scholarly journals Sustained endogenous glucose production, diminished lipolysis and non-esterified fatty acid appearance and oxidation in non-obese women at high risk of type 2 diabetes

2006 ◽  
Vol 155 (3) ◽  
pp. 469-476 ◽  
Author(s):  
Shareen Forbes ◽  
Stephen Robinson ◽  
Jason Dungu ◽  
Victor Anyaoku ◽  
Peter Bannister ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
At Risk ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Oxidation ◽  
Glucose Production ◽  
Whole Body ◽  
Acid Oxidation ◽  
Obese Women

Objective: To evaluate early defects in glucose production, lipolysis and fatty acid oxidation in non-obese, normally glucose tolerant women, who are nevertheless at risk of type 2 diabetes. Methods: Ten women with previous gestational diabetes (pGDM) and ten controls were studied in two 4 h infusions of stable isotopes 6,6-2H2-glucose, 1-13C-palmitate, and 1,1,2,3,3-2H5-glycerol with and without infusion of adrenaline. Fatty acid oxidation was quantified using indirect calorimetry and 13CO2 measurements. Insulin sensitivity was evaluated using the short insulin tolerance test. Results: The pGDM and control women were non-obese and carefully matched for body mass index and fat mass. Whole body insulin sensitivity and basal insulin concentrations did not differ significantly but basal glucose concentrations were increased in women with pGDM. During a 0.9% saline infusion, glucose appearance was not significantly different at the first (90–120 min) and second (210–240 min) steady states. However, glucose appearance decreased in controls but was maintained in the pGDM women (−0.33 ± 0.02 vs −0.03 ± 0.08 mg/kg per min; P = 0.004). Basal glycerol appearance (0.27 ± 0.02 vs 0.38 ± 0.03 mg/kg per min; P = 0.02), palmitate appearance (0.74 ± 0.09 vs 1.05 ± 0.09 mg/kg per min; P = 0.03) and palmitate oxidation (0.07 ± 0.01 vs 0.10 ± 0.01 mg/kg per min; P = 0.03) were lower in the pGDM women. During the adrenaline infusion, changes in glucose, glycerol and palmitate concentrations and kinetics were similar in both groups. Conclusions: Sustained glucose production during fasting is an early abnormality in non-obese subjects at risk of type 2 diabetes. Lipolysis and non-esterified fatty acid appearance and oxidation are diminished, suggesting an increased tendency to store fat. The observations are not readily attributable to differences in insulin or catecholamine sensitivity.

scholarly journals Muscle-Specific Overexpression of CD36 Reverses the Insulin Resistance and Diabetes of MKR Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4667-4676 ◽  
Author(s):  
Lisa Héron-Milhavet ◽  
Martin Haluzik ◽  
Shoshana Yakar ◽  
Oksana Gavrilova ◽  
Stephanie Pack ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cell Function ◽  
Dominant Negative ◽  
Whole Body ◽  
Acid Oxidation

Abstract Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5–6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, β-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.

Effect of adipocyte β3-adrenergic receptor activation on the type 2 diabetic MKR mice

2006 ◽  
Vol 290 (6) ◽  
pp. E1227-E1236 ◽  
Author(s):  
Hyunsook Kim ◽  
Patricia A. Pennisi ◽  
Oksana Gavrilova ◽  
Stephanie Pack ◽  
William Jou ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Receptor Activation ◽  
Whole Body ◽  
Acid Oxidation ◽  
Adrenergic Agonists ◽  
Nonobese Diabetic ◽  
Type 2 Diabetic

The antiobesity and antidiabetic effects of the β3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a β3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that β3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for β3-adrenergic agonists in nonobese diabetic subjects.

scholarly journals Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

2016 ◽  
Vol 310 (6) ◽  
pp. E452-E460 ◽  
Author(s):  
K. J. Mather ◽  
G. D. Hutchins ◽  
K. Perry ◽  
W. Territo ◽  
R. Chisholm ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Metabolic Flexibility ◽  
Work Efficiency ◽  
Myocardial Fatty Acid ◽  
Fuel Selection

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m−2·min−1) to 3-h saline infusion. Lean controls ( n = 10) were compared with glycemically controlled volunteers with T2DM ( n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption ( P = 0.04) and perfusion ( P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids ( P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions ( P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups ( P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM ( P = 0.003). Myocardial work efficiency was lower in T2DM ( P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization ( P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

scholarly journals Blunted Reduction of Postprandial Acylcarnitine in Type 2 Diabetes and Identification of C16:0 as a New Marker of Excessive Fatty Acid Oxidation

2013 ◽  
Vol 37 ◽  
pp. S62
Author(s):  
Fatima-Zahra Bouchouirab ◽  
Mélanie Fortin ◽  
Frédérique Frish ◽  
Jean Dubé ◽  
André Carpentier
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

Lipid metabolism, exercise and insulin action

2006 ◽  
Vol 42 ◽  
pp. 47-59 ◽  
Author(s):  
Arend Bonen ◽  
G. Lynis Dohm ◽  
Luc J.C. van Loon
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Severely Obese

Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

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.

Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria

2013 ◽  
Vol 305 (5) ◽  
pp. H634-H643 ◽  
Author(s):  
Paul M. Rindler ◽  
Clair L. Crewe ◽  
Jolyn Fernandes ◽  
Michael Kinter ◽  
Luke I. Szweda
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Redox Regulation ◽  
Acid Oxidation ◽  
Glucose Accumulation ◽  
Intracellular Glucose

Obesity enhances the risk for the development of type 2 diabetes and cardiovascular disease. Loss in insulin sensitivity and diminished ability of muscle to take up and use glucose are characteristics of type 2 diabetes. Paradoxically, regulatory mechanisms that promote utilization of fatty acids appear to initiate diet-induced insulin insensitivity. In this review, we discuss recent findings implicating increased mitochondrial production of the prooxidant H2O2 due to enhanced utilization of fatty acids, as a signal to diminish reliance on glucose and its metabolites for energy. In the short term, the ability to preferentially use fatty acids may be beneficial, promoting a metabolic shift that ensures use of available fat by skeletal muscle and heart while preventing intracellular glucose accumulation and toxicity. However, with prolonged consumption of high dietary fat and ensuing obesity, the near exclusive dependence on fatty acid oxidation for production of energy by the mitochondria drives insulin resistance, diabetes, and cardiovascular disease.

scholarly journals Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity

2000 ◽  
Vol 89 (6) ◽  
pp. 2276-2282 ◽  
Author(s):  
Jeffrey F. Horowitz ◽  
Samuel Klein
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Abdominal Obesity ◽  
Fat Free Mass ◽  
Peak Oxygen Consumption ◽  
Whole Body ◽  
Acid Oxidation ◽  
Plasma Fatty Acid ◽  
Obese Women

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 ± 1 vs. 38 ± 1 kg/m2), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([13C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 ± 0.4 vs. 4.0 ± 0.3 μmol · kg fat free mass (FFM)−1 · min−1]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 ± 1.7 vs. 14.5 ± 1.8 μmol · kg FFM−1 · min−1; P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 ± 1.2 vs. 17.5 ± 1.6 μmol · kg FFM−1 · min−1; P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.

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