Higher Insulin Sensitivity Research Articles

Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes

ObjectiveA growing number of ultra-endurance athletes have switched to a very low-carbohydrate/high-fat eating pattern. We compared markers of cholesterol and the lipoprotein profile in a group of elite ultra-runners consuming...

Associations of Physical Behaviours and Behavioural Reallocations with Markers of Metabolic Health: A Compositional Data Analysis.

Standard statistical modelling has shown that the reallocation of sitting time to either standing or stepping may be beneficial for metabolic health. However, this overlooks the inherent dependency of time spent in all behaviours. The aim is to examine the associations between physical behaviours and markers of metabolic health (fasting glucose, fasting insulin, 2-h glucose, 2-h insulin, Homeostasis Model Assessment of Insulin Sensitivity (HOMA-IS), Matsuda Insulin Sensitivity Index (Matsuda-ISI) while quantifying the associations of reallocating time from one physical behaviour to another using compositional analysis. Objectively measured physical behaviour data were analysed (n = 435) using compositional analysis and compositional isotemporal substitutions to estimate the association of reallocating time from one behaviour to another in a population at high risk of type 2 diabetes mellitus (T2DM). Stepping time was associated with all markers of metabolic health relative to all other behaviours. Reallocating 30 min from sleep, sitting, or standing to stepping was associated with 5–6 fold lower 2-h glucose, 15–17 fold lower 2-h insulin, and higher insulin sensitivity (10–11 fold via HOMA-IS, 12–15 fold via Matsuda-ISI). Associations of reallocating time from any behaviour to stepping were maintained for 2-h glucose, 2-h insulin, and Matsuda-ISI after further adjusting for body mass index (BMI). Relocating time from stepping into sleep, sitting, or standing was associated with lower insulin sensitivity. Stepping time may be the most important behavioural composition when promoting improved metabolic health in adults at risk of T2DM.

Cardiovascular Effects and Benefits of Exercise.

It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise.

Dissociation of Fatty Liver and Insulin Resistance in I148M PNPLA3 Carriers: Differences in Diacylglycerol (DAG) FA18:1 Lipid Species as a Possible Explanation.

Fatty liver is tightly associated with insulin resistance and the development of type 2 diabetes. I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat but normal insulin sensitivity. The underlying mechanism of the disassociation between high liver fat but normal insulin sensitivity remains obscure. We investigated the effect of I148M variant on hepatic lipidome of subjects with or without fatty liver, using the Lipidyzer method. Liver samples of four groups of subjects consisting of normal liver fat with wild-type PNPLA3 allele (group 1); normal liver fat with variant PNPLA3 allele (group 2); high liver fat with wild-type PNPLA3 allele (group 3); high liver fat with variant PNPLA3 allele (group 4); were analyzed. When high liver fat to normal liver fat groups were compared, wild-type carriers (group 3 vs. group 1) showed similar lipid changes compared to I148M PNPLA3 carriers (group 4 vs. group 2). On the other hand, in wild-type carriers, increased liver fat significantly elevated the proportion of specific DAGs (diacylglycerols), mostly DAG (FA18:1) which, however, remained unchanged in I148M PNPLA3 carriers. Since DAG (FA18:1) has been implicated in hepatic insulin resistance, the unaltered proportion of DAG (FA18:1) in I148M PNPLA3 carriers with fatty liver may explain the normal insulin sensitivity in these subjects.

Different lipid profiles, insulin sensitivity, and insulin resistance among Han, Uygur, and Kazak men with normal glucose tolerance in Xinjiang, China

BackgroundThis study aimed to determine the differences in clinical parameters among Han, Uygur, and Kazak men with normal glucose tolerance.MethodsParticipants’ data from the China National Diabetes and Metabolic Disorders Study pertaining to Han, Uygur, and Kazak men from the Xinjiang province were used (n = 930). Pearson’s correlation was used to examine the relationship between HOMA-IR, Matsuda Index, and clinical characteristics.ResultsHOMA-IR of Han men was significantly higher than in Uygurs and Kazaks (P < 0.001). The Matsuda Index of Kazaks was significantly higher than that of Hans and Uygurs (P < 0.001). While Kazaks had the highest BMI, WC, SBP, and DBP; they also had the highest HDL-C and lowest TG (P < 0.001). TG of Uygurs was significantly higher than that of Hans and Kazaks (P < 0.001). In Hans and Kazaks, the TG/HDL-C ratio increased with HOMA-IR quartiles; there was no association in Uygurs. In Hans and Kazaks, the TG/HDL-C ratio decreased with Matsuda index quartiles; there was no association in Uygurs. Multivariate linear regression showed that HOMA-IR was independently associated with ethnicity, BMI and TG/HDL-C ratio (P < 0.01), while Matsuda index was independently associated with ethnicity, BMI, LDL-C levels (P < 0.001) and TG/HDL-C ratio (P < 0.001).ConclusionsIn conclusion, Han, Uygur, and Kazak men had different lipid profiles, BMI, and WC. Han men had the highest insulin resistance while Kazak men had the highest insulin sensitivity.

Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue.

The aim of the present work was to study the consequences of chronic exercise training on factors involved in the regulation of mitochondrial remodeling and biogenesis, as well as the ability to produce energy and improve insulin sensitivity and glucose uptake in rat brown adipose tissue (BAT). Male Wistar rats were divided into two groups: (1) control group (C; n = 10) and (2) exercise-trained rats (ET; n = 10) for 8 weeks on a motor treadmill (five times per week for 50 min). Exercise training reduced body weight, plasma insulin, and oxidized LDL concentrations. Protein expression of ATP-independent metalloprotease (OMA1), short optic atrophy 1 (S-OPA1), and dynamin-related protein 1 (DRP1) in BAT increased in trained rats, and long optic atrophy 1 (L-OPA1) and mitofusin 1 (MFN1) expression decreased. BAT expression of nuclear respiratory factor type 1 (NRF1) and mitochondrial transcription factor A (TFAM), the main factors involved in mitochondrial biogenesis, was higher in trained rats compared to controls. Exercise training increased protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and AMP-activated protein kinase (pAMPK/AMPK ratio) in BAT. In addition, training increased carnitine palmitoyltransferase II (CPT II), mitochondrial F1 ATP synthase α-chain, mitochondrial malate dehydrogenase 2 (mMDH) and uncoupling protein (UCP) 1,2,3 expression in BAT. Moreover, exercise increased insulin receptor (IR) ratio (IRA/IRB ratio), IRA-insulin-like growth factor 1 receptor (IGF-1R) hybrids and p42/44 activation, and decreased IGF-1R expression and IR substrate 1 (p-IRS-1) (S307) indicating higher insulin sensitivity and favoring glucose uptake in BAT in response to chronic exercise training. In summary, the present study indicates that chronic exercise is able to improve the energetic profile of BAT in terms of increased mitochondrial function and insulin sensitivity.

Normal Glucose Tolerance (NGT) in Obese African-Americans (AA) with Ketosis-Prone Diabetes (KPDM)

KPDM is characterized by new-onset DKA and near-normoglycemia remission (HbA1c &amp;lt;7%, fasting blood glucose [BG] &amp;lt;130 mg/dl, and maintain glycemic control for at least one week off insulin) with intensive insulin treatment. Glycemic status at insulin remission varies from NGT, prediabetes or diabetes on OGTT. We hypothesized that patients with NGT at near-normoglycemia remission will have higher insulin sensitivity (Si) and secretion and longer hyperglycemia relapse-free survival. Obese AA who presented with DKA (n=33) and severe hyperglycemia (n=42) (BG &amp;gt;400 mg/dl with no DKA) underwent 2 hour 75-gm OGTT a week after insulin remission. NGT, prediabetes and diabetes were defined as per ADA criteria. At near-normoglycemia remission, Si was calculated using the OGTT minimal model analysis. Insulin secretion was calculated as incremental area under the curve of insulin (IncreAUCi) with insulin levels from OGTT. Disposition index (DI) was calculated as Si x IncreAUCi. Hyperglycemia relapse was defined as fasting BG ≥ 130 mg/dl, HbA1c &amp;gt;7% or 2 random BG ≥ 180 mg/dl. There were no differences in baseline characteristics among patients with NGT (12%), prediabetes (45%) and diabetes (43%). DI was higher in patients with NGT vs. prediabetes vs. diabetes (1.88±1.63 vs. 1.05±1.14 vs. 0.35±0.92, p&amp;lt;0.001). The difference in DI was explained by higher Si than IncreAUCi in NGT compared to prediabetes and diabetes (Si:4.2±4.4 vs. 2.4±3.5 vs. 1.2±2.5 10-4.(mU/l)-1.min-1, p&amp;lt;0.001; IncreAUCi: 6571±3451 vs. 6585±4947 vs. 4450±3051, p=0.14 mU/ml2). Multivariate Cox regression showed that age, sex, DKA presentation, OGTT status, and DI were not associated with long-term relapse-free survival. There were no differences in any variables between patients presenting with DKA or severe hyperglycemia. NGT at near-normoglycemia remission is characterized by higher insulin sensitivity than higher insulin secretion. However, none of these markers were associated with long-term hyperglycemia-free survival. Disclosure P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. D. Stefanovski: None. V. Narwani: None. I. Anzola: None. L. Peng: None. D. Smiley-Byrd: Speaker's Bureau; Self; Sanofi, Merck &amp; Co., Inc., Novo Nordisk Inc. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck &amp; Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..

Lower Ectopic Fat Accumulation in Obese Women May Help Explain Sex Differences in the Magnitude of Insulin Resistance

Accumulating evidence suggests obese women maintain higher insulin sensitivity than obese men, but factors underlying this sex difference in insulin resistance remain unclear. We recently developed a semi-automated method for quantifying visceral and hepatic fat using advanced chemical shift-encoded magnetic resonance imaging (MRI). Using this method, we explored whether sex differences in ectopic fat accumulation may contribute to differences in insulin resistance. Twenty-one obese women (32 ± 6 year, 34.5 ± 3.1 kg/m2, 43.1 ± 5.5 kg fat mass (FM)) and a well-matched cohort of fifteen obese men (29 ± 6 year, 34.5 ± 3.3 kg/m2, 42.0 ± 7.8 kg FM) underwent an MRI scan during which 5mm axial slices were acquired from the abdominal region. Using 3D Slicer software, visceral fat area was quantified on three axial slices from the L2-L3 vertebrae region and averaged. Hepatic fat was quantified as the average percentage fat from three axial slices of the liver. On a separate day, subjects underwent a hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity. Compared with men, women had lower hepatic (4.2 ± 5.5 vs. 13.1 ± 9.7%, p&amp;lt;0.001) and visceral (114 ± 49 vs. 201 ± 87 cm2, p&amp;lt;0.001) fat, which corresponded with higher insulin sensitivity (Glucose infusion rate during clamp [GIR]: 514 ± 330 vs. 263 ± 134 umol/kgFFM/SSI/min, p&amp;lt;0.05). To further examine the relationship between ectopic lipid accumulation and insulin resistance, we stratified subjects into tertiles by hepatic fat content (n=12 per group). Interestingly, nearly all subjects in the lowest tertile for hepatic fat (1.1 ± 0.6%) were women, and when compared to the highest hepatic fat tertile (17.7 ± 8.2%), they also had lower visceral fat (101 ± 61 vs. 214 ± 83 cm2, p&amp;lt;0.001) and importantly, were also more insulin sensitive (GIR: 626 ± 350 vs. 279 ± 238 umol/kgFFM/SSI/min, p&amp;lt;0.05). Our findings suggest lower ectopic fat deposition may help explain the lower degree of insulin resistance in obese women compared with men. Disclosure J.B. Gillen: None. B.J. Ryan: None. R.A. Gioscia-Ryan: None. A. Ludzki: None. T.L. Chenevert: None. J.F. Horowitz: None.

Skeletal Muscle Lipid Composition Parallels Clinical Phenotype Extremes

Intramyocellular lipid (IMCL) is generally associated with insulin resistance and lipotoxicity. However, the “athlete’s paradox” is well documented, where IMCL levels are similar between athletes and patients with type 2 diabetes despite discrepant levels of insulin sensitivity. Differences in muscle lipid metabolites between aerobically trained, lean, insulin-sensitive (LT) vs. sedentary, overweight/obese, insulin-resistant (OIR) individuals remain insufficiently characterized and may help to explain the “athlete’s paradox.” LT [n=14: 50% females, 28.5±1.6 years (Mean±SE)] and OIR [n=24: 79% females, 29.8±1.6 years] subjects each provided 2 muscle biopsies from the vastus lateralis (bilateral, 6 hours apart, ≥48 hours after last exercise, ≥8 fasting, overnight admission prior to biopsy) for mass spectrometry analysis. At a separate visit, insulin sensitivity was quantified by a hyperinsulinemic-euglycemic clamp (mg glucose/kg FFM/min). As the sequential biopsy results were not significantly different, the results were averaged for each subject. Compared with the OIR group, the LT group had lower BMI (22.3±0.5 vs. 36.2±1.2 kg/m2:p&amp;lt;0.01), higher fitness (VO2max:53.4±2.2 vs. 26.7±1.1 ml/kg/min: p&amp;lt;0.01), and higher insulin sensitivity (M-value: 17.1±0.7 vs. 8±0.5, p&amp;lt;0.01). Muscle triglycerides in the LT group were lower (nmol/mg muscle) in oleic acid (3.2±0.6 vs. 6.0±1.0, p=0.02) and palmitic acid (1.5±0.2 vs. 3.1±0.5, p&amp;lt;0.01) than the OIR group. Diacylglycerol (DAG) and palmitoylcarnitine concentrations were not significantly different. Only in the OIR group, palmitoylcarnitine correlated with the following: oleic acid (r=0.73, p&amp;lt;0.01), palmitic acid (r=0.73, p&amp;lt;0.01) and DAG (dipalmitate:r=0.53, p=0.03, palmitate+oleate: r=0.51, p=0.04). These findings suggest that either incomplete muscle lipid oxidation or increased acylcarnitine generation is present in the OIR group, thus warranting further research on training effects on muscle lipid turnover. Disclosure L.S. Chow: Research Support; Self; Eli Lilly and Company, National Institute of Diabetes and Digestive and Kidney Diseases. D.G. Mashek: None. T. Bosch: None. A. Bantle: None. M. Petterson: None. D.R. Dengel: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S.

Unraveling the Athlete’s Paradox—Higher Insulin Sensitivity and Lower PKC? Activation Despite Higher Bioactive Lipids in Endurance-Trained Athletes

High intramyocellular lipid (IMCL) content associates negatively with insulin sensitivity (IS) in insulin resistant, but not in endurance-trained humans. It has been hypothesized that different cellular distribution of bioactive lipids such as diacylglycerols (DAG) and ceramides (CER) could interfere with insulin action and underlie this “athlete’s paradox.” We examined endurance-trained athletes (ATH; n=9) and sedentary individuals (SED; n=12) with comparable total IMCL, as measured by 1H-magnetic resonance spectroscopy, who underwent spiroergometry and hyperinsulinemic-euglycemic clamps to assess maximal oxidative capacity and IS, respectively. In skeletal muscle biopsies, translocation of protein kinase C (PKC) θ and ε were determined by Western blotting and concentrations of DAG and CER were measured using targeted LC-tandem mass spectrometry upon separating fractions of cellular membranes, lipid droplets and cytosol by ultracentrifugation. Maximal oxidative capacity and IS were 46% and 47% higher in ATH than in SED (both p&amp;lt;0.01), respectively. The membrane:cytosol ratio of PKCθ, which reflects PKCθ activity, was 62% lower in ATH consistent with their increased IS (p&amp;lt;0.01), while there was no group difference for PKCε. Total and membrane DAG (40% and 48%, both p&amp;lt;0.01) as well as membrane CER (15%, p&amp;lt;0.05) were higher in ATH while the respective concentrations in lipid droplets and cytosol did not differ. In SED, IS correlated inversely with all stereoselective subspecies of lipid-droplet DAG. On the other hand, cytosolic sn-1,2 (C16:0-C18:2) and sn-1,3 (C18:1-C18:0) DAG correlated positively with IS in ATH. In conclusion, higher IS in endurance-trained ATH can be explained by lower muscle PKCθ activation, which may be due to differences in the stereoselectivity and/or subcompartmentation of cellular DAG between ATH and insulin resistant SED. Disclosure D. Pesta: None. E. Anadol-Schmitz: None. S. Gancheva: None. D.F. Markgraf: None. O.P. Zaharia: None. H. Katsuyama: None. Y. Kupriyanova: None. J. Hwang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.

Brain Insulin Sensitivity Predicts Adiposity—Nine-Year Results of the Tulip Study

Lifestyle intervention reduces body weight and prevents type 2 diabetes. One crucial modulator of food intake and whole body energy metabolism is insulin action in the brain. We now test whether brain insulin sensitivity is a long-term predictor of weight and body fat distribution during and after a lifestyle intervention program. Before, after 9 months, at the end of lifestyle intervention at 24 months, as well as after 8.7 ±1.6 years follow-up, participants of the Tuebingen Lifestyle Intervention Program underwent a 75g OGTT, and whole body MRI. Brain insulin sensitivity was measured at baseline by changes in neuronal signals (theta frequency band) with magnetoencephalography during a hyperinsulinemic-euglycemic clamp in a subgroup of 28 participants of whom long-term follow-up was available in 15 persons. Higher brain insulin sensitivity before lifestyle intervention was associated with a more pronounced reduction in total and visceral fat during the lifestyle intervention (all p&amp;lt;0.01). High brain insulin sensitivity was also associated with less regain of fat mass during the long-term follow-up. In contrast to visceral fat, changes in subcutaneous adipose tissue were independent of the brain insulin responsiveness. Our results extend previous findings on the role of brain insulin for the success of lifestyle intervention to a long-term perspective. Insulin action in the human brain appears to be not only important for weight loss, but seems to determine regain of body weight and especially total and visceral fat mass thereafter. Experimental findings demonstrated that insulin administration to the brain modulates peripheral energy fluxes in humans. In line, our results indicate fat depots specific effects of brain insulin with particular benefits in the visceral compartment. These findings support the role of brain insulin in the regulation of body fat distribution and body weight. Disclosure V. Schmid: None. O. Tschritter: None. J. Machann: None. R. Wagner: None. N. Stefan: Consultant; Self; Merck Sharp &amp; Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd.. H. Preissl: None. H. Haering: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc..

Interval Outcomes of a Lifestyle Weight-Loss Intervention in Early Adolescence.

We undertook a feasibility study to reassess metabolic outcomes in young people with early onset obesity who attended a hospital-based lifestyle weight-loss intervention during adolescence. Comparisons of metabolic assessments, including body mass index standard deviation scores (BMI–SDSs), blood pressure (BP), oral glucose tolerance tests (OGTTs), lipid profile, and alanine transaminase (ALT), before and after treatment were made. Twenty-five subjects (10 males) with median ages (interquartile range, IQR) of 14.5 (12.6–15.4) years at the beginning of intervention and 18.2 (17.2–18.9) years at reassessment and who were 3.5 (2.4–6.5) years post-intervention were recruited. Twenty-eight percent had a ≥0.25 reduction in BMI–SDS from baseline (responders). Responders demonstrated significantly lower BMI–SDS, systolic BP, and glucose disposal at reassessment compared with baseline. They also showed significantly lower total fat percentage SDSs, trunk fat percentages, 120 min insulin, and ALT, as well as higher insulin sensitivity index (ISIcomp) than non-responders. Male gender and younger age at the initiation of intervention showed a non-significant trend towards greater success in weight loss. Long-term benefits were demonstrated in around one-quarter of obese adolescents after lifestyle modification treatment, with associated improvements in body composition and metabolic parameters.

Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity.

Metabolic flexibility to lipid (MetFlex-lip) is the capacity to adapt lipid oxidation to lipid availability. Hypothetically, impaired MetFlex-lip in skeletal muscle induces accumulation of lipid metabolites that interfere with insulin signaling. Our aim was to compare MetFlex-lip during exercise in subjects with low (Low_IS) vs. high (High_IS) insulin sensitivity. Twenty healthy men were designated as Low_IS or High_IS on the basis of the median of the homeostatic model assessment of insulin resistance index. Groups had similar age, body mass index, and maximum oxygen uptake (V̇o2max). Subjects cycled at 50% V̇o2max until expending 650 kcal. Adaptation in lipid oxidation was calculated as the drop in respiratory quotient (RQ) at the end of exercise vs. the maximum RQ (ΔRQ). Lipid availability was calculated as the increase in circulating nonesterified fatty acids (NEFA) at the end of exercise vs. the minimum NEFA (ΔNEFA). ΔRQ as a function of ΔNEFA was used to determine MetFlex-lip. On average, RQ and circulating NEFA changed similarly in both groups. However, ΔRQ correlated with ΔNEFA in High_IS ( r = -0.83, P < 0.01) but not in Low_IS ( r = -0.25, P = 0.48) subjects. Thus the slope of the ΔRQ vs. ΔNEFA relationship was steeper in High_IS vs. Low_IS subjects (-0.139 ± 0.03 vs. -0.025 ± 0.03 RQ·mmol-1·l-1, respectively; P < 0.05), with similar intercepts. We conclude that in subjects with High_IS lipid-to-carbohydrate oxidation ratio adapts to the increased circulating NEFA availability during exercise. Such MetFlex-lip appears impaired in subjects with Low_IS. Whether a cause-effect relationship exists between impaired MetFlex-lip and low insulin sensitivity remains to be determined.

Renal function markers and insulin sensitivity after 3\xa0years in a healthy cohort, the EGIR-RISC study

BackgroundPeople with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later.MethodsWe studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally.ResultsIn men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90–105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates.ConclusionsThere was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population.

Ganoderic Acid A improves high fat diet-induced obesity, lipid accumulation and insulin sensitivity through regulating SREBP pathway

Obesity and its major co-morbidity, type 2 diabetes, have been an alarming epidemic prevalence without an effective treatment available. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. Therefore, inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Here, we identify a small molecule, Ganoderic Acid A (GAA), inhibits the SREBP expression and decreases the cellular levels of cholesterol and fatty acid in vitro. GAA also ameliorates body weight gain and fat accumulation in liver or adipose tissues, and improves serum lipid levels and insulin sensitivity in high fat diet (HFD)-induced obese mice. Consistently, GAA regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Taken together, GAA could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.

Sarcopoterium spinosum extract improved insulin sensitivity in mice models of glucose intolerance and diabetes.

BackgroundThe glucose lowering properties of Sarcopoterium spinosum, a traditional medicinal plant, were previously validated by us using KK-Ay mice as a genetic model for type 2 diabetes (T2D).ObjectiveTo clarify the effects of Sarcopoterium spinosum extract (SSE) on diet-induced glucose intolerance and to investigate SSE effects on carbohydrate and lipid metabolism in target tissues of both high-fat-diet (HFD)-fed and KK-Ay mice.ResultsMice were given SSE (70 mg/day) for 6 weeks. SSE improved glucose tolerance and insulin sensitivity in HFD-fed mice as was demonstrated previously in KK-Ay mice. Higher insulin sensitivity was validated by lower serum insulin and activation of the insulin signaling cascade in skeletal muscle and liver of SSE-treated mice in both models. H&E staining of the livers demonstrated lower severity of steatosis in SSE-treated mice. Several model-specific effects of SSE were observed–mRNA expression of proinflammatory genes and CD36 was reduced in SSE-treated KK-Ay mice. Hepatic mRNA expression of PEPCK was also reduced in SSE-treated KK-Ay mice, while other genes involved in carbohydrates and lipid metabolism were not affected. HFD-fed mice treated by SSE had elevated hepatic glycogen stores. Gluconeogenic gene expression was not affected, while GCK expression was increased. HFD-induced hepatic steatosis was not affected by SSE. However, while genes involved in lipid metabolism were downregulated by HFD, this was not found in HFD-fed mice given SSE, demonstrating an expression profile which is similar to that of standard diet-fed mice.ConclusionOur study supports the insulin sensitizing activity of SSE and suggests that this extract might improve other manifestations of the metabolic syndrome.

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55–65% VO2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.

Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92cm) and 17.5% had CVD (P=0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112cm), and 25.5% had CVD (P<0.0001 vs classical diabetes). Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Intralipid/Heparin Infusion Alters Brain Metabolites Assessed With 1H-MRS Spectroscopy in Young Healthy Men.

We previously demonstrated that insulin infusion altered metabolite concentrations in cerebral tissues assessed with proton magnetic resonance spectroscopy (1H-MRS) in young subjects with high insulin sensitivity, but not in those with low insulin sensitivity. Fat overload is an important factor leading to insulin resistance. The purpose of the current study was to examine the effect of elevated circulating free fatty acid (FFA) levels on metabolites in cerebral tissues assessed with 1H-MRS. The study group comprised 10 young, healthy male subjects. 1H-MRS was performed at baseline and after 4-hour Intralipid (Fresenius Kabi)/heparin or saline infusions administered in random order. Voxels were positioned in the left frontal lobe, left temporal lobe, and hippocampus. The ratios of N-acetylaspartate (NAA), choline (Cho)-containing compounds, myo-inositol (mI), and glutamate/glutamine/γ-aminobutyric acid complex (Glx) to creatine (Cr) and nonsuppressed water signal were determined. Intralipid/heparin infusion resulted in a significant increase in circulating FFAs (P < 0.0001). Significant changes in brain neurometabolite concentrations in response to Intralipid/heparin infusion were increases in frontal mI/Cr (P = 0.041) and mI/H2O (P = 0.037), decreases in frontal and hippocampal Glx/Cr (P = 0.018 and P = 0.015, respectively) and Glx/H2O (P = 0.03 and P = 0.067, respectively), and a decrease in hippocampal NAA/Cr (P = 0.007) and NAA/H2O (P = 0.019). No changes in neurometabolites were observed during the saline infusion. Acute circulating FFA elevation influenced cerebral metabolites in healthy humans and lipid-induced insulin resistance could be partly responsible for these effects.

Protein-restriction diet during the suckling phase programs rat metabolism against obesity and insulin resistance exacerbation induced by a high-fat diet in adulthood

Protein restriction during the suckling phase can malprogram rat offspring to a lean phenotype associated with metabolic dysfunctions later in life. We tested whether protein-caloric restriction during lactation can exacerbate the effect of a high-fat (HF) diet at adulthood. To test this hypothesis, we fed lactating Wistar dams with a low-protein (LP; 4% protein) diet during the first 2 weeks of lactation or a normal-protein (NP; 23% protein) diet throughout lactation. Rat offspring from NP and LP mothers received a normal-protein diet until 60 days old. At this time, a batch of animals from both groups was fed an HF (35% fat) diet, while another received an NF (7% fat) diet. Maternal protein-caloric restriction provoked lower body weight and fat pad stores, hypoinsulinemia, glucose intolerance, higher insulin sensitivity, reduced insulin secretion and altered autonomic nervous system (ANS) function in adult rat offspring. At 90 days old, NP rats fed an HF diet in adulthood displayed obesity, impaired glucose homeostasis and altered insulin secretion and ANS activity. Interestingly, the LP/HF group also presented fat pad and body weight gain, altered glucose homeostasis, hyperleptinemia and impaired insulin secretion but at a smaller magnitude than the NP-HF group. In addition, LP/HF rats displayed elevated insulin sensitivity. We concluded that protein-caloric restriction during the first 14 days of life programs the rat metabolism against obesity and insulin resistance exacerbation induced by an obesogenic HF diet.