Suppression Of Nonesterified Fatty Acids Research Articles

NEFA Dynamics in Adults With Severe Obesity and Insulin Resistance: No Coupling to the rs9939609 FTO Risk Allele.

The FTO gene is highly expressed in adipose tissues; however, whether nonesterified fatty acids (NEFA) dynamics are impacted by FTO has not been rigorously tested for in a uniformly obese study population comprising both sexes. To test for associations of the rs9939609 FTO risk allele with NEFA suppression. We investigated 97 subjects with severe obesity but without diabetes, having genotype TT (n = 32), AT (n = 31), or AA (n = 34) in a cross-sectional observation study. NEFA suppression was assessed from a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer as well as from the response to a standardized meal. Insulin sensitivity was assessed by hepatic and total insulin sensitivity measurements in the clamp and by the Matsuda index during the meal. Variables of possible importance for NEFA dynamics were primarily assessed by linear regression. No genotype associations with fasting or suppressed NEFA were found, whether in the clamp or meal situation (P > .7 for all comparisons). Independent of genotype, higher fasting concentrations of NEFA and larger NEFA suppression were found in female compared with male subjects. Fasting NEFA or degree of suppression were not associated with total fat mass or body mass index. The respiratory quotient was negatively associated with NEFA suppression. In a gender-mixed adult population of obese individuals, an FTO obesity-risk allele did not affect fasting NEFA nor suppression thereof. These negative results on NEFA dynamics appear strengthened by the documentation of gender influence and associations with parameters reflective of insulin resistance.

Effects of a High Fat Meal Challenge with Different Doses of Spice Blend on Postprandial Fatty Acid Suppression (P08-094-19)

ObjectivesHigh fat meals can increase inflammation and plasma triglycerides. Poor suppression of postprandial adipocyte lipolysis results in higher levels of non-esterified fatty acids (NEFA) in insulin resistant subjects. This impaired suppression of NEFA may exacerbate hypertriglyceridemia following a high fat meal by increasing available fatty acids. We have shown myristic acid (MA) and stearic acid (SA) are less suppressed than other fatty acids 1 hour following a glucose challenge, and this pattern may indicate optimal adipocyte insulin sensitivity. It is unknown if the same pattern occurs in other contexts, such as high fat meal. MethodsPlasma samples were collected from 12 obese male subjects at baseline and 4 time points following a high fat meal (1076 kcal, 39% kcal from saturated fat) on three visits. Meals contained either 0, 2, or 6 grams of a spice blend. Plasma was analyzed by GC-MS to measure multiple fatty acids, including MA, SA, palmitic acid (PA), oleic acid (OA), and linoleic acid (LA). ResultsAt 1 hour following the high fat meal, MA and SA were less suppressed than OA, PA, and LA (P < 0.0001). Total NEFA concentrations were most suppressed (61%; CI: 46%, 76%) at 2 hours following the meal and remained suppressed until 4 hours. PA (59%, P < 0.0001), SA (43%, P < 0.001), OA (68%, P < 0.0001), and LA (71%, P < 0.0001) also achieved maximal suppression at 2 hours and remained suppressed. MA was suppressed (34%, P = 0.0002) at 1 hour, then returned to baseline. Compared to baseline, all saturated fatty acids increased as % of total NEFA at 2 hours (MA: 0 hr, 1.8%, 2 hr, 3.7%, P < 0.0001; PA: 0 hr, 24%, 2 hr, 26%, P = 0.009; SA: 0 hr, 8%, 2 hr, 12%, P < 0.0001), while the unsaturated fatty acids decreased (OA: 0 hr, 33%, 2 hr, 25%, P < 0.0001; LA: 0 hr, 24%, 2 hr, 19%, P < 0.0001). There was no significant effect of spice. ConclusionsNEFA was most suppressed at 2 hours following a high fat meal challenge, but MA and SA were suppressed less than all other fatty acids. Saturated fatty acids increased as a % of total NEFA following the meal challenge, while unsaturated fatty acids decreased. These data support our previous findings that MA and SA are less suppressed by insulin than other fatty acids. Funding SourcesMcCormick Science Institute; Penn State Department of Nutritional Sciences; National Center for Advancing Translational Sciences, NIH, (UL1 TR002014).

The acute effects of dietary carbohydrate reduction on postprandial responses of non-esterified fatty acids and triglycerides: a randomized trial

BackgroundPostprandial non-esterified fatty acid (NEFA) and triglyceride (TG) responses are increased in subjects with type 2 diabetes mellitus (T2DM) and may impair insulin action and increase risk of cardiovascular disease and death. Dietary carbohydrate reduction has been suggested as non-pharmacological therapy for T2DM, but the acute effects on NEFA and TG during subsequent meals remain to be investigated.MethodsPostprandial NEFA and TG responses were assessed in subjects with T2DM by comparing a carbohydrate-reduced high-protein (CRHP) diet with a conventional diabetes (CD) diet in an open-label, randomized, cross-over study. Each diet was consumed on two consecutive days, separated by a wash-out period. The iso-caloric CRHP/CD diets contained 31/54 E% from carbohydrate, 29/16 E% energy from protein and 40/30 E% from fat, respectively. Sixteen subjects with well-controlled T2DM (median HbA1c 47 mmol/mol, (37–67 mmol/mol) and BMI 30 ± 4.4 kg/m2) participated in the study. NEFA and TG were evaluated following breakfast and lunch.ResultsNEFA net area under curve (AUC) was increased by 97 ± 38 μmol/Lx270 min (p = 0.024) after breakfast but reduced by 141 ± 33 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. Likewise, TG net AUC was increased by 80 ± 28 μmol/Lx270 min (p = 0.012) after breakfast but reduced by 320 ± 60 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet.ConclusionsIn well-controlled T2DM a modest reduction of dietary carbohydrate with a corresponding increase in protein and fat acutely reduced postprandial serum NEFA suppression and increased serum TG responses after a breakfast meal but had the opposite effect after a lunch meal. The mechanism behind this second-meal phenomenon of CRHP diet on important risk factors for aggravating T2DM and cardiovascular disease awaits further investigation.Trial registrationThe study was registered at clinicaltrials.gov ID: NCT02472951. https://clinicaltrials.gov/ct2/show/NCT02472951. Registered June 16, 2015.

Whey protein lowers systolic blood pressure and Ca-caseinate reduces serum TAG after a high-fat meal in mildly hypertensive adults

Epidemiological studies show an inverse association between dairy consumption and blood pressure (BP) but there are few data on the postprandial effects of milk proteins. This study examined their effects, compared to maltodextrin, on postprandial BP and other CVD risk markers in volunteers with mild and pre-hypertension over an 8 h period. In this double-blinded, randomised, cross-over, controlled study 27 adults ingested a high-fat, isoenergetic breakfast and lunch with 28 g whey protein, 28 g Ca-caseinate or 27 g maltodextrin. Whey protein reduced systolic BP compared with Ca-caseinate (−15.2 ± 13.6 mmHg) and maltodextrin (−23.4 ± 10.5 mmHg) up to 5 h post-ingestion. There was an improvement in arterial stiffness after whey protein compared with maltodextrin (incremental Area Under the Curve- iAUC0–8h: +14.4 ± 6.2%). Despite similar glucose levels after both whey protein and Ca-caseinate, whey protein induced a higher insulin response than Ca-caseinate (iAUC0–8h: +219.5 ± 54.6 pmol/L). Ca-caseinate induced less suppression of non-esterified fatty acids than whey protein (iAUC0–5h: −58.9 ± 135.5 μmol/L) and maltodextrin (iAUC0–5h: −106.9 ± 89.4 μmol/L) and induced a smaller postprandial triacylglycerol response than whey protein (iAUC0–8h: −1.68 ± 0.6 mmol/L). Milk proteins co-ingestion with high-fat meals may have the potential to maintain or improve CVD risk factors.

Evolution of metabolic alterations 5\xa0Years after early puberty in a cohort of girls predisposed to polycystic ovary syndrome

BackgroundWe and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty.MethodsWe conducted a prospective cohort study between 2007 and 2015 with 4–6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8–14 years old and re-assessed after a median follow-up of 5.4 years, at 13–21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DIFSivGTT); and indices of NEFA suppression during FSivGTT (logn-linear slope of NEFA and T50 of NEFA suppression).ResultsAt follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DIFSivGTT = 1926 vs 1380 (p = 0.44), logn-linear slope = −0.032 vs −0.032 (p = 0.88) and T50NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DIFSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p < 0.05).ConclusionsImpaired metabolism observed during early puberty in girls predisposed to PCOS remains stable after 5 years whereas control girls deteriorated their metabolic parameters. Therefore, both groups become comparable in late/post-puberty. Early puberty may thus represent a window during which metabolic alterations are transiently apparent in girls at risk of PCOS.

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Increased Adipose and Muscle Insulin Sensitivity Without Changes in Serum Adiponectin in Young Female Collegiate Athletes.

Background: Effects of endurance training on adipose insulin sensitivity in association with body composition, circulating adipokines, and markers of inflammation have been studied less in young Asian subjects.Methods: Adipose insulin sensitivity/resistance was compared between 170 female Japanese collegiate athletes and 311 nonathletes (18–24 years), who underwent measurements of serum adipokines, markers of insulin sensitivity, inflammation, and dual-energy X-ray absorptiometry. Two separate subsamples of two groups of women underwent either a 75-gram oral glucose tolerance test or a standardized meal test, but not both.Results: As compared with nonathletes, athletes, characterized by higher skeletal muscle mass and lower percentage of body fat (both P < 0.001), had lower adipose insulin resistance (IR) (a product of fasting insulin and nonesterified fatty acid (NEFA) and lower leptin/adiponectin ratio (both P < 0.001). Although athletes had lower postmeal/postglucose insulinemia (P = 0.009 and 0.01, respectively), the two groups did not differ in postmeal percentage NEFA suppression and postmeal/postglucose glycemia, suggesting increased insulin sensitivity in adipose tissue and skeletal muscle, respectively. Serum leptin (P < 0.001) and tumor necrosis factor-α (P = 0.01) were lower in athletes, whereas adiponectin and homeostasis model assessment IR did not differ.Conclusions: Endurance training was associated with increased insulin sensitivity in adipose tissue as well as skeletal muscle without changes in circulating adiponectin even in young, normal-weight Japanese women.

0071 ROLE OF SLEEP RESTRICTION IN ADIPOCYTE INSULIN SENSITIVITY DURING AN INTRAVENOUS GLUCOSE TOLERANCE TEST IN HEALTHY ADULT MEN

Sleep restriction, or chronic partial sleep loss, increases obesity and diabetes risk by disrupting glucose metabolism and reducing whole-body insulin sensitivity without a compensatory increase in insulin secretion. Healthy adipocytes suppress hormone sensitive lipase (HSL) activity in response to insulin, which severely limits non-esterified fatty acid (NEFA) release. Elevated overnight NEFA levels are correlated with the reduction in insulin sensitivity that occurs in sleep restriction. Additionally, subcutaneous adipose biopsies from sleep-restricted subjects have reduced pAKT, evidence that sleep restriction decreases insulin sensitivity in adipocytes. The objective of this pilot study was to extend previous findings of the effects of sleep restriction on plasma glucose to mechanistic shifts within adipocyte metabolism. Subjects (20–35 y/o) were enrolled in an 11-day in-lab protocol; light exposure, activity, temperature, and diet were carefully controlled. An intravenous glucose tolerance test (IVGTT) was performed at three time points: after three nights of baseline sleep (10 hrs/night), after five nights of sleep restriction (5 hrs/night), and after two nights of recovery sleep (10 hrs/night). NEFA were quantified (Wako Diagnostics) and parameters describing NEFA kinetics (i.e. rate of NEFA production, utilization, suppression threshold) in the Boston and Moate minimal model were calculated using WinSAAM Compartmental Modeling software. Five subjects completed the sleep restriction protocol; one did not complete IVGTT procedures for safety reasons. Preliminary results from four subjects show the fractional rate of NEFA utilization was increased by 0.024 [0.009, 0.039] min-1 in the restricted condition (p=0.008). Restriction also increased the modifier of the inhibitory effect of remote glucose on NEFA production by 4.3 fold [1.2, 15.9] from baseline (p=0.04). Sleep restriction induces symmetrical changes in both glucose and lipid markers of insulin sensitivity in vivo. Preliminary evidence indicates that NEFA rate of utilization is increased in response to sleep restriction. In the context of whole-body metabolism, this indicates a shift in Randle cycle fuel selection by metabolic tissues. Additionally, a greater concentration of glucose was required to initiate NEFA suppression, evidence that sleep restriction functionally impairs HSL activity. UL1TR000127 (Chang PI) T32GM108563 (to KMN; Korzick PI).

Adverse effects on insulin secretion of replacing saturated fat with refined carbohydrate but not with monounsaturated fat: A randomized controlled trial in centrally obese subjects

Current dietary guidelines recommend the replacement of saturated fatty acids (SAFAs) with carbohydrates or monounsaturated fatty acids (MUFAs) based on evidence on lipid profile alone, the chronic effects of the mentioned replacements on insulin secretion and insulin sensitivity are however unclear. To assess the chronic effects of the substitution of refined carbohydrate or MUFA for SAFA on insulin secretion and insulin sensitivity in centrally obese subjects. Using a crossover design, randomized controlled trial in abdominally overweight men and women, we compared the effects of substitution of 7% energy as carbohydrate or MUFA for SAFA for a period of 6weeks each. Fasting and postprandial blood samples in response to corresponding SAFA, carbohydrate, or MUFA-enriched meal-challenges were collected after 6weeks on each diet treatment for the assessment of outcomes. As expected, postprandial nonesterified fatty acid suppression and elevation of C-peptide, insulin and glucose secretion were the greatest with high-carbohydrate (CARB) meal. Interestingly, CARB meal attenuated postprandial insulin secretion corrected for glucose response; however, the insulin sensitivity and disposition index were not affected. SAFA and MUFA had similar effects on all markers except for fasting glucose-dependent insulinotropic peptide concentrations, which increased after MUFA but not SAFA when compared with CARB. In conclusion, a 6-week lower-fat/higher-carbohydrate (increased by 7% refined carbohydrate) diet may have greater adverse effect on insulin secretion corrected for glucose compared with isocaloric higher-fat diets. In contrast, exchanging MUFA for SAFA at 7% energy had no appreciable adverse impact on insulin secretion.

Significantly greater triglyceridemia in Black African compared to White European men following high added fructose and glucose feeding: a randomized crossover trial.

BackgroundBlack African (BA) populations are losing the cardio-protective lipid profile they historically exhibited, which may be linked with increasing fructose intakes. The metabolic effects of high fructose diets and how they relate to blood lipids are documented for Caucasians, but have not been described in BA individuals.ObjectiveThe principle objective of this pilot study was to assess the independent impacts of high glucose and fructose feeding in men of BA ancestry compared to men of White European (WE) ancestry on circulating triglyceride (TG) concentrations.MethodsHealthy males, aged 25–60 years, of BA (n = 9) and WE (n = 11) ethnicity were randomly assigned to 2 feeding days in a crossover design, providing mixed nutrient meals with 20 % total daily caloric requirements from either added glucose or fructose. Circulating TG, non-esterified fatty acids (NEFA), glucose, insulin and C-peptide were measured over two 24-h periods.ResultsFasting TGs were lower in BAs than WEs on the fructose feeding day (p < 0.05). There was a trend for fasting TG concentrations 24 h following fructose feeding to increase in both BA (baseline median fasting: 0.80, IQR 0.6–1.1 vs 24-h median post-fructose: 1.09, 0.8–1.4 mmol/L; p = 0.06) and WE (baseline median fasting 1.10, IQR 0.9–1.5 vs 24-h median post-fructose: 1.16, IQR 0.96–1.73 mmol/L; p = 0.06). Analysis within ethnic group demonstrated that in TG iAUC was significantly higher in BA compared to WE on both glucose (35, IQR 11–56 vs −4, IQR −10–1 mmol/L/min; p = 0.004) and fructose (48, IQR 15–68 vs 13, IQR −7–38 mmol/L/min; p = 0.04). Greater suppression of postprandial NEFA was evident in WE than BA after glucose feeding (−73, IQR −81– −52 vs −26, IQR −48– −3 nmol/L/min; p = 0.001) but there was no ethnic difference following fructose feeding.ConclusionsUnderstanding the metabolic effects of dietary acculturation and Westernisation that occurs in Black communities is important for developing prevention strategies for chronic disease development. These data show postprandial hypertriglyceridemia following acute feeding of high added fructose and glucose in BA men, compared to WE men, may contribute to metabolic changes observed during dietary acculturation and Westernisation.Trial registrationThe study was retrospectively registered on clinicaltrials.gov: NCT02533817.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0315-3) contains supplementary material, which is available to authorized users.

Interaction of low dose of fish oil and glucocorticoids on insulin sensitivity and lipolysis in healthy humans: A randomized controlled study.

This study examined the interaction of fish oil (FO) with dexamethasone on glucose and lipid metabolisms in healthy subjects. The study included two consecutive parts. Part A (randomized) in 16 subjects studied the effects of dexamethasone (2 days, 2 mg/day) versus placebo (lactose), part B (two parallel subgroups of eight) studied the interaction of FO (3 wk, 840 mg/day of EPA + DHA) with dexamethasone. Insulin sensitivity of lipolysis (d5-glycerol infusion + microdialysis), endogenous glucose production, and muscle glucose uptake were assessed by a three-step hot insulin clamp and substrate oxidation by indirect calorimetry. Dexamethasone induced liver and peripheral insulin resistance, an increase in fat oxidation, and a decrease in suppression of plasma nonesterified fatty acids (NEFAs). FO amplified the effects of dexamethasone by increasing liver and muscle insulin resistance, by reducing suppression of plasma NEFAs and fat oxidation and by increasing adipose tissue (AT) lipolysis. FO, given at a moderate dose in healthy subjects prior to a very short-term (2 days) low dose of a synthetic glucocorticoid, worsened its deleterious effects on insulin sensitivity. The enhancing effect of FO on fat oxidation and AT lipolysis might be a protective effect toward an increase in fat mass.

Breaking Up Prolonged Sitting With Standing or Walking Attenuates the Postprandial Metabolic Response in Postmenopausal Women: A Randomized Acute Study.

To determine whether breaking up prolonged sitting with short bouts of standing or walking improves postprandial markers of cardiometabolic health in women at high risk of type 2 diabetes. Twenty-two overweight/obese, dysglycemic, postmenopausal women (mean ± SD age 66.6 ± 4.7 years) each participated in two of the following treatments: prolonged, unbroken sitting (7.5 h) or prolonged sitting broken up with either standing or walking at a self-perceived light intensity (for 5 min every 30 min). Both allocation and treatment order were randomized. The incremental area under the curves (iAUCs) for glucose, insulin, nonesterified fatty acids (NEFA), and triglycerides were calculated for each treatment condition (mean ± SEM). The following day, all participants underwent the 7.5-h sitting protocol. Compared with a prolonged bout of sitting (iAUC 5.3 ± 0.8 mmol/L ⋅ h), both standing (3.5 ± 0.8 mmol/L ⋅ h) and walking (3.8 ± 0.7 mmol/L ⋅ h) significantly reduced the glucose iAUC (both P < 0.05). When compared with prolonged sitting (548.2 ± 71.8 mU/L ⋅ h), insulin was also reduced for both activity conditions (standing, 437.2 ± 73.5 mU/L ⋅ h; walking, 347.9 ± 78.7 mU/L ⋅ h; both P < 0.05). Both standing (-1.0 ± 0.2 mmol/L ⋅ h) and walking (-0.8 ± 0.2 mmol/L ⋅ h) attenuated the suppression of NEFA compared with prolonged sitting (-1.5 ± 0.2 mmol/L ⋅ h) (both P < 0.05). There was no significant effect on triglyceride iAUC. The effects on glucose (standing and walking) and insulin (walking only) persisted into the following day. Breaking up prolonged sitting with 5-min bouts of standing or walking at a self-perceived light intensity reduced postprandial glucose, insulin, and NEFA responses in women at high risk of type 2 diabetes. This simple, behavioral approach could inform future public health interventions aimed at improving the metabolic profile of postmenopausal, dysglycemic women.

Liver fat content and hepatic insulin sensitivity in overweight patients with type 1 diabetes.

Patients with type 1 diabetes mellitus (T1DM) lack the portal/peripheral insulin gradient, which might diminish insulin stimulation of hepatic lipogenesis and protect against development of nonalcoholic fatty liver disease (NAFLD). We compared liver fat content and insulin sensitivity of hepatic glucose production and lipolysis between overweight T1DM patients and nondiabetic subjects. We compared 32 overweight adult T1DM patients and 32 nondiabetic subjects matched for age, body mass index (BMI), and gender. Liver fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS), body composition by magnetic resonance imaging, and insulin sensitivity using the euglycemic-hyperinsulinemic clamp technique (insulin 0.4 mU/kg · min combined with infusion of D-[3-(3)H]glucose). We also hypothesized that low liver fat might protect from obesity-associated increases in insulin requirements and, therefore, determined insulin requirements across BMI categories in 3164 T1DM patients. Liver fat content was significantly lower in T1DM patients than in nondiabetic subjects (0.6% [25th-75th quartiles, 0.3%-1.1%] vs 9.0% [3.0%-18.0%]; P < .001). The endogenous rate of glucose production (R(a)) during euglycemic hyperinsulinemia was significantly lower (0.4 [-0.7 to 0.8] mg/kg fat-free mass · min vs 0.9 [0.2-1.6] fat-free mass · min; P = .012) and the percent suppression of endogenous Ra by insulin was significantly greater (89% [78%-112%] vs 77% [50%-94%]; p = .009) in T1DM patients than in nondiabetic subjects. Serum nonesterified fatty acid concentrations during euglycemic hyperinsulinemia were significantly lower (78.5 [33.0-155.0] vs 306 [200.0-438.0] μmol/L; P < .001) and the percent suppression of nonesterified fatty acids significantly higher (89.1% [78.6%-93.3%] vs 51.4% [36.5%-71.1%]; P < .001) in T1DM patients than in nondiabetic subjects. Insulin doses were similar across BMI categories. T1DM patients might be protected from steatosis and hepatic insulin resistance. Obesity may not increase insulin requirements in T1DM.

The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment.

Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.9 ± 4.2 kg/m(2) ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l · h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l · h, p = 0.05]. Fasting α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) µg/ml · h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 ± 16 vs. 35 ± 10 mEq/l · h, p = 0.005). Compared to placebo, both BCAA [-6.4(21.1) vs. 0.0(48.0) mmol/l · h, p = 0.01] and α-HB increments [-114(250) vs. 114(428) µg/ml · h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity (ρ = -0.37 and -0.43, p ≤ 0.01). T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload.

Efficacy of increased resistant starch consumption in human type 2 diabetes

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.

Sex-related differences in the effects of the mediterranean diet on glucose and insulin homeostasis.

Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet) on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA). Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y) during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P = 0.02; women: +9.4%, P = 0.63; P for sex-by-time interaction = 0.005). A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P = 0.03), for which only men experienced improvements (men: +8.1%, P = 0.047; women: −5.9%, P = 0.94). No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P = 0.06) and an increase in NEFA suppression rate (P = 0.06) were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344.

Differences in insulin sensitivity, lipid metabolism and inflammation between young adult Pakistani and Norwegian patients with type 2 diabetes: a cross sectional study

BackgroundImmigrants from South Asia to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM). We explored pathogenic factors that might contribute to the high risk of T2DM in Pakistani immigrants to Norway.MethodsA cross-sectional study was performed in 18 Pakistani and 21 Norwegian men and women with T2DM (age 29 – 45 years), recruited from two hospital out-patient clinics. Anthropometrics and a two-step euglycemic, hyperinsulinemic clamp with measurements of non-esterified fatty acids (NEFA) during clamp, was performed in all patients. Insulin sensitivity, given as the Glucose Infusion Rate (GIR) and Insulin Sensitivity Index (ISI), was calculated from the two euglycemic clamp steps. Fasting adipokines and inflammatory mediators were measured. Continuous variables between groups were compared using Student’s t test or Mann–Whitney U test as appropriate. Spearman’s correlation coefficient and multiple linear regression analyses were used.ResultsDespite having a lower BMI, Pakistani patients were more insulin resistant than Norwegian patients, during both low and high insulin infusion rates, after adjustment for sex and % body fat: median (interquartile range) GIR(low insulin): 339.8(468.0) vs 468.4(587.3) μmol/m2/min (p = 0.060), ISI(low insulin): 57.1(74.1) vs 79.7(137.9) μmol/m2/min (p = 0.012), GIR(high insulin): 1661.1(672.3) vs 2055.6(907.0) μmol/m2/min (p = 0.042), ISI(high insulin): 14.2(7.3) vs 20.7(17.2) μmol/m2/min (p = 0.014). Pakistani patients had lower percentage NEFA suppression 30 minutes into clamp hyperinsulinemia than Norwegians: 41.9(90.6)% vs 71.2(42.1)%, (p = 0.042). The relationship of ISI to BMI, leptin and interleukin-1 receptor antagonist also differed between Norwegians and Pakistanis.ConclusionsCompared with Norwegian patients, Pakistani patients with T2DM had lower insulin sensitivity, affecting both glucose and lipid metabolism. The relation of insulin sensitivity to BMI and some adipokines also differed between the groups.

Indices of Insulin Suppression of Non-Esterified Fatty Acids Measured During an Oral Glucose Challenge and Their Association with the Insulin-Glucose Clamp Index and Central Adiposity

To determine the indices of insulin-induced NEFA suppressibility derived from the oral glucose tolerance test (OGTT) that are best associated with the standard measure derived from the insulin-glucose clamp and with central adiposity. Sixteen men and 10 women, aged 20 to 35 years, without any disease or family history of type 2 diabetes, underwent a 75 g OGTT and a 2-step euglycemic clamp with low- and high-dose insulin infusions (10 and 40 mU/kg/min). OGTT indices of NEFA suppressibility were: area under the curve (AUC) of NEFA, AUCNEFA×AUCinsulin, NEFA T50, insulin concentration at T50 (EC50) and negative slope of the log-linear portion of NEFA suppression curve corrected by AUCinsulin (NegSlopeLnNEFA/AUCIns). NEFA insulin suppression during the clamp was calculated by ΔNEFA/Δinsulin at low-dose insulin (from baseline=positive results). Central adiposity was estimated mainly by the waist-to-hip ratio (WHR) and glucose insulin sensitivity, by the M/I value (clamp, high-dose insulin). OGTT-derived indices of insulin-induced NEFA suppression significantly associated with clamp ΔNEFA/Δinsulin: AUCNEFA×AUCinsulin (r=0.54), EC50 (r=0.50), NegSlopeLnNEFA/AUCIns (r=–0.44) and %reductionNEFA/AUCinsulin (r=–0.42). The only index significantly associated with WHR: AUCNEFA×AUCinsulin (r=0.55). Based on a step-wise regression analysis, the variables significantly and independently associated with WHR were: AUCNEFA×AUCinsulin (p=0.002) and AUCglucose (p=0.01) (model R2=0.49). AUCNEFA×AUCinsulin may represent the best OGTT-derived parameter to estimate sensitivity to insulin suppression of lipolysis because, in our sample, it was the only one significantly correlated with central adiposity. Moreover, among all metabolic parameters measured in our study, AUCNEFA×AUCinsulin and AUCglucose were the two main factors independently associated with central adiposity.

Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin-resistant humans

The purpose of this study was to evaluate the variability of subcutaneous abdominal adipose tissue (AT) dynamics in obese subjects with a wide range of insulin sensitivity (IS) and the correlation between these two metabolic measures. Ten obese (BMI 30-40 kg/m²) nondiabetic subjects with (n = 6) and without (n = 4) the metabolic syndrome were studied following a 12-wk ²H₂O labeling period. Subcutaneous abdominal AT biopsies were collected. Deuterium incorporation into triglyceride (TG)-glycerol and TG-palmitate were measured by gas chromatography-mass spectrometry for the calculation of fractional TG synthesis (fTG) and fractional de novo lipogenesis (fDNL). Muscle IS and insulin-mediated nonesterified fatty acid (NEFA) suppression (a measure for adipose IS) indexes were derived from the oral glucose tolerance test (OGTT). The ability of subcutaneous abdominal AT to synthesize lipids varied significantly in obese subjects (fTG range 7-28%, fDNL range 1.1-4.6%) with significantly lower values (>35% reduction) for both parameters in obese with the metabolic syndrome. fTG correlated positively with muscle IS (r = 0.64, P = 0.04) and inversely with NEFA suppression during the OGTT (r = -0.69, P = 0.03). These results demonstrate a large variability in subcutaneous abdominal AT lipid turnover in obesity. Moreover, a reduced capacity for subcutaneous abdominal AT fat storage is associated with muscle and adipose tissue insulin resistance as well as with the metabolic syndrome, thus identifying a form of obesity at heightened risk for type 2 diabetes and cardiovascular disease.

Effects of pioglitazone versus glimepiride exposure on hepatocellular fat content in type 2 diabetes

Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide (PIO) interferes with hepatocellular lipid (HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus (T2DM). Sixteen patients [body mass index (BMI): 28 ± 1 kg/m(2) ; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects (CON), BMI: 26 ± 1 kg/m(2)] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide (PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo (GLI arm). Multinuclei magnetic resonance spectroscopy (MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid (IMCL) contents, non-esterified fatty acids (NEFA) and adipokines. At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups. Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin.