[Show abstract][Hide abstract] ABSTRACT: Background:
Insulin glargine 300 U/mL (Gla-300) has a more constant and prolonged action profile than insulin glargine 100 U/mL and in clinical studies is associated with similar glycemic control but less hypoglycemia. Whether its effects are altered by variability of injection time was examined in two 3-month substudies.
Materials and methods:
Eligible participants completing 6 months of optimized treatment with Gla-300 in EDITION 1 (n = 109) and EDITION 2 (n = 89), having a mean hemoglobin A1c (HbA1c) level of 7.3 % (SD 1.0 %), were randomized (1:1) to groups advised to increase variability of between-injection intervals to 24 ± up to 3 h or to maintain fixed 24-h intervals for 3 months. Changes of HbA1c level and other efficacy and safety measures were assessed.
In the fixed-dosing group, 64% of participants reported all intervals within the 23-25-h range, compared with 15% of those advised flexible dosing. In the fixed- and flexible-dosing groups, 12% and 41%, respectively, of between-injection intervals were outside the 23-25-h range, and 2% and 16%, respectively, were outside the 21-27-h range. Least squares mean between-group difference in HbA1c change from baseline was 0.05 % (95% confidence interval [CI], -0.13 to 0.23); for fasting plasma glucose, 2.7 mg/dL (95% CI, -9.0 to 14.4); and for daily basal insulin dose, 0.00 U/kg (95% CI, -0.02 to 0.03). Frequencies of hypoglycemia and adverse events did not differ between groups.
The efficacy and safety of Gla-300 demonstrated in EDITION 1 and EDITION 2 are maintained in substudies when the insulin was injected up to 3 h before or after the usual time of administration.
No preview · Article · Feb 2016 · Diabetes Technology & Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Early detection of fibrosis is important in identifying individuals at risk for advanced liver disease in non-alcoholic fatty liver disease (NAFLD). We tested whether second-harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy, detecting fibrillar collagen and fat in a label-free manner, might allow automated and sensitive quantification of early fibrosis in NAFLD.
We analyzed 32 surgical biopsies from patients covering histological fibrosis stages 0-4, using multimodal label-free microscopy. Native samples were visualized by SHG and CARS imaging for detecting fibrillar collagen and fat. Furthermore, we developed a method for quantitative assessment of early fibrosis using automated analysis of SHG signals.
We found that the SHG mean signal intensity correlated well with fibrosis stage and the mean CARS signal intensity with liver fat. Little overlap in SHG signal intensities between fibrosis stages 0 and 1 was observed. A specific fibrillar SHG signal was detected in the liver parenchyma outside portal areas in all samples histologically classified as having no fibrosis. This signal correlated with immunohistochemical location of fibrillar collagens I and III.
This study demonstrates that label-free SHG imaging detects fibrillar collagen deposition in NAFLD more sensitively than routine histological staging and enables observer-independent quantification of early fibrosis in NAFLD with continuous grading.
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver.
Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither.
Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI) vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups.
Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and CVD.
No preview · Article · Jan 2016 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) control gene expression by reducing mRNA stability and translation. We aimed to identify alterations in human liver miRNA expression/function in nonalcoholic fatty liver disease (NAFLD). Subjects with the highest (median liver fat 30%, n = 15) and lowest (0%, n = 15) liver fat content were selected from >100 obese patients for miRNA profiling of liver biopsies on microarrays carrying probes for 1438 human miRNAs (a cross-sectional study). Target mRNAs and pathways were predicted for the miRNAs most significantly upregulated in NAFLD, their cell-type-specific expression was investigated by quantitative PCR (qPCR), and the transcriptome of immortalized human hepatocytes (IHH) transfected with the miRNA with the highest number of predicted targets, miR-576-5p, was studied. The screen revealed 42 miRNAs up- and two downregulated in the NAFLD as compared to non-NAFLD liver. The miRNAs differing most significantly between the groups, miR-103a-2*, miR-106b, miR-576-5p, miRPlus-I137*, miR-892a, miR-1282, miR-3663-5p, and miR-3924, were all upregulated in NAFLD liver. Target pathways predicted for these miRNAs included ones involved in cancer, metabolic regulation, insulin signaling, and inflammation. Consistent transcriptome changes were observed in IHH transfected with miR-576-5p, and western analysis revealed a marked reduction of the RAC1 protein belonging to several miR-576-5p target pathways. To conclude, we identified 44 miRNAs differentially expressed in NAFLD versus non-NAFLD liver, 42 of these being novel in the context of NAFLD. The study demonstrates that by applying a novel study set-up and a broad-coverage array platform one can reveal a wealth of previously undiscovered miRNA dysregulation in metabolic disease.
[Show abstract][Hide abstract] ABSTRACT: We investigated the expression of miR-192* (miR-192-3p) in the visceral adipose tissue (VAT) of obese subjects and its function in cultured human adipocytes. This miRNA is a 3' arm derived from the same pre-miRNA as miR-192 (miR-192-5p) implicated in type 2 diabetes, liver disease and cancers, and is predicted to target key genes in lipid metabolism. In morbidly obese subjects undergoing bariatric surgery preceded by a very low calorie diet, miR-192* in VAT correlated negatively (r=-0.387; p=0.046) with serum triglyceride (TG) and positively with high-density lipoprotein (HDL) concentration (r=0.396; p=0.041). In a less obese patient cohort, the miRNA correlated negatively with the body mass index (r=-0.537; p=0.026). To characterize the function of miR-192*, we overexpressed it in cultured adipocytes and analyzed the expression of adipogenic differentiation markers as well as cellular TG content. Reduced TG and expression of the adipocyte marker proteins aP2 (adipocyte protein 2) and perilipin 1 were observed. The function of miR-192* was further investigated by transcriptomic profiling of adipocytes expressing this miRNA, revealing impacts on key lipogenic genes. A number of the mRNA alterations were validated by qPCR. Western analysis confirmed a marked reduction of the lipogenic enzyme SCD (stearoyl coenzyme A desaturase-1), the fatty aldehyde dehydrogenase ALDH3A2 (aldehyde dehydrogenase 3 family member A2) and the high-density lipoprotein receptor SCARB1 (scavenger receptor B, type I). SCD and ALDH3A2 were demonstrated to be direct targets of miR-192*. To conclude, the present data identify miR-192* as a novel controller of adipocyte differentiation and lipid homeostasis.
Full-text · Article · Dec 2015 · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
[Show abstract][Hide abstract] ABSTRACT: Aim:
To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin.
This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks.
A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n=475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with linagliptin was -7 (±1) mmol/mol [-0.7 (±0.1) %; 95% CI -0.8, -0.6; P<0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: linagliptin, -0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg].
Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain. This article is protected by copyright. All rights reserved.
No preview · Article · Nov 2015 · Diabetic Medicine
[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.
Full-text · Article · Jul 2015 · The Journal of Clinical Endocrinology and Metabolism
[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.
[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.
This article is protected by copyright. All rights reserved.
No preview · Article · Apr 2015 · Diabetes Obesity and Metabolism