Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial.

AIM: To use continuous glucose monitoring (CGM)-based time-in-range (TIR) as a primary efficacy endpoint to compare the second-generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla-300) and insulin degludec 100 U/ml (IDeg-100) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: InRange was a 12-week, multicentre, randomized, active-controlled, parallel-group, open-label study comparing glucose TIR and variability between Gla-300 and IDeg-100 using blinded 20-day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid-acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. RESULTS: Overall, 343 participants were randomized: 172 received Gla-300 and 171 IDeg-100. Non-inferiority (10% relative margin) of Gla-300 versus IDeg-100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla-300 and 55.09% (53.34%, 56.84%) for IDeg-100; LS mean difference (non-inferiority): 3.16% (0.88%, 5.44%) (non-inferiority P = .0067). Non-inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non-inferiority) -5.44% (-6.50%, -4.38%) (non-inferiority P < .0001). Superiority of Gla-300 over IDeg-100 was not shown on TIR. Occurrences of self-measured and CGM-derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. CONCLUSIONS: Using clinically relevant CGM metrics, InRange shows that Gla-300 is non-inferior to IDeg-100 in people with T1D, with comparable hypoglycaemia and safety profiles.

Real-world outcomes of addition of insulin glargine 300 U/mL (Gla-300) to glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in people with type 2 diabetes: The DELIVER-G study.

AIMS: To provide real-world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. However, real-world data on the addition of BI to GLP-1RA therapy are limited. MATERIALS AND METHODS: We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real-world impact of adding the second-generation BI analogue insulin glargine 300 U/mL (Gla-300) to GLP-1RA therapy. Insulin-naïve PWD2 receiving GLP-1RAs who also received Gla-300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla-300. RESULTS: The mean (standard deviation [SD]) age of participants (N = 271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (-0.97 [SD 1.60]%; P < 0.0001) after addition of Gla-300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla-300 (HbA1c <7.0%: 4.80% vs. 22.14%, P < 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P < 0.0001). The incidence of overall (8.49% vs. 9.59%; P = 0.513) and inpatient/emergency department (ED)-associated hypoglycaemia (0.37% vs. 0.74%; P = 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P = 0.170) and inpatient/ED-associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P = 0.466) were similar before and after addition of Gla-300. CONCLUSIONS: In US real-world clinical practice, adding Gla-300 to GLP-1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla-300 to GLP-1RA therapy is warranted.

How many people with type 2 diabetes fulfil the eligibility criteria for randomized, controlled trials of insulin glargine 300 U/mL in a real-world setting?

Randomized controlled trial (RCT) populations often do not reflect those typically seen in clinical practice. This retrospective, observational cohort study analysed the real-world data of people with type 2 diabetes (T2DM) prescribed basal insulin analogues from electronic medical records (EMRs) in the Explorys database, which includes data from 39 integrated healthcare systems in the United States, to determine how representative selected RCTs investigating insulin glargine 300 U/mL (Gla-300) are of T2DM populations in a real-world setting. Applying eligibility criteria derived from the EDITION 1, 2 and 3 (Gla-300 vs. insulin glargine 100 U/mL [Gla-100]) and BRIGHT (Gla-300 vs. insulin degludec) RCTs, we observed that only 17% (33 345/191 218) of people captured in the real-world database would have been eligible for such trials. Those who were ineligible tended to be older, had more comorbidities and a higher baseline hypoglycaemia rate than the eligible group. Using another large US EMR database (Optum Humedica) as corroboration, we found that 15% (36 285/235 697) would have been eligible to participate in the EDITION/BRIGHT RCTs. Furthermore, only 7% (1734/24 547) would have been eligible for the CONCLUDE (insulin degludec vs. Gla-300) RCT. Our findings remind us of the value of real-world data studies, complementing the results of RCTs, and providing additional insights into groups who would typically be excluded from RCTs.

Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL and insulin degludec 100 U/mL in older participants in the BRIGHT trial.

AIM: To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus insulin degludec 100 U/mL (IDeg-100) in predefined (

Differential glycaemic control with basal insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 diabetes: A subanalysis from the BRIGHT trial.

AIMS: Chronic kidney disease (CKD) challenges diabetes management and is associated with increased cardiovascular morbidity and mortality. We examined whether clinical outcomes with insulin glargine 300 U/mL (Gla-300) and insulin degludec 100 U/mL (IDeg-100) are affected by renal function in a prespecified subgroup analysis from the BRIGHT trial. MATERIALS AND METHODS: BRIGHT (NCT02738151) was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve uncontrolled type 2 diabetes (T2D). Participants were randomized 1:1 to evening Gla-300 (n = 466) or IDeg-100 (n = 463) and stratified based on baseline estimated glomerular filtration rate (eGFR) for this analysis. RESULTS: Heterogeneity of treatment effect across renal function subgroups was observed (P = .02), reflecting a greater mean glycated haemoglobin (HbA1c) reduction from baseline to week 24 with Gla-300 versus IDeg-100 in the eGFR <60 mL/min/1.73 m2 subgroup (least squares mean difference: -0.43% [95% confidence interval: -0.74% to -0.12%]), while there were no differences in hypoglycaemia incidence or rates over 24 weeks in that subgroup. HbA1c reductions were similar between treatments in the other eGFR subgroups. However, heterogeneity was observed for annualized rates of anytime (24 hours) or nocturnal (00:00-05:59 hours) confirmed hypoglycaemia (≤70 mg/dL [≤3.9 mmol/L]) over 24 weeks showing less hypoglycaemia with Gla-300 versus IDeg-100 in the ≥90 mL/min/1.73 m2 . CONCLUSIONS: Kidney function seems to affect the glucose-lowering effects of Gla-300 versus IDeg-100 in insulin-naïve T2D. Greater HbA1c reductions with Gla-300 without increase in hypoglycaemia risk, were observed in patients with eGFR <60 mL/min/1.73 m2 .

Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 units/mL and degludec 100 units/mL: A subanalysis of the BRIGHT study.

AIM: To further investigate glycaemic control and hypoglycaemia in BRIGHT, focusing on the titration period. MATERIALS AND METHODS: BRIGHT was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve patients with uncontrolled type 2 diabetes initiated on glargine 300 U/mL (Gla-300) (N = 466) or degludec (IDeg-100) (N = 463). Predefined efficacy and safety outcomes were investigated during the initial 12-week titration period. In addition, patients' characteristics and clinical outcomes were assessed descriptively, stratified by confirmed (≤3.9 mmol/L) hypoglycaemia incidence during the initial titration period. RESULTS: At week 12, HbA1c was comparable between Gla-300 (7.32%) and IDeg-100 (7.23%), with similar least squares (LS) mean reductions from baseline (-1.37% and - 1.39%, respectively; LS mean difference of 0.02; 95% confidence interval: -0.08 to 0.12). Patients who experienced hypoglycaemia during the initial titration period had numerically greater HbA1c reductions by week 12 than patients who did not (-1.46% vs. -1.28%), and higher incidence of anytime (24 hours; 73.3% vs. 35.7%) and nocturnal (00:00-06:00 hours; 30.0% vs. 11.9%) hypoglycaemia between weeks 13-24. CONCLUSIONS: The use of Gla-300 resulted in similar glycaemic control as IDeg-100 during the initial 12-week titration period of the BRIGHT study, when less anytime (24 hours) hypoglycaemia with Gla-300 versus IDeg-100 has been reported. Experiencing hypoglycaemia shortly after initiating Gla-300 or IDeg-100 may be associated with hypoglycaemia incidence in the longer term, potentially impacting glycaemic management.

Comparable glycaemic control and hypoglycaemia in adults with type 2 diabetes after initiating insulin glargine 300 units/mL or insulin degludec: The DELIVER Naïve D real-world study.

AIM: To compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla-300) and insulin degludec (IDeg) in a real-world study of insulin-naïve adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin-naïve adults with T2D who started Gla-300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla-300 or IDeg and had HbA1c measurements during 6-month baseline and 3- to 6-month follow-up. Outcomes were compared among 1:1 propensity score-matched cohorts. RESULTS: In the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla-300 and IDeg cohorts (-1.67% [2.22] and -1.58% [2.20]; P = 0.51), as were HbA1c target attainment [<7% (53 mmol/mol): 23.8% and 27.4%; P = 0.20; <8% (64 mmol/mol): 55.0% and 57.1%; P = 0.63] and treatment discontinuation (29.2% and 32.6%; P = 0.14). Overall and inpatient/emergency department-associated hypoglycaemia incidences and event rates were similar in both cohorts using fixed 6-month or variable on-treatment follow-up. CONCLUSIONS: Among real-world insulin-naïve adults with T2D, initiation of Gla-300 or IDeg resulted in comparable improvements in glycaemic control and similar rates of hypoglycaemia. These real-world data complement and confirm a randomized trial and other real-world studies.

The Diabetes Unmet Need with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: Achieving HbA1c targets with basal insulin in a real-world setting.

AIMS: To describe in a real-world setting the achievement of physician-selected individualized HbA1c targets in individuals with type 2 diabetes, newly or recently initiated with basal insulin, and the association of hypoglycaemia with target achievement. MATERIALS AND METHODS: A 12-week, prospective, single-arm, observational study of adults with type 2 diabetes, either newly initiated with any basal insulin or start on basal insulin within the preceding 12 months. At enrollment, eligible participants from 28 countries were treated with or without oral antihyperglycaemic drugs and/or GLP-1 receptor agonists. RESULTS: Individualized targets for almost all of the 3139 evaluable participants (99.7%) had been set by their physicians, with 57% of participants having HbA1c targets between 7.0% and <7.5% (53 and <58 mmol/mol). By week 12, 28% and 27% of newly and previously initiated participants, respectively, achieved individualized HbA1c targets with modest average increases in daily insulin dose of 9 and 5 U (0.10 and 0.06 U/kg), respectively, from baseline (14 and 23 U [0.17 and 0.29 U/kg], respectively). Overall, 16% of participants experienced at least one episode of hypoglycaemia. Both the incidence and frequency of hypoglycaemia, but not the severity, were positively associated with a higher likelihood of achieving individualized HbA1c targets (P < 0.05). CONCLUSIONS: In this prospective real-world study, most participants using basal insulin did not achieve the individualized HbA1c targets set by their physicians. Participants who experienced symptomatic hypoglycaemia were more likely to achieve HbA1c targets than those who did not.

Switching to insulin glargine 300 units/mL in real-world older patients with type 2 diabetes (DELIVER 3).

AIM: To compare the second-generation basal insulin glargine 300 units/mL (Gla-300) and first-generation basal insulins on glycaemic control and hypoglycaemia risk in older adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER 3 was a retrospective observational cohort study of electronic medical records. A total of 1176 older adults (aged ≥ 65 years) with T2D and ≥1 HbA1c value during 6 month baseline and 3 to 6 month follow-up who switched from basal insulin to Gla-300 were propensity score-matched to 1176 older adults who switched to a first-generation basal insulin [insulin detemir (IDet) or insulin glargine 100 units/mL (Gla-100)]. Outcomes were follow-up HbA1c, achievement of HbA1c <7% and <8%, hypoglycaemia incidence and event rates, and healthcare resource utilization. RESULTS: Following basal insulin switching, HbA1c reductions were greater/similar with Gla-300 versus IDet/Gla-100 (variable follow-up: -0.45% ± 1.40% vs. -0.29% ± 1.57%; P = .021; fixed follow-up: -0.48% ± 1.49% vs. -0.38% ± 1.59%; P = .114), while HbA1c goal attainment was similar in both cohorts. Gla-300 was associated with less hypoglycaemia [event rate: adjusted rate ratio (aRR): 0.63, 95% CI: 0.53-0.75; P < .001] and inpatient/emergency department-associated hypoglycaemia (adjusted hazard ratio: 0.58, 95% CI: 0.37-0.90; P = .016; aRR: 0.43, 95% CI: 0.31-0.60; P < .001) by variable follow-up. By fixed follow-up, hypoglycaemia results significantly or numerically favoured Gla-300. CONCLUSION: Among older adults with T2D, switching to Gla-300 versus Gla-100/IDet was associated with greater/similar improvements in glycaemic control, and generally less hypoglycaemia.

Clinical outcomes in real-world patients with type 2 diabetes switching from first- to second-generation basal insulin analogues: Comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study.

AIMS: To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla-100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla-300) or insulin degludec (IDeg). MATERIALS AND METHODS: We conducted a retrospective, observational study of electronic medical records for Gla-300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12-month baseline (glycated haemoglobin [HbA1c] used a 6-month baseline period) and 6-month follow-up periods. Gla-300 and IDeg switchers were propensity score-matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow-up), and hypoglycaemia with fixed follow-up (intention-to-treat [ITT]; 6 months) and variable follow-up (on-treatment [OT]; to discontinuation or 6 months). RESULTS: Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (<7.0% [53 mmol/mol] and <8.0% [64 mmol/mol]) attainment rates were similar for Gla-300 (n = 742) and IDeg (n = 727) switchers. Using fixed follow-up (ITT method), hypoglycaemia incidence decreased significantly from baseline with Gla-300 (all hypoglycaemia: 15.6% to 12.7%; P = .006; hypoglycaemia associated with inpatient/emergency department [ED] encounter: 5.3% to 3.5%; P = .007), but not with IDeg. After adjusting for baseline hypoglycaemia, no significant differences in hypoglycaemia incidence and event rate were found at follow-up (ITT) for Gla-300 vs IDeg. Using variable follow-up (OT), hypoglycaemia incidence was similar in both groups, but Gla-300 switchers had a lower inpatient/ED hypoglycaemia event rate at follow-up (adjusted rate ratio 0.56; P = .016). CONCLUSIONS: In a real-world setting, switching from Gla-100 or IDet to Gla-300 or IDeg was associated with similar improvements in glycaemic control and hypoglycaemia in adult patients with T2D.

Real-world evidence concerning clinical and economic outcomes of switching to insulin glargine 300 units/mL vs other basal insulins in patients with type 2 diabetes using basal insulin.

This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, March 1, 2015 to May 31, 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1819 in each). Hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced the risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of associated costs.

Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects.

OBJECTIVE: Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects. METHODS AND RESULTS: Stable isotope tracers were used to elucidate the pathophysiology of the dyslipidemia in hypertriglyceridemic (n=14) and normotriglyceridemic (n=14) obese men (with comparable body mass index and visceral fat volume) and in normotriglyceridemic nonobese men (n=10). Liver fat was determined using proton magnetic resonance spectroscopy, and subcutaneous abdominal and visceral fat were measured by magnetic resonance imaging. Serum triglycerides in obese subjects were increased by the combination of increased secretion and severely impaired clearance of triglyceride-rich very-low-density lipoprotein(1) particles. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of very-low-density lipoprotein 1 particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects. CONCLUSIONS: Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects with similar levels of visceral adiposity. The results emphasize the clinical importance of assessing hypertriglyceridemic waist in obese subjects to identify subjects at high cardiometabolic risk.

Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue.

BACKGROUND: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue. METHODS: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject. RESULTS: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot. CONCLUSIONS: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.

Clinical outcomes in high-hypoglycaemia-risk patients with type 2 diabetes switching to insulin glargine 300 U/mL versus a first-generation basal insulin analogue in the United States : Results from the DELIVER High Risk real-world study.

AIMS: To compare 12-month clinical effectiveness of insulin glargine 300 units/mL (Gla-300) versus first-generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla-100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla-300 or Gla-100/IDet) in a real-world setting. METHODS: DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla-300 (Gla-300 switchers) and were propensity score-matched (1:1) to patients who switched to Gla-100 or IDet (Gla-100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (<7% and <8%), and incidence and event rates of hypoglycaemia (all-hypoglycaemia and hypoglycaemia associated with an inpatient/emergency department [ED] contact). RESULTS: HbA1c reductions were similar following switching to Gla-300 or Gla-100/IDet (-0.51% vs. -0.53%; p = .67), and patients showed similar attainment of HbA1c goals. Patients in both cohorts had comparable all-hypoglycaemia incidence and event rates. However, the Gla-300 switcher cohort had a significantly lower risk of inpatient/ED-associated hypoglycaemia (adjusted odds ratio: 0.73, 95% confidence interval: 0.60-0.89; p = .002) and experienced significantly fewer inpatient/ED-associated hypoglycaemic events (0.21 vs. 0.33 events per patient per year; p < .001). CONCLUSION: In patients with T2D at high risk of hypoglycaemia, switching to Gla-300 or Gla-100/IDet achieved similar HbA1c reductions and glycaemic goal attainment, but Gla-300 switchers had a significantly lower risk of hypoglycaemia associated with an inpatient/ED contact during 12 months after switching.

Splanchnic balance of free fatty acids, endocannabinoids, and lipids in subjects with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Animal studies suggest that endocannabinoids could contribute to the development of nonalcoholic fatty liver disease (NAFLD). In addition, NAFLD has been shown to be associated with multiple changes in lipid concentrations in liver biopsies. There are no data on splanchnic free fatty acid (FFA), glycerol, ketone body, endocannabinoid, and lipid fluxes in vivo in subjects with NAFLD. METHODS: We performed hepatic venous catheterization studies in combination with [(2)H(2)]palmitate infusion in the fasting state and during a low-dose insulin infusion in 9 subjects with various degrees of hepatic steatosis as determined using liver biopsy. Splanchnic balance of endocannabinoids and individual lipids was determined using ultra performance liquid chromatography coupled to mass spectrometry. RESULTS: Concentrations of the endocannabinoid 2-arachidonoylglycerol were higher in arterialized (91 ± 33 µg/L basally) than in hepatic venous (51 ± 19 µg/L; P < .05) plasma. Fasting arterial (r = 0.72; P = .031) and hepatic venous (r = 0.70; P = .037) concentrations of 2-arachidonoylglycerol were related positively to liver fat content. Analysis of fluxes of 85 different triglycerides showed that the fatty liver overproduces saturated triglycerides. In the plasma FFA fraction in the basal state, the relative amounts of palmitoleate and linoleate were lower and those of stearate and oleate were higher in the hepatic vein than in the artery. Absolute concentrations of all nontriglyceride lipids were comparable in arterialized venous plasma and the hepatic vein both in the basal and insulin-stimulated states. CONCLUSIONS: The human fatty liver takes up 2-arachidonoylglycerol and overproduces triacylglycerols containing saturated fatty acids, which might reflect increased de novo lipogenesis.

Long-TE 1H MRS suggests that liver fat is more saturated than subcutaneous and visceral fat.

Cross-talk between adipose tissue and liver is disturbed in the metabolic syndrome. Moreover, the relative fatty acid composition of adipose and liver fat is poorly characterized. Long-TE (1)H MRS can determine the unsaturation and polyunsaturation of adipose tissue. The aim of this study was to use long-TE (1)H MRS to determine the composition of liver fat and its relation to adipose tissue composition. Sixteen subjects with increased liver fat (>5%) were recruited for the study. Using TE = 200 ms, we were able to resolve the olefinic (=CH, 5.3 ppm) and water (H(2)O, 4.7 ppm) resonances in liver spectra and to obtain a repeatable estimate of liver fat unsaturation (coefficient of variation, 2.3%). With TE = 135 ms, the diallylic (=C-CH(2)-C=, 2.8 ppm) resonance was detectable in subjects with a liver fat content above 15%. Long-TE (1)H MRS was also used to determine the unsaturation in subcutaneous (n = 16) and visceral (n = 11) adipose tissue in the same subjects. Liver fat was more saturated (double bonds per fatty acid chain, 0.812 ± 0.022) than subcutaneous (double bonds per fatty acid chain, 0.862 ± 0.022, p < 0.0004) or visceral (double bonds per fatty acid chain, 0.865 ± 0.033, p < 0.0004) fat. Liver fat unsaturation correlated with subcutaneous unsaturation (R = 0.837, p < 0.0001) and visceral unsaturation (R = 0.879, p < 0.0004). The present study introduces a new noninvasive method for the assessment of the composition of liver fat. The results suggest that liver fat is more saturated than subcutaneous or visceral adipose tissue, which may be attributed to differences in de novo lipogenesis.

A review of reusable insulin pens and features of TouStar-a new reusable pen with a dedicated cartridge.

BACKGROUND: Since the introduction of the first reusable insulin pen, the advancement in the design of these pens is still ongoing to develop a safe, more efficacious, less painful, and easy to use insulin pen device. MAIN BODY: Possible errors in insulin delivery can occur at any stage of insulin delivery such as during the prescription stage, dispensing stage, or at administration stage. Mismatch of the insulin pen and cartridge is not uncommon and is a potential risk for individuals with diabetes due to serious consequences associated with incorrect insulin usage. The similarities in insulin cartridges of different manufacturers with regard to color and product names could lead to mix-up of insulin pens and cartridges. These unmet needs have led to the ongoing search for developing insulin pens that can address these errors and provide more efficacious and safer choices for patients with diabetes. CONCLUSION: This review provides an overview of currently available reusable pens in the market and highlights the features of TouStar®, a new reusable pen with a dedicated cartridge intended to mitigate the risk of mismatch of the cartridge.

Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease.

Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.

Nonalcoholic fatty liver disease: detection of elevated nicotinamide adenine dinucleotide phosphate with in vivo 3.0-T 31P MR spectroscopy with proton decoupling.

PURPOSE: To determine if 3.0-T proton-decoupled phosphorus 31 ((31)P) magnetic resonance (MR) spectroscopy can be used to differentiate between stages of nonalcoholic fatty liver disease (NAFLD) by resolving the components of phosphomonoester (PME) and phosphodiester (PDE) and enabling detection of a greater number of other phosphorus-containing compounds. MATERIALS AND METHODS: This study was approved by the ethics committee of Helsinki University Central Hospital, and written informed consent was obtained from all study subjects. A 3.0-T clinical imager was used to obtain proton-decoupled (31)P MR spectra in the liver of control subjects (n = 12), patients with biopsy-proved simple steatosis due to nonalcoholic causes (nonalcoholic fatty liver, n = 13; nonalcoholic steatohepatitis [NASH], n = 9), and patients with cirrhosis (n = 9) to determine PME, phosphoethanolamine (PE), phosphocholine, PDE, glycerophosphocholine (GPC), glycerophosphoryl ethanolamine, uridine diphosphoglucose, nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate, phosphoenolpyruvate, and alpha-, beta- and gamma-nucleotide triphosphate levels. Liver fat was determined with hydrogen 1 MR spectroscopy. Differences between the disease groups were analyzed with one-way analysis of variance. RESULTS: The PME/(PME + PDE), PME/PDE, and PE/(PME + PDE) ratios were higher and the GPC/(PME + PDE) ratio was lower in patients with cirrhosis than in the other study groups (P < or = .001, one-way analysis of variance). The NADPH/(PME + PDE) ratio was higher in patients with NASH and those with cirrhosis than in control subjects (P < .05, post hoc analyses) and correlated with disease severity (P = .007). CONCLUSION: NADPH, a marker of inflammation and fibrinogenic activity in the liver, is increased in patients with NASH and those with cirrhosis. Proton-decoupled (31)P 3.0-T MR spectroscopy shows promise in the differentiation of NAFLD stages.

Characterizing human adipose tissue lipids by long echo time 1H-MRS in vivo at 1.5 Tesla: validation by gas chromatography.

The aim of this study was to investigate the use of (1)H-MRS with various echo times to characterize subcutaneous human adipose tissue (SAT) triglyceride composition and to validate the findings with fatty acid (FA) analysis of SAT biopsies by gas chromatography (GC). (1)H-MRS spectra were acquired with a 1.5 Tesla clinical imager from the SAT of 17 healthy volunteers, with 10 undergoing SAT biopsy. Spectra were localized with PRESS and a series of echo times; 30, 50, 80, 135, 200, 300 and 540 ms were acquired with TR = 3000 ms. Prior knowledge from phantom measurements was used to construct AMARES fitting models for the lipid spectra. SAT FA composition were compared with serum lipid levels and subject characteristics in 17 subjects.Long TE (135, 200 ms) spectra corresponded better with the GC data than short TE (30, 50 ms) spectra. TE = 135 ms was found optimal for determining diallylic content (R = 0.952, p < 0.001) and TE = 200 ms was optimal for determining olefinic content (R = 0.800, p < 0.01). The improved performance of long TE spectra is a result of an improved baseline and better peak separation, due to J-modulation and suppression of water. The peak position of the diallylic resonance correlated with the average double bond content of polyunsatured fatty acids with R = 0.899 (p < 0.005). The apparent T(2) of the methylene resonance displayed relatively small inter-individual variation, 88.1 +/- 1.1 ms (mean +/- SD). The outer methyl triplet line of omega-3 PUFA at 1.08 ppm could be readily detected and quantitated from spectra obtained at TE = 540. The omega-3 resonance correlated with the omega-3 content determined by GC with R = 0.737 (p < 0.05, n = 8). Age correlated significantly with SAT diallylic content (R = 0.569, p = 0.017, n = 17), but serum lipid levels showed no apparent relation to SAT FA composition. We conclude that long TE (1)H-MRS provides a robust non-invasive method for characterizing adipose tissue triglycerides in vivo.