Basal Plasma Nonesterified Fatty Acids Research Articles

Pregnancy but Not Moderate Undernutrition Attenuates Insulin Suppression of Fat Mobilization in Sheep , ,

Nonpregnant and late-pregnant ditocous ewes were fed either to maintain zero energy balance in maternal tissues (fed) or at 50% of this level (underfed) for several weeks. Plasma concentrations of nonesterified fatty acids (NEFA) and glycerol were measured under basal conditions and during infusion of various doses of insulin while maintaining euglycemia (hyperinsulinemic, euglycemic clamp technique). Pregnancy and undernutrition separately increased basal plasma NEFA concentration in an additive manner; plasma glycerol was increased by pregnancy but unaffected by undernutrition. The molar ratio of NEFA to glycerol was significantly greater in underfed ewes. Analysis of dose-response relations between plasma insulin and metabolites during insulin infusions showed that maximally insulin-suppressed concentrations of NEFA and glycerol were significantly greater in pregnant than in nonpregnant ewes but were unaffected by undernutrition. Neither pregnancy nor undernutrition affected the maximally insulin-suppressed NEFA to glycerol ratio, or the plasma insulin concentration for 50% maximal responses to insulin of plasma NEFA, plasma glycerol, or the plasma NEFA to glycerol ratio. Thus, even in ewes at or close to zero energy balance, pregnancy seems to reduce adipose responsiveness but not sensitivity to the antilipolytic effect of insulin. This is another manifestation of the normal development of insulin resistance in maternal tissues during late pregnancy.

Alterations in plasma non-esterified fatty acid (NEFA) kinetics and relationship with insulin resistance in polycystic ovary syndrome.

Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. Not applicable.

Effects of abomasal infusion of tallow or camelina oil on responses to glucose and insulin in dairy cows during late pregnancy

Late pregnancy is associated with moderate insulin resistance in ruminants. Reduced suppression of lipolysis by insulin facilitates mobilization of nonesterified fatty acids (NEFA) from adipose tissue, resulting in elevated plasma NEFA concentrations. Decrease in dry matter intake (DMI) before parturition leads to accelerated lipomobilization and increases plasma NEFA, which may further impair insulin sensitivity. The aim of the study was to evaluate the effects of elevation of plasma NEFA concentration by abomasal infusions tallow (TAL) or camelina oil (CAM) on whole-body responses to exogenous glucose and insulin. We further assessed whether CAM, rich in C18:3n-3, enhances whole-body insulin sensitivity compared with TAL. Six late-pregnant, second-parity, rumen-cannulated dry Ayrshire dairy cows fed grass silage to meet 95% of metabolizable energy requirements were used in a replicated 3×3 Latin square with 5-d periods and 5 recovery days between each period. Treatments consisted of abomasal infusion of 500mL/d (430g of lipids/d) of water (control), TAL, or CAM administered in 10 equal doses daily. Intravenous glucose tolerance test (IVGTT) and i.v. insulin challenge (IC) were performed on d 5 after 98 and 108h of treatment infusions, respectively. Infusion of lipids increased basal plasma NEFA concentrations on d 5 (CAM: 0.25; TAL: 0.28; control: 0.17mmol/L). Following glucose injection, the rate of glucose clearance (CR) was lower in lipid-treated cows (CAM: 1.34; TAL: 1.48; control: 1.74%/min) and time to reach half-maximal glucose concentration (T1/2) was longer (CAM: 54; TAL: 47; control: 42min). Similar responses were observed after insulin injection. Increased plasma NEFA concentration tended to decrease insulin secretion in IVGTT. Infusion of CAM increased plasma C18:3n-3 content (CAM: 26.4; TAL: 16.1; control: 20.9 g/100g of fatty acids). Data suggest that CAM had an insulin-sensitizing effect, because the disposition index and insulin sensitivity index, derived from minimal model analysis, were higher in CAM than in TAL during IVGTT, and lower insulin concentrations during IC led to similar glucose clearance in CAM as in TAL. These results indicate that elevated plasma NEFA concentration per se induces whole-body insulin resistance in late-pregnant dry cows.

Multitissue Insulin Resistance Despite Near-Normoglycemic Remission in Africans With Ketosis-Prone Diabetes

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m−2 body surface · min−1 and 80 mU · m−2 · min −1 insulin infusion rates) euglycemic clamp with [6,6-2H2]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg−1 · min−1; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg−1 · min−1; P = 0.001) and after 200-min insulin infusion (10 mU · m−2 · min−1: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m−2 · min−1: 0.3 ± 0.1 vs. 0 mg · kg−1 · min−1, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m−2 · min−1 insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015).CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.

Effects of Abomasal Infusion of Linseed Oil on Responses to Glucose and Insulin in Holstein Cows

The objective was to study the effects of abomasal infusion of linseed oil, a source rich in n-3 C18:3, on whole-body response to insulin (experiment 1) and on insulin antilipolytic effects during feed restriction (experiment 2). In experiment 1, eight nonlactating, non-gestating cows were assigned to a crossover design, fed to meet maintenance requirements, and infused abomasally with either linseed oil (LIN) or tallow (TAL) at a rate of 0.54g/kg of body weight per d for 5.5 d. Infusions were performed every 8h during the first 3 d of each period and every 4h thereafter. Intravenous glucose tolerance tests (IVGTT) were performed on d 5 of each period, followed by i.v. insulin challenges (IC) 12h later. In experiment 2, six nonlactating, nongestating cows were assigned to a replicated 3×3 Latin square design. The experimental protocol included a water (WTR) treatment and feeding was suspended on d 3, leading to 50 and 62h of feed restriction before IVGTT and IC, respectively. Clearance of glucose during IVGTT and IC was not affected by treatments in either experiment. However, LIN had an insulin sensitizing effect in experiment 1, because a lower insulin concentration led to the same clearance of glucose as TAL. In experiment 1, plasma nonesterified fatty acid (NEFA) concentration was low, reflecting a postprandial state, but NEFA was greater for LIN than TAL during IVGTT (108 vs. 88±4μEq/L) and IC (133 vs. 83±9μEq/L). In experiment 2, insulin concentrations during IVGTT did not differ across treatments. Basal plasma NEFA concentration before IVGTT tended to be greater for LIN than for TAL (612 vs. 508μEq/L). Plasma NEFA clearance rate during IVGTT was greater for LIN than for TAL (2.8 vs. 2.5%/min), leading to a shorter time to reach half NEFA concentration (25 vs. 29min) and greater absolute value of NEFA response area under the curve [AUC; −64,150 vs. −46,402 (μEq/L)×180 min]. Data suggest that LIN enhanced the antilipolytic effects of insulin. Yet, other factors could have been involved because plasma NEFA concentration before IVGTT was 104μEq/L greater for LIN than TAL for unknown reasons.

Plasma non-esterified fatty acid response to a β-adrenergic challenge before or after feeding in energy underfed or overfed, dry or lactating cows

AbstractThe effects of adrenergic challenge (in order to evaluate the adipose tissue lipolytic potential) and time of challenge relative to feeding on the response curve of plasma non-esterified fatty acids (NEFA) in four underfed or overfed non-lactating non-pregnant cows were studied. Basal NEFA and NEFA response to isoproterenol (ISO; 4 nmol/kg body weight) were higher when challenged before than after feeding and higher in underfed than overfed cows. Interaction between feeding level and time of challenge was significant (P < 0·001) for the rising part of NEFA response. Pooled NEFA response curves from several trials (no. = 63 challenges) were analysed in order to obtain a simplified procedure for the prediction of the NEFA response. High correlations were found between the response area or maximal NEFA response and NEFA response at 15 min (r = 0·95 and 0·98, respectively). This simplified procedure was applied on pooled data from 84 challenges in order to evaluate the effects of energy balance, physiological status, body condition score (BCS) and time of challenge relative to feeding. Energy balance had a significant effect on basal plasma NEFA and NEFA response at 15 min after ISO challenge (–7·6 and –14·2 μmol/l when the daily energy balance increased by 1 MJ, respectively). Time of ISO injection relative to feeding had a greater effect on stimulated NEFA than on basal NEFA (308 v. 239 μmol/l). There was a significant effect of BCS (41 μmol/l per unit of BCS) on the basal plasma NEFA level. The NEFA response at 15 min after ISO challenge was lower (387 μmol/l) in lactating cows than in dry cows. The NEFA response to ISO at 15 min could provide an efficient method of studying the adipose tissue lipolytic potential of cattle in vivo.

Somatotropin Treatment Does Not Affect Nonesterified Fatty Acid Response to Adrenergic Injections in Underfed or Overfed Nonlactating Cows

This experiment was conducted to determine the respective effects of bovine somatotropin (bST) and energy balance on the in vivo responses on plasma nonesterified fatty acids and glucose to isoproterenol (a nonselective β-agonist) or epinephrine injection in nonlactating nonpregnant cows. Two groups of adult Holstein cows were either underfed (n = 4) at 75%, or overfed (n = 5) at 150% of maintenance energy requirement, respectively. Cows received or did not receive a subcutaneous injection of Sometribove (500 mg) during two experimental periods (cross-over design). Adrenergic or placebo injections (4 nmol/kg body weight of epinephrine or isoproterenol or 4 mL of sterile saline) were administered intravenously on d 7–9 after bovine somatotropin injection, 1 h before or 3.5 h after feeding for under- or overfed cows, respectively. Glucose and nonesterified fatty acid responses to each challenge were calculated as area under the response curve and above the base line, from the time of challenge until 60 min postchallenge. Basal plasma nonesterified fatty acids and their response to adrenergic injections were enhanced by underfeeding. Responses of nonesterified fatty acids to isoproterenol injection were higher than they were to epinephrine injection. Basal plasma glucose was enhanced by bovine somatotropin treatment, which increased the glucose response at 5 min after adrenergic injections. Response of plasma glucose was higher after epinephrine than after isoproterenol injection. Treatment with bovine somatotropin did not change plasma nonesterified fatty acid responses to epinephrine or isoproterenol injection in under- or overfed cows, at constant energy intake, whereas underfeeding modified these responses markedly.

Effects of bovine somatotropin and insulin on whole-body and hindlimb glucose metabolism in growing steers

Six Holstein steers (245 kg initial BW) were surgically prepared with chronic catheters to allow measurement of blood flow and nutrient flux across the hindlimb. Steers were used in a single-reversal design with 16-d treatment periods of daily i.m. injection of either excipient (control) or recombinantly derived bovine somatotropin (120 micrograms/kg BW). On d 15 of each period, whole-body and hindlimb glucose metabolism were studied during a primed continuous infusion of [6(-3)H]glucose, under both basal conditions and during a hyperinsulinemic/euglycemic clamp. Somatotropin increased (P < .01) basal blood glucose and serum insulin by 7 and 150% respectively, with no change in glucose irreversible loss rate (ILR). There was no effect of somatotropin on hindlimb blood flow or oxygen consumption. In contrast, hindlimb lactate uptake (P < .02) and the ratio of glucose to oxygen uptake (P < .08) were reduced by somatotropin. Insulin infusion stimulated (P < .01) glucose ILR and inhibited (P < .02) endogenous glucose production to a lesser extent during somatotropin treatment. Basal plasma nonesterified fatty acid concentrations were increased (P < .01) during somatotropin treatment and decreased (P < .02) during insulin infusion. Insulin infusion increased hindlimb blood flow and glucose uptake to similar extents during both treatment periods. These data demonstrate that somatotropin treatment of growing steers decreases response of tissues to insulin (sensitivity in muscle, sensitivity, and responsiveness in liver and adipose tissue), thereby increasing glucose availability to other tissues.

Pregnancy but Not Moderate Undernutrition Attenuates Insulin Suppression of Fat Mobilization in Sheep , ,

Nonpregnant and late-pregnant ditocous ewes were fed either to maintain zero energy balance in maternal tissues (fed) or at 50% of this level (underfed) for several weeks. Plasma concentrations of nonesterified fatty acids (NEFA) and glycerol were measured under basal conditions and during infusion of various doses of insulin while maintaining euglycemia (hyperinsulinemic, euglycemic clamp technique). Pregnancy and undernutrition separately increased basal plasma NEFA concentration in an additive manner; plasma glycerol was increased by pregnancy but unaffected by undernutrition. The molar ratio of NEFA to glycerol was significantly greater in underfed ewes. Analysis of dose-response relations between plasma insulin and metabolites during insulin infusions showed that maximally insulin-suppressed concentrations of NEFA and glycerol were significantly greater in pregnant than in nonpregnant ewes but were unaffected by under-nutrition. Neither pregnancy nor undernutrition affected the maximally insulin-suppressed NEFA to glycerol ratio, or the plasma insulin concentration for 50% maximal responses to insulin of plasma NEFA, plasma glycerol, or the plasma NEFA to glycerol ratio. Thus, even in ewes at or close to zero energy balance, pregnancy seems to reduce adipose responsiveness but not sensitivity to the antilipolytic effect of insulin. This is another manifestation of the normal development of insulin resistance in maternal tissues during late pregnancy.