Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus.

Objective- Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). Approach and Results- We performed an in vivo kinetic study with stable isotopes (D8-valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d). We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron. In diabetic patients, liraglutide treatment induced a dramatic reduction of ApoB48 pool (65±38 versus 162±87 mg; P=0.005) because of a significant decrease in ApoB48 production rate (3.02±1.33 versus 6.14±4.27 mg kg-1 d-1; P=0.009) and a significant increase in ApoB48 fractional catabolic rate (5.12±1.35 versus 3.69±0.75 pool d-1; P=0.005). One-week treatment with liraglutide significantly reduced postload plasma triglycerides in mice and liraglutide, in vitro, reduced the expression of ApoB48, DGAT1 (diacylglycerol O-acyltransferase 1), and MTP (microsomal transfer protein) genes. Conclusions- We show that treatment with liraglutide induces a significant reduction of the ApoB48 pool because of both a reduction of ApoB48 production and an increase in ApoB48 catabolism. In vitro, liraglutide reduces the expression of genes involved in chylomicron synthesis. These effects might benefit cardiovascular health. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02721888.

Circulating apelin is increased in patients with type 1 or type 2 diabetes and is associated with better glycaemic control.

CONTEXT: Apelin is an adipokine expressed in several tissues and it appears to be involved in energy metabolism. OBJECTIVE: The aim of this study was to determine serum apelin levels in a large cohort of patients with type 1 and type 2 diabetes and control subjects and to correlate the results with glycaemic control. DESIGN AND PARTICIPANTS: One hundred and thirty patients with type 1 diabetes, 98 patients with type 2 diabetes and 162 controls were enrolled in the study. Apelin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum apelin levels were significantly higher in type 1 and type 2 diabetic patients than in controls (P < 0·0001). Serum apelin levels were higher in type 1 than in type 2 diabetic patients (P = 0·02). In multivariate analysis, serum apelin levels were higher in patients with type 1 diabetes and in patients with type 2 diabetes versus controls. We found a negative correlation between glycosylated haemoglobin and serum apelin levels in all diabetic patients (r = -0·17, P = 0·008) and in patients with type 2 diabetes (r = -0·24 P = 0·01). No correlation was found in type 1 diabetic patients. CONCLUSION: Our study showed that apelin concentrations were increased in diabetic patients. This rise, which was greater in type 1 than in type 2 diabetic patients, suggests that obesity is not the main determinant of plasma apelin levels. The negative correlation with glycosylated haemoglobin in patients with type 2 diabetes could indicate that apelin plays a role in glycaemic balance and even insulin sensitivity.

Chronic hyperinsulinemia does not increase the production rate of high-density lipoprotein apolipoprotein AI: evidence from a kinetic study in patients with insulinoma.

OBJECTIVE: In vitro studies showed that insulin stimulates the production of apolipoprotein AI (apoAI). Thus, we hypothesized that chronic hyperinsulinemia could contribute to the increase in the production of high-density lipoprotein apoAI that is observed in metabolic syndrome. APPROACH AND RESULTS: We performed an in vivo kinetic study with stable isotope in 7 patients with insulinoma who showed hyperinsulinemia but no insulin resistance, 8 patients with insulin resistance, and 16 controls. Insulinemia was 3.1× (P<0.01) higher in patients with insulinoma or insulin resistance than in controls in the fasting state and, respectively, 3.5× and 2.6× (P<0.05) higher in the fed state. The high-density lipoprotein apoAI pool size was smaller in patients with insulin resistance than in controls (49.3 ± 5.4 versus 59.6 ± 7.7 mg · kg(-1); P<0.01), whereas both the high-density lipoprotein apoAI fractional catabolic rate and the high-density lipoprotein apoAI production rate were higher (0.30 ± 0.07 versus 0.20 ± 0.04 pool · d(-1); P<0.0001 and 14.6 ± 1.5 versus 11.5 ± 1.9 mg · kg(-1) · d(-1); P<0.01, respectively). In contrast, no significant difference was observed for these parameters between patients with insulinoma and controls. In patients with insulinoma, the apoAI pool size tended to be greater than in patients with insulin resistance (56.3 ± 8.6 versus 49.3 ± 5.4 mg · kg(-1); P=0.078), whereas both the apoAI fractional catabolic rate and the production rate were lower (0.20 ± 0.06 versus 0.30 ± 0.07 pool · d(-1); P<0.01 and 11.1 ± 1.6 versus 14.6 ± 1.5 mg·kg(-1) · d(-1); P<0.01, respectively). The apoAI fractional catabolic rate was the only variable associated with the apoAI production rate in multivariate analysis and explained 80% of its variance. CONCLUSIONS: Chronic endogenous hyperinsulinemia does not induce any increase in the apoAI production rate, which seems to be more dependent on the apoAI fractional catabolic rate.

First use of Simulation in Therapeutic Patient Education (S-TPE) in adults with diabetes: a pilot study.

OBJECTIVE: To pilot test the feasibility and acceptability of Simulation in Therapeutic Patient Education (S-TPE), in both adult patients with diabetes and educators. CONCEPTION: Adult patients with insulin-dependent diabetes and who participated in a full TPE programme for the implementation of a FreeStyle were included in this monocentric pilot study. S-TPE intervention was based on a consensus conference determining the conditions and objectives of S-TPE. Main outcomes were the patients' and educators' perception of the usefulness of S-TPE and the patient's satisfaction level at the conclusion of the simulation sequence, measured on validated scales. Secondary outcomes were organisational, human, material and temporal, facilitating and limiting factors for patients and educators, patient self-efficacy and anxiety scores. INTERVENTIONS: The final session of TPE used the simulation. For each group, one patient volunteered to be the simulated patient. Intervention was divided into three steps: (1) a pre-briefing, (2) a simulation of hypoglycaemia and (3) a debriefing with the group of patients and educators. The whole intervention lasted about 2 hours. RESULTS: We included 23 patients (mean age ±SD 63±15 years, 14 men) and 3 educators. After S-TPE intervention, patients' and educators' perceived usefulness score were 20.6/25 and 37.5/40, respectively. Patient's satisfaction score was 51.9/60. Qualitative analysis revealed no limiting factors to implementing S-TPE. Self-efficacy was stable. Decrease in anxiety score after S-TPE reached statistical significance in women (from 35.1±4.5 to 32.7±5.5, p=0.04) but not in men. CONCLUSION: No limiting factors that could prevent the conduct of clinical trials to assess S-TPE efficacy in patients with diabetes were identified. S-TPE appears as a promising technique to improve diabetes management. TRIAL REGISTRATION NUMBER: Registration N°: 2019-A00773-54 and NTC: 03956927.

Glycemic Variability Assessment with a 14-Day Continuous Glucose Monitoring System: When and How Long to Measure MAGE (Mean Amplitude of Glucose Excursion) for Optimal Reliability?

Mean amplitude of glucose excursion (MAGE) is considered as the "gold standard" for assessing the short-term within-day glycemic variability (GV), which is an important component of overall glycemic control. A 14-day continuous glucose monitoring system is now widely used and allows easier assessment of GV. However, it is still unknown whether MAGE, usually calculated on a 48-hour period is identical whatever the time during the 14-day lifespan of the sensor and whether a longer time period might give additional information. We evaluated in 68 patients with type 1 diabetes, MAGE during three 2-day periods (day1-day3; day6-day8; day11-day13) and during periods of 3 days and 4 days. MAGE calculated at the three 2-day periods were identical and not different from MAGE of the 3-day or 4-day periods.

Increased body fat mass reduces the association between fructosamine and glycated hemoglobin in obese type 2 diabetes patients.

Obesity is increasing in patients with type 2 diabetes. A possible reduced association between fructosamine and glycated hemoglobin (HbA1c) in obese individuals has been previously discussed, but this has never been specifically evaluated in type 2 diabetes, and the potential influence of body fat mass and fat distribution has never been studied. We studied 112 type 2 diabetes patients with assessment of fat mass, liver fat and fat distribution. Patients with body mass index (BMI) above the median (34.9 kg/m2 ), versus BMI below the median, had a correlation coefficient between fructosamine and HbA1c significantly reduced (r = 0.358 vs r = 0.765). In the whole population, fructosamine was correlated negatively with BMI and fat mass. In multivariate analysis, fructosamine was associated with HbA1c (positively) and fat mass (negatively), but not with BMI, liver fat or fat distribution. The association between fructosamine and HbA1c is significantly reduced in the most obese type 2 diabetes patients, and this is mostly driven by increased fat mass.

Liraglutide Increases the Catabolism of Apolipoprotein B100-Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression.

OBJECTIVE: Dyslipidemia observed in type 2 diabetes (T2D) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles, which all have apolipoprotein B100 (apoB100) as a major apolipoprotein. This prompted us to study the effect of the GLP-1 agonist liraglutide on the metabolism of apoB100-containing lipoproteins. RESEARCH DESIGN AND METHODS: We performed an in vivo kinetic study with stable isotopes (L-[1-13C]leucine) in 10 patients with T2D before and after 6 months of treatment with liraglutide (1.2 mg/day). We also evaluated in mice the effect of liraglutide on the expression of genes involved in apoB100-containing lipoprotein clearance. RESULTS: In patients with T2D, liraglutide treatment significantly reduced plasma apoB100 (0.93 ± 0.13 vs. 1.09 ± 0.11 g/L, P = 0.011) and fasting triglycerides (1.76 ± 0.37 vs. 2.48 ± 0.69 mmol/L, P = 0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL1-apoB100 (4.11 ± 1.91 vs. 2.96 ± 1.61 pools/day, P = 0.005), VLDL2-apoB100 (5.17 ± 2.53 vs. 2.84 ± 1.65 pools/day, P = 0.008), and IDL-apoB100 (5.27 ± 2.77 vs. 3.74 ± 1.85 pools/day, P = 0.017) and in catabolism of LDL-apoB100 (0.72 ± 0.22 vs. 0.56 ± 0.22 pools/day, P = 0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced proprotein convertase subtilisin/kexin type 9 (PCSK9), retinol-binding protein 4 (RBP4), and tumor necrosis factor-α (TNF-α) gene expression in adipose tissue and decreased PCSK9 mRNA and increased LDL receptor protein expression in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver. CONCLUSIONS: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100-containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2D.

Evaluation of the Adherence to Continuous Glucose Monitoring in the Management of Type 1 Diabetes Patients on Sensor-Augmented Pump Therapy: The SENLOCOR Study.

BACKGROUND: Continuous glucose monitoring (CGM) and sensor-augmented pump (SAP) therapy improve glucose control provided good adherence. In France, not only diabetologists, nurses, and dieticians but also nurses employed by homecare providers (HCPNs) are together involved in the initiation and/or follow-up of continuous subcutaneous insulin injection (CSII) and SAP training. The SENLOCOR Study is an observational study designed to assess SAP adherence over 6 months (primary objective). Secondary objectives included the impact of SAP on metabolic control and patients' satisfaction. MATERIALS AND METHODS: CGM initiation (M0) was performed within 3 months after CSII. CGM adherence, defined by sensor wear >70% of the time, glycated hemoglobin (HbA1c) levels, and satisfaction questionnaires were collected at inclusion and at 3 (M3) and 6 (M6) months. RESULTS: The analysis population was 234 patients, including 27 children. Of the physicians, 88.0% were involved in SAP education for the whole cohort (median time, 45 min), whereas HCPNs were involved in CGM training for 190 patients (81.2%) (median time: at M0, 156 min; at M3, 20 min). Good adherence was obtained in 86.1% (M0-M3) and 68.9% (M3-M6) of the patients. The HbA1c level decreased from 8.16 ± 1.35% (M0) to 7.67 ± 1.01% (M6) in 189 patients (change, -0.48%; 95% confidence interval, -0.64, -0.33). The percentage of patients who experienced severe hypoglycemia decreased from 20.7% (M0) to 13.6% (M3) and 13.3% (M6). Satisfaction scores were high. CONCLUSIONS: In patients with type 1 diabetes, a 6-month training on SAP involving a multidisciplinary team, and especially HCPNs, improved metabolic control with a high level of adherence and satisfaction.

Comparison of apolipoprotein B100 metabolism between continuous subcutaneous and intraperitoneal insulin therapy in type 1 diabetes.

OBJECTIVE: In type 1 diabetic patients, the replacement of s.c. insulin infusion with i.p. insulin infusion restores the normal physiological gradient between the portal vein and the peripheral circulation, which is likely to modify lipoprotein metabolism. DESIGN: To check this hypothesis, we performed two apolipoprotein (apo) B100 kinetic studies in seven type 1 diabetic patients, first under s.c. insulin infusion and then 3 months after the beginning of i.p. insulin infusion. RESULTS: Glycemic control was similar under s.c. insulin infusion and i.p. insulin infusion, as assessed by glycated hemoglobin A1c and the capillary glycemic curve determined during the kinetic study. Very low-density and intermediate-density lipoprotein apoB100 pool size, production rate, and fractional catabolic rate (FCR) were similar under s.c. insulin infusion and i.p. insulin infusion. The low-density lipoprotein apoB100 FCR tended to decrease under ip insulin (0.45 +/- 0.06 vs. 0.55 +/- 0.11 pool/d), but the difference did not reach statistical significance (95% confidence interval for the difference, -0.33, 0.11). The low-density lipoprotein apoB100 pool size and production rate remained unchanged under i.p. insulin infusion compared with s.c. insulin infusion. CONCLUSION: In type 1 diabetic patients, the replacement of s.c. insulin infusion with i.p. insulin infusion does not induce profound modifications of apoB100-containing lipoprotein production and FCRs.

Assessment of a new insulin preparation for implanted pumps used in the treatment of type 1 diabetes.

BACKGROUND: Implanted insulin pumps using the peritoneal route provide long-term improvement of glucose control compared with subcutaneous insulin therapy in type 1 diabetes (T1D) patients. The stability of insulin preparation is critical for a safe use in implanted pumps. Insuman implantable(®) (400 IU/mL) (Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany), a recombinant human insulin, has been developed as a replacement for Insuplant(®) (Aventis Pharma, Frankfurt am Main, Germany), a semisynthetic insulin, the only one used so far. The aim of the study was to demonstrate the noninferiority of Insuman versus Insuplant, in terms of safety and effectiveness when used in implanted pumps. SUBJECTS AND METHODS: The patients enrolled, currently treated for T1D by the Medtronic MiniMed (Northridge, CA) implantable pump model 2007 with Insuplant, were randomized into two study arms and received either Insuman or Insuplant for four pump refill cycles. Each pump refill cycle was 40±5 days. The co-primary end points included glycated hemoglobin (HbA1c) change from baseline and pump infusion accuracy. RESULTS: In total, 169 patients were randomized. Noninferiority of Insuman versus Insuplant was demonstrated both for the HbA1c change from baseline (as a percentage) with intergroup difference of 95% confidence interval (-0.36;+0.11) and for the infusion accuracy assessed by the measured percentage of error at pump refill, as shown by intergroup difference of 95% confidence interval (-5.81; -0.50), in per-protocol populations, although the insulin daily dose was similar. Severe hypoglycemia occurred at least once in 12 versus 11 patients, respectively, and metabolic or technical adverse events were comparable. CONCLUSIONS: Findings suggest that Insuman can safely and effectively replace Insuplant in implanted pumps.

A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients.

BACKGROUND: This article reports a prolonged trial with insulin pumps implanted in patients with type 1 diabetes showing poor glucose control and a high rate of complications. METHODS: We reviewed data from 181 patients undergoing implanted insulin pump therapy. Analysis included hemoglobin A1c (HbA1c) values, body weight, and diabetes complications status. RESULTS: At implantation, the mean age was 43 (range, 19-72) years, mean duration of diabetes was 22.2 (2-52) years, and mean body weight was 68.6 (43-104) kg. The complication status involved retinopathy (62% of patients), neuropathy (34.6%), nephropathy (26%), and cardiovascular disease (14%). Patients' previous insulin treatment regimen was multiple daily injections (17.1%) or continuous subcutaneous insulin infusion (82.9%). HbA1c levels significantly dropped from 7.9 ± 1.2% to 7.6 ± 1.2% after 1 year (P < 0.01) and remained within the range of 7.5-7.6% for up to 5 years. No significant variation of body weight or complications status occurred. CONCLUSIONS: Implanted insulin pump therapy demonstrates long-term benefits in type 1 diabetes patients who have poor prognosis under intensive subcutaneous treatment.

Low HDL-cholesterol: a strong predictor of glycemic response to glitazone treatment in patients with type 2 diabetes.

We performed a study in 102 people with type 2 diabetes aiming to determine "easy-to-use" predictive factors for glycemic response to glitazones. We found that low baseline HDL-cholesterol (<40 mg/L [1.04 mmol/L] in males, <50 mg/L [1.30 mmol/L] in females) was a strong independent predictor of glycemic response to glitazones (OR=2.67 [2.02-3.52], p=0.0004).

Endogenous chronic hyperinsulinemia does not increase the production rate of VLDL apolipoprotein B: proof from a kinetic study in patients with insulinoma.

OBJECTIVE: It is currently suggested that chronic hyperinsulinemia is a causal factor for the increased production rate of very-low-density lipoproteins (VLDL) associated with metabolic syndrome. However, the involvement of hyperinsulinemia independently of the other abnormalities also observed in metabolic syndrome has never been proven in humans. DESIGN: We used patients with insulinoma showing hyperinsulinemia but no insulin resistance as a model and conducted an apolipoprotein B (apoB) kinetic study in seven patients with insulinoma, seven insulin-resistant (IR) obese patients, and 12 controls. RESULTS: Insulinemia was higher in patients with insulinoma or IR than in controls both in the fasting state [2.4-fold (P = 0.039) and 3.1-fold (P = 0.003), respectively] and in the fed state [3.5-fold (P = 0.006) and 2.6-fold (P = 0.05), respectively]. Patients with insulinoma were not IR (steady state plasma glucose = 80 ± 46 mg/dl, a value lower than in IR subjects (231 ± 75, P = 0.0013). In the fed state, triglyceridemia and VLDL apoB pool size were higher in IR subjects compared with controls and patients with insulinoma [208 ± 56 vs. 89 ± 30 mg/dl (P < 0.0001) and 96 ± 42 mg/dl (P < 0.0001), respectively, for triglyceridemia and 3.56 ± 0.60 vs. 1.85 ± 0.88 mg/kg (P = 0.004) and 2.32 ± 1.79 (P = 0.052) mg/kg for VLDL apoB pool size]. The production rate of VLDL apoB in subjects with insulinoma was not significantly different from that in controls (14.56 ± 7.43 vs. 16.40 ± 7.70 mg/kg · d) but was higher in IR subjects compared with these two groups [25.66 ± 12.84 mg/kg · d (P = 0.046 and 0.035, respectively)]. CONCLUSION: Chronic endogenous hyperinsulinemia is not directly responsible for any increase in the production rate of VLDL apoB in humans.

Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes.

Catabolism of HDL particles is accelerated in type 2 diabetes, leading to a reduction in plasma residence time, which may be detrimental. Rosuvastatin is the most powerful statin to reduce LDL-cholesterol, but its effects on HDL metabolism in type 2 diabetes remain unknown. We performed a randomized double-blind cross-over trial of 6-week treatment period with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes. An in vivo kinetic study of HDL-apolipoprotein A-I (apoA-I) with (13)C leucine was performed at the end of each treatment period. Moreover, a similar kinetic study was carried out in eight nondiabetic normolipidemic controls. Rosuvastatin significantly reduced plasma LDL-cholesterol (-51%), triglycerides (TGs) (-38%), and HDL-TG (-23%). HDL-apoA-I fractional catabolic rate (FCR) was decreased by rosuvastatin (0.25 +/- 0.06 vs. 0.32 +/- 0.07 pool/day, P = 0.011), leading to an increase in plasma HDL-apoA-I residence time (4.21 +/- 1.02 vs. 3.30 +/- 0.73 day, P = 0.011). Treatment with rosuvastatin was associated with a concomitant reduction of HDL-apoA-I production rate. The decrease in HDL-apoA-I FCR, induced by rosuvastatin, was correlated with the reduction of plasma TGs and HDL-TG. HDL apoA-I FCR and production rate values in diabetic patients on rosuvastatin were not different from those found in controls. Rosuvastatin is responsible for a 22% reduction of HDL-apoA-I FCR and restores to normal the increased HDL turnover observed in type 2 diabetes. These kinetic modifications may have beneficial effects by increasing HDL plasma residence time.

No change in apolipoprotein AI metabolism when subcutaneous insulin infusion is replaced by intraperitoneal insulin infusion in type 1 diabetic patients.

In type 1 diabetic patients, the replacement of subcutaneous insulin infusion by intraperitoneal insulin infusion restores the normal physiological gradient between the portal vein and the peripheral circulation, which is likely to modify HDL metabolism. This stable isotope kinetic study was designed to compare HDL apolipoprotein (apo) AI metabolism in seven type 1 diabetic patients first treated by continuous subcutaneous insulin infusion by an external pump and then 3 months after the beginning of intraperitoneal insulin infusion by an implantable pump. Glycaemic control was comparable under subcutaneous and intraperitoneal insulin infusion (HbA1c=7.34+/-0.94% versus 7.24+/-1.00%, NS). HDL composition was similar under both insulin regimens (esterified cholesterol=20.1+/-2.5% versus 24.0+/-3.0% (NS), free cholesterol=3.4+/-1.1% versus 3.3+/-0.9% (NS), triglycerides=2.4+/-0.9% versus 2.1+/-0.9% (NS), phospholipids=22.7+/-5.3% versus 25.2+/-6.5% (NS) and proteins=51.2+/-6.3% versus 45.5+/-4.7% (NS)). The replacement of subcutaneous insulin infusion by intraperitoneal insulin infusion induced significant changes neither in apoAI fractional catabolic rate, nor in apoAI production rate, nor in apoAI pool size (respectively, 0.199+/-0.051 pool d(-1) versus 0.211+/-0.017 pool d(-1), 12.0+/-3.2 mg kg(-1)d(-1) versus 12.1+/-1.8 mg kg(-1)d(-1), 60.4+/-5.0 mg kg(-1) versus 57.5+/-7.5 mg kg(-1)). In conclusion, HDL metabolism is not modified by the replacement of subcutaneous insulin infusion by intraperitoneal insulin infusion when glycaemia is well controlled under both insulin regimens. As far as HDL metabolism is concerned there is no advantage in favour of one way of insulin administration or another.