined with infusion of [3-3H]glucose in 111 subjects.
LFAT content was 34% higher in TM6SF2EK/KK (13.07±1.57%) than TM6SF2EE (9.77±0.58%, p = 0.013). Insulin sensitivities of glucose production and lipolysis were significantly higher at any given LFAT in the TM6SF2EK/KK than in the TM6SF2EE group. Comparison of three NAFLD groups with similar LFATs showed that both the ‘TM6SF2 NAFLD’ and ‘PNPLA3 NAFLD’ had significantly lower triglyceride levels and were characterized by lower levels of most common TAGs compared to the ‘Non-risk NAFLD’ group.
We conclude that the E167K variant in TM6SF2 is associated with distinct subtype of NAFLD characterized by preserved insulin sensitivity of lipolysis and hepatic glucose production and lack of hypertriglyceridemia despite clearly increased LFAT content.
Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.010 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To compare the efficacy and safety of new insulin glargine 300 units/mL (Gla-300) with glargine 100 units/mL (Gla-100) in people with type 2 diabetes using basal insulin (≥42 units/day) plus oral antihyperglycemic drugs (OADs).
Research design and methods:
EDITION 2 was a multicenter, open-label, two-arm study. Adults receiving basal insulin plus OADs were randomized to Gla-300 or Gla-100 once daily for 6 months. The primary end point was change in HbA1c. The main secondary end point was percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemic events from week 9 to month 6.
Randomized participants (n = 811) had a mean (SD) HbA₁c of 8.24% (0.82) and BMI of 34.8 kg/m(2) (6.4). Glycemic control improved similarly with both basal insulins; least squares mean (SD) reduction from baseline was -0.57% (0.09) for Gla-300 and -0.56% (0.09) for Gla-100 (mean difference -0.01% [95% CI -0.14 to 0.12]), with 10% higher dose of Gla-300. Less nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemia was observed with Gla-300 from week 9 to month 6 (relative risk 0.77 [95% CI 0.61-0.99]; P = 0.038) and during the first 8 weeks. Fewer nocturnal and any time (24 h) hypoglycemic events were reported during the entire 6-month period. Weight gain was lower with Gla-300 than with Gla-100 (P = 0.015). No between-treatment differences in safety parameters were identified.
Gla-300 was as effective as Gla-100 and associated with a lower risk of hypoglycemia during the night and at any time of the day.
Diabetes Care 09/2014; 37(12). DOI:10.2337/dc14-0990 · 8.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and "whitening" of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.