Abstract 16993: An Antisense Inhibitor of Apolipoprotein C-III Significantly Decreases Nonesterified Fatty Acid Levels in Severe Hypertriglyceridemic Patients

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Veronica Alexander ◽  
Diane Brisson ◽  
JoAnn Flaim ◽  
Steve Hughes ◽  
Walter Singleton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Nonesterified Fatty Acid ◽  
Serum Samples ◽  
Double Blind ◽  
Apolipoprotein C ◽  
Severe Hypertriglyceridemia ◽  
End Of Treatment

Background: Apolipoprotein C-III (apoC-III), a CV risk factor, plays a pivotal role in regulating plasma triglyceride (TG) levels. Elevated TG and its nonesterified fatty acid (NEFA) derivatives are associated with insulin resistance and type 2 diabetes. ISIS-APOCIII Rx selectively inhibits apoC-III protein synthesis in the liver and studies show it may improve insulin sensitivity in patients with type 2 diabetes. Treatment with ISIS-APOCIII Rx results in significant dose-dependent decreases in apoC-III and TG levels (Table) in patients with severe hypertriglyceridemia (SHTG) as monotherapy or add on to a stable dose of fibrate. The present study assessed the potential resulting change in NEFA levels in these patients. Methods: Adult patients with SHTG treated or untreated with fibrate were enrolled in a double-blind Phase 2 study to receive ISIS-APOCIII Rx (up to 300 mg) or placebo as weekly SC injections for 13 weeks. Baseline and end-of-treatment fasting serum samples were analyzed for NEFA levels. Results: Results show significant reductions in NEFA levels in line with reductions in TG levels at the 300 mg/week dose (the Phase 3 dose) of ISIS-APOCIII Rx (Table). ISIS-APOCIII Rx was generally safe and well tolerated. There were no clinically meaningful changes in liver tests or other laboratory values. Conclusions: Treatment with ISIS-APOCIII Rx reduces NEFA levels together with decreases in TG in patients with treated or untreated SHTG suggesting the potential for improvement in peripheral insulin sensitivity in these patients.

scholarly journals Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haya Al-Sulaiti ◽  
Ilhame Diboun ◽  
Maha V. Agha ◽  
Fatima F. S. Mohamed ◽  
Stephen Atkin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Serum Samples ◽  
Metabolic Markers ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Novel Biomarkers ◽  
Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

scholarly journals Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial

2021 ◽  
Author(s):  
Yvo J.M. Op den Kamp ◽  
Marlies de Ligt ◽  
Bas Dautzenberg ◽  
Esther Kornips ◽  
Russell Esterline ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Caloric Restriction ◽  
Sglt2 Inhibitor ◽  
Metabolic Effects ◽  
Night Time ◽  
Double Blind ◽  
Urinary Glucose

<b>Background:</b> SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24h energy metabolism and insulin sensitivity in patients with type 2 diabetes mellitus. <p><b>Methods</b>: Twenty-six type 2 diabetes patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. 24h energy metabolism and respiratory exchange ratio (RER) were measured by indirect calorimetry, both by whole-room calorimetry and by ventilated hood during a two-step euglycemic hyperinsulinemic clamp. Results are presented as the differences in least squares mean (LSM) (95% CI) between treatments.</p> <p><b>Results</b>: Evaluable patients (n=24) had a mean (SD) age of 64<b>.</b>2(4<b>.</b>6) years, BMI of 28<b>.</b>1(2<b>.</b>4) kg/m2, and HbA1c of 6.9 (0.7)% (51<b>.</b>7 (6<b>.</b>8) mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, while fasting endogenous glucose production (EGP) increased by dapagliflozin (+2<b>.</b>27 (1<b>.</b>39, 3<b>.</b>14) μmol/kg/min, p<0<b>.</b>0001). Insulin-induced suppression of EGP (-1<b>.</b>71 (-2<b>.</b>75, -0<b>.</b>63) μmol/kg/min, p=0<b>.</b>0036) and plasma free fatty acids (-21<b>.</b>93 (-39<b>.</b>31, -4<b>.</b>54) %, p=0.016) was greater with dapagliflozin. 24h energy expenditure (-0.11 (-0.24, 0.03) MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced RER during day- and night-time resulting in an increased day to night-time difference in RER (-0.010 (-0.017, -0.002), p=0.016). Dapagliflozin treatment resulted in a negative 24h energy and fat balance (-20.51 (-27.90, -13.12) g/day). </p> <p><b>Interpretation</b>: Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction; increased fat oxidation, improved hepatic and adipose insulin sensitivity and improved 24h energy metabolism.</p>

Examining the benefits of cold exposure as a therapeutic strategy for obesity and type 2 diabetes.

2021 ◽  
Author(s):  
Yoanna M. Ivanova ◽  
Denis P. Blondin
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Cold Exposure ◽  
Skeletal Muscles ◽  
Cardiovascular Responses ◽  
Whole Body ◽  
Healthy Individuals

The pathogenesis of metabolic diseases such as obesity and type 2 diabetes are characterized by a progressive dysregulation in energy partitioning, often leading to end-organ complications. One emerging approach proposed to target this metabolic dysregulation is the application of mild cold exposure. In healthy individuals, cold exposure can increase energy expenditure and whole-body glucose and fatty acid utilization. Repeated exposures can lower fasting glucose and insulin levels and improve dietary fatty acid handling, even in healthy individuals. Despite its apparent therapeutic potential, little is known regarding the effects of cold exposure in populations for which this stimulation could benefit the most. The few studies available, have shown that both acute and repeated exposures to the cold improve insulin sensitivity and reduce fasting glycemia in individuals with type 2 diabetes. However, critical gaps remain in understanding the prolonged effects of repeated cold exposures on glucose regulation and whole-body insulin sensitivity in individuals with metabolic syndrome. Much of the metabolic benefits appear to be attributable to the recruitment of shivering skeletal muscles. However, further work is required to determine whether the broader recruitment of skeletal muscles observed during cold exposure can confer metabolic benefits that surpass what has been historically observed from endurance exercise. In addition, while cold exposure offers unique cardiovascular responses for a physiological stimulus that increases energy expenditure, further work is required to determine how acute and repeated cold exposure can impact cardiovascular responses and myocardial function across a broader scope of individuals.

scholarly journals Impaired Plasma Nonesterified Fatty Acid Tolerance Is an Early Defect in the Natural History of Type 2 Diabetes

2008 ◽  
Vol 93 (3) ◽  
pp. 837-844 ◽  
Author(s):  
P. Brassard ◽  
F. Frisch ◽  
F. Lavoie ◽  
D. Cyr ◽  
A. Bourbonnais ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Natural History ◽  
Healthy Subjects ◽  
Nonesterified Fatty Acid ◽  
Isotopic Tracers ◽  
Insulin Levels ◽  
High Insulin ◽  
History Of

Abstract Context: Abnormal plasma nonesterified fatty acid (NEFA) metabolism may play a role in the development of type 2 diabetes. Objectives: Our objectives were to demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (RaNEFA) and oxidation (OxNEFA) during enhanced intravascular triacylglycerol lipolysis early in the natural history of type 2 diabetes, and if so, to determine whether other mechanisms than reduced insulin-mediated suppression of intracellular lipolysis are involved. Design: These are cross-sectional studies. Setting: The studies were performed at an academic clinical research center. Participants: Nine healthy subjects with both parents with type 2 diabetes (FH+) and nine healthy subjects with no first-degree relatives with type 2 diabetes (FH−) with similar anthropometric features were included in the studies. Interventions: Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-2H5]-glycerol and [U-13C]-palmitate or [1,2-13C]-acetate) were performed while intravascular triacylglycerol lipolysis was simultaneously clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Oral nicotinic acid (NA) was used to inhibit intracellular lipolysis. Main Outcome Measures: RaNEFA and OxNEFA were determined. Results: During heparin plus Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher RaNEFA and OxNEFA than FH− (RaNEFA: 17.4 ± 6.3 vs. 9.2 ± 4.2; OxNEFA: 4.5 ± 1.8 vs. 2.3 ± 1.5 μmol/kg lean body mass/min), independent of NA intake, gender, age, and body composition. In the presence of NA, insulin-mediated suppression of RaNEFA was still observed in FH−, but not in FH+. Conclusions: Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.

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