Insulin Resistance In Elderly Research Articles

Dietary Advanced Glycation End Products: Their Role in the Insulin Resistance of Aging.

Insulin resistance (IR) is commonly observed during aging and is at the root of many of the chronic nontransmissible diseases experienced as people grow older. Many factors may play a role in causing IR, but diet is undoubtedly an important one. Whether it is total caloric intake or specific components of the diet, the factors responsible remain to be confirmed. Of the many dietary influences that may play a role in aging-related decreased insulin sensitivity, advanced glycation end products (AGEs) appear particularly important. Herein, we have reviewed in detail in vitro, animal, and human evidence linking dietary AGEs contributing to the bodily burden of AGEs with the development of IR. We conclude that numerous small clinical trials assessing the effect of dietary AGE intake in combination with strong evidence in many animal studies strongly suggest that reducing dietary AGE intake is associated with improved IR in a variety of disease conditions. Reducing AGE content of common foods by simple changes in culinary techniques is a feasible, safe, and easily applicable intervention in both health and disease. Large-scale clinical trials are still needed to provide broader evidence for the deleterious role of dietary AGEs in chronic disease.

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity.

Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides.

Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity.

Does vitamin D affect sarcopenia with insulin resistance in aging?

There are many studies investigating nutritional factors that affect both sarcopenia and muscle formation. According to extensive research, protein has an essential role in muscle formation. More recently, vitamin D has emerged as an important factor that regulates muscle metabolism. However, studies and research of association between 25-Hydroxyvitamin D (25(OH)D) status and components of homeostasis model assessment of insulin resistance (HOMA-IR) in older are limited. Nineteen studies were found through a search of electronic databases and were subjected to a meta-analysis to investigate the differences in serum levels of 25(OH)D and HOMA-IR between patients with controls and sarcopenia. The random-effects standardized mean difference (SD) and 95% confidence interval (CI) were calculated as the effect size. Nineteen studies with 19,528 participants (5,081 with sarcopenia and 14,447 without) were analyzed. Sarcopenic participants had significantly lower serum levels of 25(OH)D (SD =1.163; 95% CI 0.514, 1.812; p<0.001; I2=99.652%) and HOMA-IR (SD=-2.040; 95% CI -3.376, -0.705; p<0.005; I2=99.837%) than controls. It has been reiterated that sarcopenia may be related serum levels of 25(OH)D and HOMA-IR. This relationship needs to be clarified by future longitudinal studies.

Age-Related Alteration in Serum Adiponectin in Rats and Its Association with Insulin Resistance Markers

Introduction: Adiponectin is one of the most important adipose derived hormone that conflicting data are available about serum changes of adiponectin at different ages.The present study was done to determine the age related changes in serum adiponectin and its association with insulin resistance (IR) indices in aging in male rats.&#x0D; Methods: In this study, serum samples were obtained from male rats at different ages, including 2, 5, 10, 18, 52 and 72 weeks age (n=10 in each age group). Oral glucose tolerance and glucose stimulated insulin secretion tests were measured using determination of glucose concentrations at 15, 30, 45 and 60 min after oral ingestion of glucose (1 mg/kg body weight) for each animal. Serum adiponectin and insulin levels were determined using species specific ELISA kits. HOMA-IR was calculated based on glucose and insulin concentrations. Data were analyzed using SPSS version 16 software (SPSS Inc., Chicago, IL) also using one way analysis of variance and LSD posthoc tests.&#x0D; Results: Our results showed an age dependent decrease in serum adiponectin concentration, and 72-week old rats had the lowest level of adiponectin compared with those in other ages (p&lt;0.05). IR indices, including fasting glucose, insulin, HOMA-IR and response to oral glucose ingestion was increased in an age dependent manner and 72-week old rats showed the highest levels of the IR indices.&#x0D; Conclusion: Regarding the role of adiponectin in glucose homeostasis and insulin sensitization, it seems that reduction of serum adiponectin with age progression may be an important mechanism of insulin resistance in aging.

The HOMA-IR cut-off values for diagnosis of insulin resistance and relationship of metabolic syndrome with insulin resistance in elderly people in Minhang District of Shanghai

Objective To investigate the threshold values of insulin resistance (IR) assessed by homeostasis model and the prevalence of IR in elderly people over 60 years old in Minhang district of Shanghai, and to evaluate the relationship between IR and metabolic syndrome (MS). Methods A total of 3 003 elderly people aged 60 and over in the Jiangchuan community of Minhang District, Shanghai, were recruited, including 1 286 males and 1 717 females. Blood pressure, waist circumference, BMI, blood routine, serum creatinine, blood lipids, glucose, and fasting insulin were measured in all populations studied. Homeostasis model assessment (HOMA) was used to estimate IR, and MS, and defined according to three diagnostic criteria including NCEP-ATPIII, IDF, and CDS. Results 75th percentile, 80th percentile and 90th percentile of HOMA values in 268 subjects with normotensive and normal BMI, glucose tolerance were considered as the thresholds of IR. The cut-off values were 2.78, 3.01 and 3.56, respectively. And the prevalence of IR were 50.0%, 42.1%, and 27.2%, respectively. IR level was significantly higher in people with MS. Based on the receiver operating characteristic(ROC) curve analysis, HOMA-IR and QUICKI index predicted MS well, and the optimal thresholds for diagnosing MS of HOMA-IR were 3.17 for NCEP-ATPⅢ, 3.02 for IDF and 3.03 for CDS. BMI was the best factor for diagnosing IR among different MS components. Logistic regression analysis showed that gender, WC, BMI, SBP, HDL-C, TG, FBG and WBC were independent risk factors for IR. FBG≥5.84 mmol/L was the most dangerous factor of IR (OR=3.603, P<0.01), followed by WC≥85.4 cm(OR=2.152, P<0.01) and BMI≥24.6 kg/m2(OR=2.150, P<0.01). Conclusion The cut-off values of IR estimated by HOMA and the prevalence of IR were higher in elder subjects than other populations. IR was significantly positively correlated with MS. Excluding the conditions that insulin measurement were affected by external factors, HOMA-IR may predict the risk of MS. The components of MS were relative specific measurements of IR, FBG, BMI and WC were important risk predictors of IR in the elderly. Key words: Elderly Population; Insulin resistance; Metabolic syndrome

Vascular Dysfunction and Insulin Resistance in Aging.

Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function. Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.

Energy Metabolism and Allocation in Selfish Immune System and Brain: A Beneficial Role of Insulin Resistance in Aging

There is relatively limited knowledge concerning our understanding of how our immune system and brain take most of the available energy in a selfish manner to compensate for their own needs on priority in high energy demanding situations. The main objective of this review is to understand the energy allocation to immune system and brain in infections and/or fight or flight situations. The immune system and brain behave in a selfish manner as they allocate themselves majority of the total available energy. Insulin resistance (IR) is used as a tool for energy allocation by these systems. The immune system is activated as a response to stress and infection. Similarly, the brain gets activated as a response to any external environmental impulse, anxiety, and/or mental factor. These situations need to be dealt in a way to minimize their adverse health effects. The immune system and the brain in such situations need enormous energy for activation which is derived from the energy quota otherwise allocated to other organs. This maximum flux of energy towards these systems is achieved by making rest of the organs less responsive to insulin, a condition known as IR. As immune system and brain do not depend upon insulin for uptake of glucose, these systems are benefited from IR. IR is indicated as a beneficial role ensuring maximum energy allocation to these systems for improving health and well-being.

Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

Cross-Sectional Inverse Association of Regular Soy Intake with Insulin Resistance in Japanese Elderly

Levels of isoflavones, biomarkers of soy intake, in 24-hour urine (24U) were inversely related to coronary heart disease (CHD) mortality in the World Health Organization’s Cardiovascular Disease and Alimentary Comparison Study. Considering 24 U isoflavone levels were highest and CHD mortality was lowest in the Japanese, who maintained the world’s longest life expectancy, the association of regular soy intake with cardiometabolic risk was investigated in Japanese adults (20–49 years old) and elderly (50–79 years old). In multivariate analysis adjusted for age, sex, and drug treatments, mean 24 U isoflavone excretion was significantly inversely associated with insulin resistance in the elderly and significantly associated with blood folate and potassium in the elderly, but also positively associated with 24 U salt in the elderly. These findings indicate that low-salt soy should be recommended to improve glucose metabolism in elderly Japanese.

A Randomized Placebo Controlled Clinical Trial to Determine the Impact of Digestion Resistant Starch MSPrebiotic® on Glucose, Insulin, and Insulin Resistance in Elderly and Mid-Age Adults

Type 2 diabetes (T2D) has reached epidemic proportions in North America. Recent evidence suggests that prebiotics can modulate the gut microbiome, which then plays an important role in regulating lipid metabolism, blood glucose, and insulin sensitivity. As such, prebiotics are appealing potential therapeutic strategies for prediabetes and T2D. The key objectives of this study were to determine the tolerability as well as the glucose and insulin modulating ability of MSPrebiotic® digestion resistant starch (DRS) in healthy mid-age (MID) and elderly (ELD) adults. This was a prospective, blinded, placebo-controlled study. Prediabetes and diabetes were among the exclusion factors. ELD (>70 years) and MID (30-50 years) Canadian adults were recruited and, after 2 weeks of consuming placebo, they were randomized to consume 30 g of either MSPrebiotic® or placebo per day for 12 weeks. In total, 42 ELD and 42 MID participants completed the study. Blood samples were collected over the 14-week study and analyzed for glucose, lipid profile, and CRP, lipid particles, TNF-α, IL-10, insulin, and insulin resistance (IR). At baseline, the ELD population had a significantly higher percentage (p < 0.01) with elevated glucose and significantly higher TNF-α (p < 0.01) compared to MID adults. MSPrebiotic® DRS was well tolerated in both MID and ELD adults. There was a significant difference over time in blood glucose (p = 0.0301) and insulin levels (p = 0.009), as well as IR (HOMA-IR; p = 0.009) in ELD adults who consumed MSPrebiotic® compared to placebo. No significant changes were found in MID adults. Our results suggest that dietary supplementation with prebiotics such as MSPrebiotic® may be part of an effective strategy to reduce IR, a major risk factor for developing T2D, in the ELD. NCT01977183 listed on NIH website: ClinicalTrials.gov, The metadata generated in this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/bioproject/381931).

Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance.

Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance (IR). Macrophages infiltrate the adipose tissue (AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4 (TLR4) and induce inflammatory responses in AT macrophages (ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b (Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs.

Insulin resistance and gray matter volume in neurodegenerative disease

The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n=21) and neurodegenerative disease (Alzheimer’s disease (AD), n=20; Parkinson’s disease (PD), n=22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p=0.002, HC vs. PD, p=0.003), although only AD subjects exhibited increased fasting glucose (p=0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p<0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia.

Bed Rest Worsens Impairments in Fat and Glucose Metabolism in Older, Overweight Adults

The effects of bed rest on the dysregulation of fatty acid and glucose metabolism have not been addressed in the older population. We examined the effect of 10 days of bed rest on fatty acid kinetics and hepatic and peripheral insulin resistance in aging. We utilized an octreotide, basal glucagon replacement, multistage insulin infusion, and the concomitant infusion of [6,6 (2)H₂]glucose to derive insulin-mediated suppression of glucose production and insulin-stimulated glucose disposal in nine older, overweight individuals (body mass index 28.1 ± 1.7 kg m(-2); 39.9% ± 1.9% fat). During the multistage insulin infusion, we also infused [1-(13)C]palmitate to examine free fatty acid rate of appearance (R(a)). Body weight, % body fat, and energy metabolism did not change with bed rest. There was a significant decrease (-2291 ± 316 cm(3)) in visceral fat, and no change in abdominal subcutaneous fat with bed rest. Insulin-mediated suppression of glucose production was modest prior to bed rest and was further reduced (>15% ± 2%) by bed rest. There was also a minor decrease in the insulin-mediated suppression of free fatty acid R(a) after bed rest and, as a consequence, a small variation in plasma free fatty acid from pre- to post-bed rest in the first stage of the multistage insulin infusion. There was also a significant bed rest-induced decline (>2.0 ± 0.6 mg kg FFM(-1) min(-1)) in insulin-stimulated glucose disposal. Preexisting impairments in insulin sensitivity are worsened by bed rest and seem linked to alterations in the regulation of free fatty acid in older, overweight individuals.

Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Aging is associated with impaired fasted oxidation of nonesterified fatty acids (NEFA) suggesting a mitochondrial defect. Aging is also associated with deficiency of glutathione (GSH), an important mitochondrial antioxidant, and with insulin resistance. This study tested whether GSH deficiency in aging contributes to impaired mitochondrial NEFA oxidation and insulin resistance, and whether GSH restoration reverses these defects. Three studies were conducted: (i) in 82-week-old C57BL/6 mice, the effect of naturally occurring GSH deficiency and its restoration on mitochondrial (13) C1 -palmitate oxidation and glucose metabolism was compared with 22-week-old C57BL/6 mice; (ii) in 20-week C57BL/6 mice, the effect of GSH depletion on mitochondrial oxidation of (13) C1 -palmitate and glucose metabolism was studied; (iii) the effect of GSH deficiency and its restoration on fasted NEFA oxidation and insulin resistance was studied in GSH-deficient elderly humans, and compared with GSH-replete young humans. Chronic GSH deficiency in old mice and elderly humans was associated with decreased fasted mitochondrial NEFA oxidation and insulin resistance, and these defects were reversed with GSH restoration. Acute depletion of GSH in young mice resulted in lower mitochondrial NEFA oxidation, but did not alter glucose metabolism. These data suggest that GSH is a novel regulator of mitochondrial NEFA oxidation and insulin resistance in aging. Chronic GSH deficiency promotes impaired NEFA oxidation and insulin resistance, and GSH restoration reverses these defects. Supplementing diets of elderly humans with cysteine and glycine to correct GSH deficiency could provide significant metabolic benefits.

Mechanisms of insulin resistance in obesity

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly.

Aging is closely associated with muscle insulin resistance, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. We examined the hypothesis that muscle insulin resistance in healthy aging promotes increased hepatic de novo lipogenesis (DNL) and hyperlipidemia by altering the distribution pattern of postprandial energy storage. Healthy, normal weight, sedentary elderly subjects pair-matched to young subjects were given two high-carbohydrate meals followed by 13C/1H magnetic resonance spectroscopy measurements of postprandial changes in muscle and liver glycogen and lipid content, and assessment of DNL using 2H2O. Net muscle glycogen synthesis was reduced by 45% (P < 0.007) in the elderly subjects compared with the young, reflecting severe muscle insulin resistance. Net liver glycogen synthesis was similar between groups (elderly, 143 ± 23 mmol/L vs. young, 138 ± 13 mmol/L; P = NS). Hepatic DNL was more than twofold higher in the elderly than in the young subjects (elderly, 14.5 ± 1.4% vs. young, 6.9 ± 0.7%; P = 0.00015) and was associated with approximately threefold higher postprandial hepatic triglyceride (TG) content (P < 0.005) and increased fasting plasma TGs (elderly, 1.19 ± 0.18 mmol/L vs. young, 0.74 ± 0.11 mmol/L; P = 0.02). These results strongly support the hypothesis that muscle insulin resistance in aging promotes hyperlipidemia and NAFLD by altering the pattern of postprandial carbohydrate storage away from muscle glycogen and into hepatic DNL.

Vasoregulatory peptides pro-endothelin-1 and pro-adrenomedullin are associated with metabolic syndrome in the population-based KORA F4 study

Metabolic alterations and endothelial dysfunction are interrelated processes in type 2 diabetes (T2D) and metabolic syndrome (MetS) that often develop in parallel. We assessed the association of vasoactive precursor peptides (VPPs) with MetS and T2D. Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM) were measured by novel sensitive assays in 1590 participants of the population-based KORA F4 study. The association of the VPPs with T2D, MetS defined by IDF criteria, the components of MetS, and insulin resistance (IR) was assessed in logistic regression models. Elevated levels of CT-proET-1 and MR-proADM were associated with T2D, MetS, and IR in age- and sex-adjusted models. After adjustment for age, sex, former vascular complications, lifestyle factors, high-sensitive C-reactive protein, and serum creatinine, significant associations with MetS were found for MR-proADM (OR=5.94, 95% CI 3.78-9.33) and CT-proET-1 (OR=5.18, 95% CI 3.48-7.71) (top quartile vs bottom quartile). CT-proET-1 and MR-proADM were strongly associated with all components of MetS as defined by IDF criteria. After multivariable adjustment, association of CT-proET-1 and MR-proADM with pathological glucose tolerance and T2D disappeared and a borderline association with IR was found only for CT-proET-1 (OR=1.34, 95% CI 0.96-1.87). We here demonstrate for the first time that plasma levels of both MR-proADM and CT-proET-1 levels are related to MetS and its components, thus suggesting that they possibly have a role as a surrogate biomarker for the disease and its complications.

Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight

Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Mitochondrial capacity for ATP synthesis was assessed by (31)phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

Abdominal Obesity in Older Women: Potential Role for Disrupted Fatty Acid Reesterification in Insulin Resistance

Excess abdominal adiposity is a primary factor for insulin resistance in older age. Our objectives were to examine the role of abdominal obesity on adipose tissue, hepatic, and peripheral insulin resistance in aging, and to examine impaired free fatty acid metabolism as a mechanism in these relations. This was a cross-sectional study. The study was performed at a General Clinical Research Center. Healthy, inactive older (>60 yr) women (n = 25) who were not on hormone replacement therapy or glucose-lowering medication were included in the study. Women with abdominal circumference values above the median (>97.5 cm) were considered abdominally obese. Whole-body peripheral glucose utilization, adipose tissue lipolysis, and hepatic glucose production were measured using in vivo techniques according to a priori hypotheses. In the simple analysis, glucose utilization at the 40 mU insulin dose (6.3 +/- 2.8 vs. 9.1 +/- 3.4; P < 0.05), the index of the insulin resistance of basal hepatic glucose production (23.6 +/- 13.0 vs. 15.1 +/- 6.0; P < 0.05), and insulin-stimulated suppression of lipolysis (35 vs. 54%; P < 0.05) were significantly different between women with and without abdominal obesity, respectively. Using the glycerol appearance rate to free fatty acid ratio as an index of fatty acid reesterification revealed markedly blunted reesterification in the women with abdominal adiposity under all conditions: basal (0.95 +/- 0.29 vs. 1.35 +/- 0.47; P < 0.02); low- (2.58 +/- 2.76 vs. 6.95 +/- 5.56; P < 0.02); and high-dose (4.46 +/- 3.70 vs. 12.22 +/- 7.13; P < 0.01) hyperinsulinemia. Importantly, fatty acid reesterification was significantly (P < 0.01) associated with abdominal circumference and hepatic and peripheral insulin resistance, regardless of total body fat. These findings support the premise of dysregulated fatty acid reesterification with abdominal obesity as a pathophysiological link to perturbed glucose metabolism across multiple tissues in aging.