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Glucose Intolerance and Aging
Abstract
Glucose tolerance is known to decrease with advancing age. This decline begins in the third or fourth decade of life and is progressive throughout the entire adult life span. The primary cause of this age-related impairment in glucose metabolism results from tissue unresponsiveness to insulin. The plasma insulin response to glucose shows little change with age. Several factors, including decreased physical activity and decreased lean body mass, probably contribute to the insulin resistance. The aging process per se, however, appears to have its own deleterious effect on tissue sensitivity to insulin.
... We divided the group of 81 subjects into 2 groups according to age. The cutoff point was defined based on the mean age of the group (28 years old), but also based on work by Tirosh et al [22], whose minimum age for participants was 26 years, and by DeFronzo [23], whose participants had a decline in glucose metabolism from 30 years of age. Thus, in our study we chose to have one group <28 years old and the other group !28 years old. ...
... These results may suggest much more than a simple increase in blood glucose within the normal range. In one review [23], 1-hour plasma glucose was found to increase by an average of 9 mg/dL per decade, and 2-hour plasma glucose increased by an average of 5 mg/dL per decade, and this was due to insulin resistance in the tissues [23,48]. ...
... These results may suggest much more than a simple increase in blood glucose within the normal range. In one review [23], 1-hour plasma glucose was found to increase by an average of 9 mg/dL per decade, and 2-hour plasma glucose increased by an average of 5 mg/dL per decade, and this was due to insulin resistance in the tissues [23,48]. ...
Objective:
To evaluate the occurrence of predictors for diabetes among the characteristics of the glycemic curve and glycohemoglobin in healthy young adults.
Patients and methods:
We established predictors for diabetes based on other studies and evaluated its occurrence in 81 healthy young adult subjects using a cross-sectional study. The volunteers underwent analysis of fasting plasma glucose, oral glucose tolerance test plasma glucose, glycohemoglobin, and inflammatory markers (leukocyte, monocytes and c-reactive protein). The non-parametric Mann-Whitney U test, Fisher's exact test, the χ2 test, the Kruskal-Wallis test, and multiple comparisons were chosen to analyze the data.
Results:
We studied two age groups, homogeneous in terms of family history of diabetes: one group aged ≥ 18 and < 28 years [median 20 years; body mass index (BMI) 24 kg/m2] and the other group aged ≥ 28 and < 45 years (median 35 years; BMI 24 kg/m2). The older group had a higher incidence of predictors (p = 0.0005) and was associated with the predictor 30-minute blood glucose ≥ 164 mg/dL (p = 0.0190), 60-minute blood glucose ≥ 125 mg/dL (p = 0.0346), glycohemoglobin ≥ 5.5% (p = 0.0162), and monophasic glycemic curve (p = 0.007). The younger group was associated with the 2-hour plasma glucose predictor ≥ 140 mg/dL (p = 0.014). All subjects had fasting glucose in the normal range.
Conclusions:
Healthy young adults may already have predictors of diabetes, identified mainly by aspects of the glycemic curve and glycohemoglobin, but at more modest levels than prediabetes.
... Determining whether the pre-stroke normalization of IR improves stroke recovery could have strong implications beyond T2D. Indeed, there is a high prevalence of IR in the elderly (prediabetes) [18][19][20], who have the highest stroke mortality and more severe and lasting stroke sequelae [21,22]. ...
... To study the efficacy of pre-stroke IR normalization for post-stroke recovery in a more clinically relevant murine model, we took advantage of middle-aged mice that spontaneously developed early IR/prediabetes, also in this case without hyperglycemia. Indeed, the high prevalence of IR/prediabetes in the elderly is well known [19,20]. Aging is also the strongest non-modifiable risk factor for stroke [50] and aged people have the highest stroke mortality and most severe and long-lasting stroke sequelae [22]. ...
Type 2 diabetes (T2D) impairs post-stroke recovery, and the underlying mechanisms are unknown. Insulin resistance (IR), a T2D hallmark that is also closely linked to aging, has been associated with impaired post-stroke recovery. However, whether IR worsens stroke recovery is unknown. We addressed this question in mouse models where early IR, with or without hyperglycemia, was induced by chronic high-fat diet feeding or sucrose supplementation in the drinking water, respectively. Furthermore, we used 10-month-old mice, spontaneously developing IR but not hyperglycemia, where IR was normalized pharmacologically pre-stroke with Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and the density of striatal cholinergic interneurons were also assessed by immunohistochemistry/quantitative microscopy. Pre-stroke induction and normalization of IR, respectively, worsened and improved post-stroke neurological recovery. Moreover, our data indicate a potential association of this impaired recovery with exacerbated neuroinflammation and a decreased density of striatal cholinergic interneurons. The global diabetes epidemic and population aging are dramatically increasing the percentage of people in need of post-stroke treatment/care. Our results suggest that future clinical studies should target pre-stroke IR to reduce stroke sequelae in both diabetics and elderly people with prediabetes.
... Ageing has been reported to decrease expression of skeletal muscle Glut 4 levels (Houmard et al., 1995). The increase in insulin resistance and decrease in insulin secretion that occurs during ageing process is believed to underlie age-related hyperglycemia (Defronzo, 1981;Chang and Halter, 2003). Blood glucose metabolism is regulated primarily by insulin secreted by the pancreatic islet β-cells. ...
Ageing is associated with elevated blood glucose levels, insulin resistance and pancreatic islet dysfunction. The age-related dysfunction of glucose metabolism has been well studied in humans and rodents. However, there is paucity of information on ageing and glucose metabolism in amphibians. This study was designed to investigate the effect of ageing on fasting blood glucose, liver and muscle glycogen levels in the common African toad, Bufo regularis. Toads of different sizes were randomly picked and used for the study. They were fasted for 24hours and anaesthetized with sodium thiopentone (50mg/kg) given intraperitoneally. Blood samples were collected from truncus arteriosus for blood glucose determination while the liver and muscle glycogen levels were determined using anthrone reagents methods. Ages of toads were determined using modified skelectochronology technique. The fasting glucose level increased with advancing age while liver and muscle glycogen levels decreased with age in Bufo regularis. The results suggest that glucose metabolism slows down with age in the toads and demonstrated similarities between the toads, humans and rodents in relation to age-related changes in glucose and glycogen metabolism
... Interestingly, these are also all characteristics of advanced age (DeFronzo, 1981;Palmer & Kirkland, 2016;Rosada et al., 2020). A comprehensive set of experiments were carried out to see if rapamycin had any effect on several structural and functional aging phenotypes in BL6 mice (Neff et al., 2013), which revealed that while rapamycin did increase mean life span, only a handful of the aging phenotypes were improved, and these were also improved in young mice. ...
Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased (‘adipose neuropathy’). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose‐resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti‐aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6 J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes. Genetically diverse HET3 mice display sex‐dependent peripheral neuropathy phenotypes as a result of age. Longevity treatment rapamycin was unable to attenuate denervation and worsened adipose tissue inflammation and fibrosis.
... Aging is usually associated with decreasing glucose tolerance and more susceptibility to diabetes (De Fronzo, 1984). It was also shown that insulin secretion in rabbits decreases with age, even with calorie restriction (Reaven and Reaven 1981). ...
... On the physiological level, circadian output from the SCN has been reported to decrease with age [10,11], though the molecular clocks in the aged SCN and in peripheral tissues express normal oscillations in vivo [11,12,13]. Previous work has also shown dampened rhythms in neuropeptides in the SCN and decreased glucose metabolism [14,15,16]. In addition, the aging of the eyes also leads to less light reaching the SCN [17]. ...
The mammalian circadian system comprises a network of cell-autonomous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects which have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following a perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.
... Both the studied age groups of diabetic patients, showed high level of fasting glucose but 46-60 year age group had statistically significant increased levels (186.9±38.1 mg/dl, p<0.05) because with increased age, the pancreas produces less insulin which means blood sugar remains elevated for longer time. Although fasting glucose levels are generally known to increase with advancing age [13] and age specific associations of fasting glucose with all-cause mortality have rarely been examined. However it has been observed that both males and females did not showed any significant differences. ...
Background: T2DM or type 2 diabetes mellitus is mostly related to the growing incidence of reduction in bone mineral density with increased porosity and susceptibility to fractures. Diabetes mellitus eventually compromise bone quality through production of advanced glycation products and misalignment of collagen fibrils, thereby culminating in reduction of bone strength. The underlying cellular mechanisms are related to suppression of osteoblast-induced bone formation and calcium accretion, as well as enhancement of osteoclast- induced bone resorption. Objectives: The aim of the present study was to evaluate the effect of high glucose level on the impairment of calcium metabolism in diabetes mellitus patients and to study the inter- relationship between diabetes mellitus and calcium metabolism. The linked association between them would be helpful to support public health policy markers and practioners. Materials and Methods: Total 100 samples were collected from Government Civil Hospital, Lopoke (Amritsar) with age group of 35-60 years having duration of diabetes more than 5 years. Blood and urine samples were analysed for biochemical parameters such as serum fasting glucose, alkaline phosphatase (ALP), albumin, vitamin D, phosphorus and calcium. Urine samples were also analysed to examine the excretion of phosphorus and calcium. Results: Decreased levels of serum calcium, albumin, vitamin D in serum along with elevated urinary calcium were observed in type 2 diabetic patients. Conclusion: From the study it has revealed that in the diabetic patients the calcium metabolism has been affected by the hyperglycemic state of the body. Hence, it is well established that effect of hyperglycemia on calcium metabolism is a risk factor for the development of osteoporosis in diabetic patients. Key words: Diabetes mellitus, Insulin, Osteoporosis, Calcium, Phosphorus, Vitamin D.
... Aging per se is an independent causative factor contributing to the development of metabolic syndrome (55)(56)(57) and insulin resistance plays a principal role in its initialisation and perpetuation (58). In this context, our study demonstrates that aging is associated with increased insulin resistance in both genders of control mice. ...
Objective
We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice.
Methods
UBC-CreERT2, Igf1r fl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i ) 13-weeks old young mice, and ii ) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice.
Results
Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice.
Conclusions
These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.
... Aging has been associated with elevated levels of both glucose and insulin after oral glucose challenge testing (glucose intolerance, DeFronzo, 1981;Kalyani and Egan, 2013). Glucose metabolism in nerve cells has been reported to be impaired during aging as a result of a compromised ability to increase glucose transport in response to insulin (Goyal and Dawood, 2017;Mattson and Arumugam, 2018). ...
While aging is an important risk factor for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, age-related cognitive decline can also manifest without apparent neurodegenerative changes. In this review, we discuss molecular, cellular, and network changes that occur during normal aging in the absence of neurodegenerative disease. Emerging findings reveal that these changes include metabolic alterations, oxidative stress, DNA damage, inflammation, calcium dyshomeostasis, and several other hallmarks of age-related neural changes that do not act on their own, but are often interconnected and together may underlie age-related alterations in brain plasticity and cognitive function. Importantly, age-related cognitive decline may not be reduced to a single neurobiological cause, but should instead be considered in terms of a densely connected system that underlies age-related cognitive alterations. We speculate that a decline in one hallmark of neural aging may trigger a decline in other, otherwise thus far stable subsystems, thereby triggering a cascade that may at some point also incur a decline of cognitive functions and mental well-being. Beyond studying the effects of these factors in isolation, considerable insight may be gained by studying the larger picture that entails a representative collection of such factors and their interactions, ranging from molecules to neural networks. Finally, we discuss some potential interventions that may help to prevent these alterations, thereby reducing cognitive decline and mental fragility, and enhancing mental well-being, and healthy aging.
... In addition, there is a positive correlation between age and BUN, which is consistent with reports of age-related decline in renal function (32). There is also a positive correlation between the subjects' age and GLU, which reflects age-related impairment of glucose tolerance (33). Finally, there was a positive correlation between the age of the subjects and ALP, which reflects hepatic dysfunction (34). ...
Background
Based on the assumption that systemic metabolic disorders affect cognitive function, we have developed a deep neural network (DNN) model that can estimate cognitive function based on basic blood test data that do not contain dementia-specific biomarkers. In this study, we used the same DNN model to assess whether basic blood data can be used to estimate cerebral atrophy.
Methods
We used data from 1,310 subjects (58.32 ± 12.91years old) enrolled in the Brain Doc Bank. The average Mini Mental State Examination score was 28.6 ± 1.9. The degree of cerebral atrophy was determined using the MRI-based index (GM-BHQ). First, we evaluated the correlations between the subjects' age, blood data, and GM-BHQ. Next, we developed DNN models to assess the GM-BHQ: one used subjects' age and blood data, while the other used only blood data for input items.
Results
There was a negative correlation between age and GM-BHQ scores (r = -0.71). The subjects' age was positively correlated with blood urea nitrogen (BUN) (r = 0.40), alkaline phosphatase (ALP) (r = 0.22), glucose (GLU) (r = 0.22), and negative correlations with red blood cell counts (RBC) (r = −0.29) and platelet counts (PLT) (r = −0.26). GM-BHQ correlated with BUN (r = −0.30), GLU (r = −0.26), PLT (r = 0.26), and ALP (r = 0.22). The GM-BHQ estimated by the DNN model with subject age exhibited a positive correlation with the ground truth GM-BHQ (r = 0.70). Furthermore, even if the DNN model without subject age was used, the estimated GM-BHQ showed a significant positive correlation with ground truth GM-BHQ (r = 0.58). Age was the most important variable for estimating GM-BHQ.
Discussion
Aging had the greatest effect on cerebral atrophy. Aging also affects various organs, such as the kidney, and causes changes in systemic metabolic status, which may contribute to cerebral atrophy and cognitive impairment. The DNN model may serve as a new screening test for dementia using basic blood tests for health examinations. Finally, the blood data reflect systemic metabolic disorders in each subject—this method may thus contribute to personalized care.
... 23 In 2016, the IRIS trial 11 was the first to show protection against atherosclerosis-associated events by the thiazolidinedione pioglitazone in a non-diabetic stroke population with insulin resistance. Decades of epidemiological data had previously strongly suggested a positive relationship between insulin resistance and cardiovascular disease, [24][25][26][27][28] including stroke. 29 Insulin resistance has been implicated as a potentially direct causative factor in atherogenesis. ...
Aims:
Pioglitazone is a potent insulin sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial.
Materials and methods:
Efficacy(myocardial infarction [MI] or recurrent stroke) new-onset diabetes) and adverse outcomes (edema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken; i.e. the dose taken on most days in the study.
Results:
Among 1938 patients randomized to pioglitazone, mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new onset diabetes with <15mg/day. For 15mg/30mg/day pooled, the Adjusted Hazard Ratios (95% CI) for Stroke/MI were 0.48 (0.30, 0.76), p = 0.002, and 0.74 (0.69, 0.94) for 45mg/day. For new onset diabetes, AHR were 0.34 (0.15,0.81) p = 0.001 and 0.31 (0.59,0.94), p = 0.001 respectively. For edema, weight gain, and heart failure, risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata.
Conclusions:
Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in stroke patients. This article is protected by copyright. All rights reserved.
... The declined mitochondrial functions (MT-CO1 [11]) in the Sparc KO mice (considered as an ageing model), as well as the anti-SPARC antibody-induced decrease in the expression of mitochondrial proteins, ubiquinol-cytochrome c reductase core protein II (UQCRC2) and succinate dehydrogenase iron-sulfur subunit (SDHB) in muscle cells [13], support the mitochondrial theory of ageing [54] and further highlight SPARC as an important factor in the age-related changes, as illustrated by the decreased myogenesis and myogenin expression in the C2C12 muscle cells following the treatment with the anti-SPARC antibody [13]. The glucose intolerance (revealed by the OGTT) in Sparc KO mice also mimics ageing-related glucose intolerance [55]. ...
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein implicated in various functions, including metabolism, tissue regeneration, and functional homeostasis. SPARC/Sparc declines with ageing but increases with exercise. We aim to verify two hypotheses: (1) SPARC deficiency leads to an ageing-like phenotype (metabolic decline, muscle loss, etc.), and (2) SPARC overexpression would mimic exercise, counteract ageing, and improve age-related changes. Our mice experiments are divided into two parts. First, we explore the consequences of Sparc knockout (KO) and compare them to the ageing effects. We also observe the effects of exercise. In the second part, we study the effects of SPARC overexpression and compare them to the exercise benefits. At the end, we make an analysis of the results to point out the analogies between Sparc KO and the ageing-like phenotype on the one hand and make comparisons between SPARC overexpression and exercise in the context of exercise counteracting ageing. The measurements were mainly related to tissue weights, adiposity, metabolism, and muscle strength. The main findings are that Sparc KO reduced glucose tolerance, muscle glucose transporter expression, and abdominal adipose tissue weight but increased glycogen content in the muscle. SPARC overexpression increased muscle strength, muscle mass, and expressions of the muscle glucose transporter and mitochondrial oxidative phosphorylation but lowered the glycemia and the adiposity, especially in males. Collectively, these findings, and the data we have previously reported, show that Sparc KO mice manifest an ageing-like phenotype, whereas SPARC overexpression and exercise generate similar benefits. The benefits are towards counteracting both the SPARC deficiency-induced ageing-like phenotype as well as reversing the age-related changes. The potential applications of these findings are to build/optimize Sparc KO-based animal models of various health conditions and, on the other hand, to develop therapies based on introducing SPARC or targeting SPARC-related pathways to mimic exercise against age-related and metabolic disorders.
... Although the roles of dietary carbohydrates in the human lifespan are unclear, the reduction in whole-body carbohydrate metabolism is associated with the elderly, and substantial evidence has shown that glucose tolerance decreases with advancing age; in fact, the decline begins in the third or fourth decade of life and is progressive throughout the entire adult lifespan [20]. These changes can increase the risk of insulin resistance and type 2 diabetes during aging, thereby decreasing the human lifespan. ...
Health and lifespan are influenced by dietary nutrients, whose balance is dependent on the supply or demand of each organism. Many studies have shown that an increased carbohydrate–lipid intake plays a critical role in metabolic dysregulation, which impacts longevity. Caenorhabditis elegans has been successfully used as an in vivo model to study the effects of several factors, such as genetic, environmental, diet, and lifestyle factors, on the molecular mechanisms that have been linked to healthspan, lifespan, and the aging process. There is evidence showing the causative effects of high glucose on lifespan in different diabetic models; however, the precise biological mechanisms affected by dietary nutrients, specifically carbohydrates and lipids, as well as their links with lifespan and longevity, remain unknown. Here, we provide an overview of the deleterious effects caused by high-carbohydrate and high-lipid diets, as well as the molecular signals that affect the lifespan of C. elegans; thus, understanding the detailed molecular mechanisms of high-glucose- and lipid-induced changes in whole organisms would allow the targeting of key regulatory factors to ameliorate metabolic disorders and age-related diseases.
... As both elevated LPS 4 and hyperglycaemia (HG) 34 were accompanied by ageing, we speculated that both LPS and HG may have promoting effect on aged microbiota-induced AF. 5 Herein, we found that the levels of plasma LPS and glucose in responding to OGTT were increased in the aged microbiota recipient. Recent study showed that the enhanced CMs-specific NLRP3-inflammasome was involved in development of AF by inducing atrial fibrosis and calcium handling dysregulation. ...
Aims
Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF.
Methods and Results
Herein, by using a fecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NLR family pyrin domain containing 3 (NLRP3)-inflammasome, promoting the development of AF which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then we conducted cross-sectional clinical studies to explore the effect of aging on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the aging phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF.
Conclusions
Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.
Translational Perspective
The current study demonstrates that aged-associated microbiota dysbiosis promotes AF in part through a microbiota–gut–atria axis. Increased AF susceptibility due to enhanced atrial NLRP3-inflammasome activity by LPS and high glucose was found in an aged FMT rat model, and also confirmed within elderly clinical individuals. In a long-term FMT rat study, the AF susceptibility was ameliorated by treatment with youthful microbiota. The present findings can further increase our understanding of aged-related AF and address a promising therapeutic strategy that involves modulation of gut microbiota composition.
... The pancreas shows an age-related decline of endocrine function that leads to an impairment in glucose homeostasis and metabolism. Aging impairs islet β-cell function and insulin secretion (Figure 2), while simultaneously increasing insulin resistance (Chen et al., 1985;Christina et al., 2009) and the incidence of type 2 diabetes (DeFronzo, 1981). The agedependent decline in insulin secretion is, in part, caused by a decrease of β-cell sensitivity to incretin stimulation (Chang and Halter, 2003), loss of Sirt1-mediated glucose stimulated insulin secretion (Ramsey et al., 2008), decreased expression of β-cell glucose transporter 2 (GLUT2) (Ihm et al., 2007), decreased mitochondrial function and increased oxidative stress (Cooksey et al., 2004). ...
The endocrine system consists of several highly vascularized glands that produce and secrete hormones to maintain body homeostasis and regulate a range of bodily functions and processes, including growth, metabolism and development. The dense and highly vascularized capillary network functions as the main transport system for hormones and regulatory factors to enable efficient endocrine function. The specialized capillary types provide the microenvironments to support stem and progenitor cells, by regulating their survival, maintenance and differentiation. Moreover, the vasculature interacts with endocrine cells supporting their endocrine function. However, the structure and niche function of vasculature in endocrine tissues remain poorly understood. Aging and endocrine disorders are associated with vascular perturbations. Understanding the cellular and molecular cues driving the disease, and age-related vascular perturbations hold potential to manage or even treat endocrine disorders and comorbidities associated with aging. This review aims to describe the structure and niche functions of the vasculature in various endocrine glands and define the vascular changes in aging and endocrine disorders.
... Aging is accompanied by reductions in insulin sensitivity and systemic glucose metabolism (Defronzo, 1981). Even within the normal physiological range, variability in systemic glucose metabolism has been correlated with working memory, such that individuals with more efficient glycemic control perform better on cognitive tests (Rolandsson et al, 2008). ...
Inquiry into relationships between energy metabolism and brain function requires a uniquely interdisciplinary mindset, and implementation of anti-aging lifestyle strategies based on this work also involves consistent mental and physical discipline. Dr. Mark P. Mattson embodies both of these qualities, based on the breadth and depth of his work on neurobiological responses to energetic stress, and on his own diligent practice of regular exercise and caloric restriction. Dr. Mattson created a neurotrophic niche in his own laboratory, allowing trainees to grow their skills, form new connections, and eventually migrate, forming their own labs while remaining part of the extended lab family. In this historical review, we highlight Dr. Mattson's many contributions to understanding neurobiological responses to physical exercise and dietary restriction, with an emphasis on the mechanisms that may underlie neuroprotection in ageing and age-related disease. On the occasion of Dr. Mattson's retirement from the National Institute on Aging, we highlight his foundational work on metabolism and neuroplasticity by reviewing the context for these findings and considering their impact on future research on the neuroscience of aging.
... The fasting plasma glucose (FPG) level is used to diagnose T2D and prediabetic conditions, and it is a key indicator of future T2D and cardiovascular diseases [13]. FPG levels generally increase with advancing age [14], which is one of the cardinal risk factor of OAG. High FPG leads to high glucose levels in the aqueous humor, which can increase fibronectin in trabecular meshwork cells, resulting in increased intraocular pressure (IOP) [15]. ...
Background:
The level of fasting plasma glucose (FPG) is positively associated with intraocular pressure. Diabetes causes early structural changes of retina, especially on ganglion cell layer. In this regard, the FPG level itself may also show an independent association with open angle glaucoma (OAG) development in general population. Herein, we investigate the association of the FPG level with the incidence of OAG.
Methods:
Using nationally representative data from the Korean National Health Insurance System, 374,376 subjects ≥40 years of age without OAG who underwent health examinations from 2009 to 2013 were enrolled and followed to the end of 2014. Incident cases of OAG using the International Classification of Diseases 10 codes and medication information were analyzed based on the levels of FPG.
Results:
Subjects with the highest FPG level (≥160 mg/dL), compared with the lowest level (<80 mg/dL), showed a higher hazard ratio (HR) [2.189; 95% confidence interval (CI): 1.779-2.695; P for trend < 0.001] for OAG after adjustments for age and sex. This result persisted after further adjustments for the presence of type 2 diabetes, current smoking, drinking, and exercise habits, diastolic blood pressure, body mass index (BMI), and total cholesterol level (HR: 1.588; 95% CI: 1.268-1.989; P for trend < 0.001). The positive association between the FPG level and the incidence of OAG was distinct in subjects 40-64 years of age, those with a BMI <25 kg/m2, and those without hypertension (HR 2.022; 95% CI: 1.494-2.736; P for trend <0.001: HR 1.817; 95% CI: 1.372-2.407; P for trend < 0.001: HR 1.706; 95% CI: 1.180-2.467; P for trend <0.001, respectively).
Conclusions:
This nationwide population-based cohort study showed that the fasting glucose was associated with an increased risk of OAG. These findings suggest that subjects with high FPG levels require special attention when screening for glaucoma.
... Age-related loss of skeletal muscle (SM) mass, strength, and function is known as sarcopenia [2,3] and is associated with an increased fall risk [4,5], disability [6,7], institutionalization [7], and all-cause mortality [7][8][9]. Pioneering studies by Lexell et al. showed that SM cross-sectional area (CSA), fiber size, and fiber number are reduced by 20-40% from adulthood to old age [10,11], paralleling the loss of aerobic fitness (VO 2max ), glucose tolerance, and anabolic hormones [12][13][14]. A conservative estimate is that >50 million of individuals are affected by sarcopenia and that this number will rise to >200 million in the next 40 years [15], with major economic implications for global health-care systems [16]. ...
Old age is associated with lower physical activity levels, suboptimal protein intake, and desensitization to anabolic stimuli, predisposing for age-related muscle loss (sarcopenia). Although resistance exercise (RE) and protein supplementation partially protect against sarcopenia under controlled conditions, the efficacy of home-based, unsupervised RE (HBRE) and multi-ingredient supplementation (MIS) is largely unknown. In this randomized, placebo-controlled and double-blind trial, we examined the effects of HBRE/MIS on muscle mass, strength, and function in free-living, older men. Thirty-two sedentary men underwent twelve weeks of home-based resistance band training (3 d/week), in combination with daily intake of a novel five-nutrient supplement (‘Muscle5’; M5, n = 16, 77.4 ± 2.8 y) containing whey, micellar casein, creatine, vitamin D, and omega-3 fatty acids, or an isocaloric/isonitrogenous placebo (PLA; n = 16, 74.4 ± 1.3 y), containing collagen and sunflower oil. Appendicular and total lean mass (ASM; +3%, TLM; +2%), lean mass to fat ratios (ASM/% body fat; +6%, TLM/% body fat; +5%), maximal strength (grip; +8%, leg press; +17%), and function (5-Times Sit-to-Stand time; −9%) were significantly improved in the M5 group following HBRE/MIS therapy (pre vs. post tests; p < 0.05). Fast-twitch muscle fiber cross-sectional areas of the quadriceps muscle were also significantly increased in the M5 group post intervention (Type IIa; +30.9%, Type IIx, +28.5%, p < 0.05). Sub-group analysis indicated even greater gains in total lean mass in sarcopenic individuals following HBRE/MIS therapy (TLM; +1.65 kg/+3.4%, p < 0.05). We conclude that the Muscle5 supplement is a safe, well-tolerated, and effective complement to low-intensity, home-based resistance exercise and improves lean mass, strength, and overall muscle quality in old age.
... Interestingly, inhibition of NLRP3-in ammasome ameliorates the age-related neurodegenerative disease by modulating the relationship between in ammation and gut microbiota composition, suggesting that NLRP3 activity to engaging for dysbiosis-induced aged-related in ammation diseases [39]. As both elevated LPS [5] and hyperglycemia [40] were accompanied by aging, we speculated that both LPS and HG may have promoting effect on aged microbiota-induced AF [4]. Herein, we found that the plasma LPS and glucose in responding to OGTT were increased in aged microbiota recipient. ...
Background: Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-associated diseases. However, whether age-associated gut microbial dysbiosis contributes to AF is still unknown. The aim of this study was to evaluate the effect of gut microbiota on the susceptibility of aging-induced AF and to elucidate the underlying mechanisms.
Results: The gut microbiota profiling of fecal samples in aged (22-24 months old) and young (2-3 months old) rats was performed by 16S ribosomal RNA gene analysis. A rat model of fecal microbiota transplantation (FMT) was established for analyzing the possible role of age-associated gut microbial dysbiosis in AF. Here, we found that aging process led to marked shift of the microbiota spectrum. The microbiota in young rats following FMT resembled that of aged microbiota and transmitted the increased AF susceptibility by elevation of circulating lipopolysaccharide (LPS). The mechanism for LPS-driven atrial pro-arrhythmic action was dependent on the activation of atrial nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing (NLRP3)-inflammasome. Inhibition of inflammasome by MCC950 resulted in lower atrial fibrosis and AF susceptibility. In addition, atrial fibrosis, plasma LPS concentration, plasma glucose to oral glucose tolerance test (OGTT), intestinal permeability, and gut pathology were significantly increased in elderly human subjects. Finally, altering the microbiota in aged recipient to resemble that of young restored the intestinal barrier dysfunction and LPS and impaired glucose tolerance, and the worse outcomes of aged dysbiosis on atrial fibrosis and AF susceptibility were abrogated.
Conclusions: These data suggest that age-associated microbial dysbiosis induces circulating LPS and impairs glucose tolerance, and thereby promotes AF susceptibility through enhanced activity of atrial NLRP3-inflammasome.
... For example, TP increases with age in the tammar wallaby Notamacropus eugenii, short-eared mountain possum Trichosurus caninus and southern hairy-nosed wombat Lasiorhinus latifrons (Barnett et al. 1979, McKenzie et al. 2002, Woolford et al. 2020; and in small mammals, RBC values are higher in juveniles when compared with adults (Sealander 1964). The significantly lower values for glucose concentrations and lymphocyte counts in adults is likely related to decreased glucose metabolism and the output of T lymphocytes as the immune response declines with age (Clot et al. 1978, Defronzo 1981, Linton and Dorshkind 2004. Given the observed maturity differences in blood parameters, it is important that sub-adult individuals are clinically evaluated with RIs specific to this age cohort. ...
Reference intervals (RIs) describe baseline parameters of healthy animals, providing a powerful tool for wildlife managers to monitor health, identify disease and assess animal welfare. This paper reports haematological, glucose and serum protein RIs for one of Australia's most iconic and managed mammals, the eastern grey kangaroo Macropus giganteus. Blood samples (n = 514) were collected from 11 populations of eastern grey kangaroos, across much of their geographic range. A species-level RI was initially established based on samples collected from four sites (n = 245) and was further partitioned based on significant differences associated with sexual maturity and season. Unique population means were established from a further seven sites to investigate the importance of biotic (sex and sexual maturity) and abiotic (season, site, rainfall, temperature and laboratory) factors on kangaroo health parameters. Random forest analysis of health parameters revealed that abiotic factors (site, rainfall, temperature and season) were largely responsible for differences in haematological, glucose and serum protein values. Sex was found to have no influence, while sexual maturity and laboratory of analysis had moderate effects. Based on these findings, interpretation of individual and population haematological and serum protein values requires careful consideration of the timing of sample collection, environmental conditions and sexual maturity. When assessing kangaroo health, the relevant sexual maturity RI must be considered initially. For populations with similarities to those described (for example high density or captive populations) users should also consider site specific mean haematological and serum protein values. The RIs reported are valuable when establishing the health status of kangaroo populations. Furthermore, understanding the influence of biotic and abiotic factors will improve the utility of these RIs to assess health, disease status and improve welfare in eastern grey kangaroos.
... This can be overcome by including an agematched control group, but still ageing itself is no simplistic linear event (chronological age), but rather a highly heterogenous, nonlinear phenomenon that is continuously affected by factors such as (epi)genetics, environment and disease (biological age) (Baker and Sprott, 1988;Coelho-junior et al., 2019). For instance, insulin sensitivity gradually decreases with advancing age (Defronzo, 1981). Therefore, some elderly experience "low" insulin resistance, affecting systemic metabolism and peripheral tissues, such as muscle, although without being diagnosed with T2D. ...
Muscle loss is an important feature that occurs in multiple pathologies including osteoarthritis (OA), chronic obstructive pulmonary disease (COPD) and type II diabetes (T2D). Despite differences in pathogenesis and disease-related complications, there are reasons to believe that some fundamental underlying mechanisms are inherent to the muscle wasting process, irrespective of the pathology. Recent evidence shows that inflammation, either local or systemic, contributes to the modulation of muscle mass and/or muscle strength, via an altered molecular profile in muscle tissue. However, it remains ambiguous to which extent and via which mechanisms inflammatory signaling affects muscle mass in disease. Therefore, the objective of the present review is to discuss the role of inflammation on skeletal muscle anabolism, catabolism and functionality in three pathologies that are characterized by an eventual loss in muscle mass (and muscle strength), i.e. OA, COPD and T2D. In OA and COPD, most rodent models confirmed that systemic (COPD) or muscle (OA) inflammation directly induces muscle loss or muscle dysfunctionality. However, in a patient population, the association between inflammation and muscular maladaptations are more ambiguous. For example, in T2D patients, systemic inflammation is associated with muscle loss whereas in OA patients this link has not consistently been established. T2D rodent models revealed that increased levels of advanced glycation end-products (AGEs) and a decreased mTORC1 activation play a key role in muscle atrophy, but it remains to be elucidated whether AGEs and mTORC1 are interconnected and contribute to muscle loss in T2D patients. Generally, if any, associations between inflammation and muscle are mainly based on observational and cross-sectional data. There is definitely a need for longitudinal evidence through well-powered randomized control trials that take into account confounders such as age, disease-phenotypes, comorbidities, physical (in) activity etc. This will allow to improve our understanding of the complex interaction between inflammatory signaling and muscle mass loss and hence contribute to the development of therapeutic strategies to combat muscle wasting in these diseases.
... Aging is usually associated with decreasing glucose tolerance and more susceptibility to diabetes (De Fronzo, 1984). It was also shown in rats that insulin secretion decreases with age, even with calorie restriction (Reaven and Reaven 1981). ...
Previous studies and clinical observations strongly suggest a close relationship between aging and diabetes mellitus. However, none of the previous published data had focused clearly on the age related cellular and histological variations in the pancreas, which is the subject of our current study. Three groups of male albino rats have been used, ten rats each; classified as group-1 (5 months old); group-2 (10 months old) and group-3 (20 months old). After decapitation, sections from the pancreatic tails were stained by haematoxylin and eosin (H&E); Gomori trichromic stain and by immunohistochemistry to identify insulin and glucagon secreting cells using their appropriate monoclonal antibodies.
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Published in: The Scientific Journal of Al-Azhar Medical Faculty (Girls), Vol. 26 No.1, 2005 PP: 1739-1750 http://www.sjamf.eg.net
... Studies comparing hepatic glucose production in younger and older adults have been mixed, and appears that hepatic glucose output may not be affected by age as much as by differences in body composition. 21,[23][24][25] Beta-cell function and insulin secretion in older adults have been shown to be decreased, accompanied by worsening insulin resistance compared with younger adults. [26][27][28] In addition, changes in body fat mass with a reduction in lean muscle mass that occurs with age, as well as adipose tissue dysfunction (a proinflammatory state) increases insulin resistance in older adults. ...
Diabetes is one of the world's fastest growing health challenges. Insulin therapy remains a useful regimen for many elderly patients, such as those with moderate to severe hyperglycemia, type 1 diabetes, hyperglycemic emergencies, and those who fail to maintain glucose control on non-insulin agents alone. Recent clinical trials have shown that several non-insulin agents as monotherapy, or in combination with low doses of basal insulin, have comparable efficacy and potential safety advantages to complex insulin therapy regimens. Determining the most appropriate diabetes management plan for older hospitalized patients requires consideration of many factors to prevent poor outcomes related to dysglycemia.
... [43][44][45][46] However, there are some other researchers showed completely opposite findings. [47][48][49][50][51][52] This controversy might come from the different methods used to quantify insulin secretion. At the same time, whether other factors, such as IR, were adjusted might also contribute. ...
It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.
Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.
The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (−0.003 × GE − 212.6 × SPIS − 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).
Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.
... Hal tersebut terjadi karena semakin bertambahnya usia, maka masa tubuh semakin berkurang dan persentase adiposit semakin meningkat. Hal ini disebabkan karena dengan adanya pertambahan usia, maka tubuh semakin resisten terhadap insulin, sehingga pengambilan atau pengangkutan glukosa ke dalam otot juga semakin berkurang, dan hal tersebut menyebabkan masa tubuh berkurang.15 Menurut penelitian di India, terdapat faktor "Asian Indian Phenotype", Pada penelitian ini, hanya terdapat 2 dari 115 pasien yang diperiksa kadar HbA1c.Sedikitnya data HbA1c yang tersedia pada rekam medis dapat disebabkan karena faktor biaya pemeriksaan yang tinggi atau tidak tersedianya alat pemeriksaan. ...
Uncontrolled hyperglycemia in people with diabetes mellitus can increase the risk of diabetes complications and comorbidities. This study aimed to determine the demographic, clinical, history, complications, and comorbid characteristics of diabetes. The study was conducted with a descriptive method and cross-sectional research design. Data were collected retrospectively using medical record data and using the Finite Population Correction formula with a sample of 115. The results showed the majority of patients were female (67.8%), aged ? 65 years (40.0%), residing in urban (87.6%), high school graduates (35.2%), and unemployed (63.6%). Patients generally have a normal BMI (45.9%) and have several variables that reach the target, namely fasting blood glucose (50.4%), triglycerides (55.3%), and creatinine (69.6%). Patients also had several variables that did not reach the target, namely postprandial 2 hour blood glucose (51.3%), blood pressure (65.8%), total cholesterol (55.6%), HDL cholesterol (54.5%), LDL cholesterol (80.0%), and urea (56.0%). Patients who use oral anti-diabetes generally have used it <5 years (76.3%) and used monotherapy (63.5%). Neuropathy (42.6%) and hypertension (85.9%) were the most common complications and comorbidities of diabetes in this study. Strict glycemic control is an important management for people with diabetes mellitus. Keywords: oral antidiabetic drugs; diabetes mellitus; comorbid
... Aging has been associated with glucose intolerance and whole-body insulin resistance [2][3][4][5][6][7][8], with the factors contributing to these disorders being complex and likely multifaceted including chronological age [2], reduced physical activity [9], inflammation [10], and/or increased body fat [9,11]. Since skeletal muscle is the primary target for insulin-mediated glucose uptake [12], age-related changes in the structure and metabolism of this tissue are also thought to play a major role in the pathogenesis of insulin resistance in older adults. ...
Aging is associated with insulin resistance and the development of type 2 diabetes. While this process is multifaceted, age-related changes to skeletal muscle are expected to contribute to impaired glucose metabolism. Some of these changes include sarcopenia, impaired insulin signaling, and imbalances in glucose utilization. Endurance and resistance exercise training have been endorsed as interventions to improve glucose tolerance and whole-body insulin sensitivity in the elderly. While both types of exercise generally increase insulin sensitivity in older adults, the metabolic pathways through which this occurs can differ and can be dependent on preexisting conditions including obesity and type 2 diabetes. In this review, we will first highlight age-related changes to skeletal muscle which can contribute to insulin resistance, followed by a comparison of endurance and resistance training adaptations to insulin-stimulated glucose metabolism in older adults.
... Diabetic neuropathy is especially prominent, affecting over 50% of diabetic individuals, and often leading to limb amputation [23,24]. Aging is associated with a loss of metabolic regulation and an increased propensity for diabetes [25][26][27], and is independently associated with an idiopathic form of peripheral neuropathy [28]. The debilitating aspects of peripheral neuropathy are largely due to the inability to prevent or treat these conditions, and the inability to halt and reverse the neurodegeneration. ...
The difficulty in obtaining as well as maintaining weight loss, together with the impairment of metabolic control in conditions like diabetes and cardiovascular disease, may represent pathological situations of inadequate neural communication between the brain and peripheral organs and tissues. Innervation of adipose tissues by peripheral nerves provides a means of communication between the master metabolic regulator in the brain (chiefly the hypothalamus), and energy-expending and energy-storing cells in the body (primarily adipocytes). Although chemical and surgical denervation studies have clearly demonstrated how crucial adipose tissue neural innervation is for maintaining proper metabolic health, we have uncovered that adipose tissue becomes neuropathic (ie: reduction in neurites) in various conditions of metabolic dysregulation. Here, utilizing both human and mouse adipose tissues, we present evidence of adipose tissue neuropathy, or loss of proper innervation, under pathophysiological conditions such as obesity, diabetes, and aging, all of which are concomitant with insult to the adipose organ as well as metabolic dysfunction. Neuropathy is indicated by loss of nerve fiber protein expression, reduction in synaptic markers, and lower neurotrophic factor expression in adipose tissue. Aging-related adipose neuropathy particularly results in loss of innervation around the tissue vasculature, which cannot be reversed by exercise. Together with indications of neuropathy in muscle and bone, these findings underscore that peripheral neuropathy is not restricted to classic tissues like the skin of distal extremities, and that loss of innervation to adipose may trigger or exacerbate metabolic diseases. In addition, we have demonstrated stimulation of adipose tissue neural plasticity with cold exposure, which may ameliorate adipose neuropathy and be a potential therapeutic option to re-innervate adipose and restore metabolic health.
... These studies reported strong associations between temporally matched measures (e.g., MRIand DXA-derived absolute measures at baseline) 16,[19][20][21] . However, when comparing percent-change over time, these studies have indicated discrepant findings with a few studies suggesting much lower associations (explained variances [R 2 -values] on the order of 4-33%) [19][20][21] , while others suggested higher levels of concordance (61% and 77%) 16,23 . The lack of understanding about how well various assessment methods of skeletal muscle size agree in longitudinal studies is a serious problem as it relates to the design and interpretation of clinical trials. ...
Dual-energy X-ray absorptiometry (DXA) derived measures of lean mass demonstrate strong associations with magnetic resonance imaging (MRI) derived measures of muscle volume (MV) in cross-sectional studies, however, few studies have compared changes in response to an intervention. The purpose of this study was to determine the accuracy of DXA at detecting changes in lean mass, using MRI-derived MV as a reference standard. 10 male and 16 female subjects (29.2 ± 9.5 years) underwent DXA and MRI scans before and after a 10-week resistance training intervention. DXA thigh lean mass was compared to MRI mid-thigh MV, and percent change in size was compared between MRI and DXA. There was a strong correlation between measures cross-sectionally (r = 0.89) in agreement with previous investigations. However, there was a modest correlation of percentage change over time between methods (r = 0.49). Bland-Altman plots revealed that the amount of random error increased as the magnitude of the change from baseline increased. DXA measures of change in lean mass were modestly associated with MRI measures of change in MV. While there are several advantages to using DXA for the measurement of lean mass, the inability to accurately detect changes over time calls into question its use in clinical trials.
... It is the primary site of insulin-mediated glucose disposal. With the advent of the glycemic clamp technique, the laboratories of DeFronzo and Olefsky demonstrated that insulin sensitivity and, more specifically, post-receptor insulin action, are significantly reduced in healthy, non-obese older women and men [46,47]. Despite effective binding to its cognate receptor, insulin-mediated activation of Akt2 and the subsequent phosphorylation and inactivation of RabGTPases, which enable glucose transporter type 4-containing vesicles to translocate to the cell membrane to import glucose, are decreased in aged skeletal muscle [48]. ...
The mammalian circadian system comprises a network of endogenous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects that have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.
The acute effect of exercise on β-cell function during a high fat meal (HFM) in young (YA) vs. old (OA) adults is unclear. In this randomized cross-over trial, YA (n=5M/7F, 23.3±3.9y) and OA (n=8M/4F, 67.7±6.0y) underwent a 180 min HFM (12 kcal/kgbw; 57% fat, 37% CHO) after a rest or exercise (~65% HRpeak) condition ~12hr prior. After an overnight fast, plasma lipids, glucose, insulin, as well as FFA were determined for peripheral, or skeletal muscle, insulin sensitivity (Matsuda Index) as well as hepatic (HOMA-IR) and adipose (Adipose-IR) insulin resistance calculations. β-cell function was derived from C-peptide and defined as early (0-30min) and total phase (0-180min) disposition index (DI, glucose-stimulated insulin secretion (GSIS) adjusted for insulin sensitivity/resistance). Hepatic insulin extraction (HIE) body composition (DXA) and VO2peak were also assessed. OA had higher TC, LDL, HIE and DI across organs as well as lower adipose-IR (all, P<0.05) and VO2peak (P=0.056) despite similar body composition and glucose tolerance. Exercise lowered early phase TC and LDL in OA vs. YA (P<0.05). However, C-peptide AUC, total phase GSIS, and adipose-IR were reduced post-exercise in YA vs. OA (P<0.05). Skeletal muscle DI increased in YA and OA after exercise (P<0.05), while adipose DI tended to decline in OA (P=0.06 and P=0.08). Exercise-induced skeletal muscle insulin sensitivity (r=-0.44, P=0.02) and total phase DI (r=-0.65, P=0.005) correlated with reduced glucose AUC180min. Together, exercise improved skeletal muscle insulin sensitivity/DI in relation to glucose tolerance in YA and OA, but only raised adipose-IR and reduced adipose DI in OA.
Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.
It is well-established that the transmission of short-wavelength light through the lens is reduced and the lens appears to "yellow" with age. The rate of this lens "yellowing" has been quantified (Pokorny, Smith and Lutze, 1987). The lens "yellows" at a relatively slow rate until the age of 60 years after which lens "yellowing" is accelerated. Here we present evidence that the lenses of young, Type I diabetics "yellow" at a similar rate to older normal controls over the age of 60 yr. We also discuss a possible molecular explanation for accelerated "yellowing" in both populations.
Prediabetes affects 1 in 3 American adults and is characterized by insulin resistance, insulin hypersecretion, and impaired glucose tolerance. Weanling LEW.1WR1 (1WR1) rats have increased blood insulin concentrations, so we hypothesized that young adult 1WR1 rats would develop impaired glucose tolerance due to the poor regulation of insulin. We monitored glucose tolerance, insulin tolerance, and weight gain for 10 weeks to assess if there was a decline in glucose processing over time. 1WR1 rats were significantly more glucose intolerant after 8 weeks. 1WR1 rats had increased body mass, yet abdominal fat mass was not significantly increased. Although the 1WR1 rats had increased circulating insulin and glucagon protein levels, 1WR1 rat beta cell area was significantly reduced. There may be underlying insulin resistance as evidenced by dysfunctional insulin regulation during fasting. Understanding the metabolic phenotype of this rat model can provide insight into the human pathophysiological changes that increase susceptibility to glucose intolerance and prediabetes.
Background
Type 2 diabetes (T2D) impairs post-stroke functional recovery, and the underlying mechanisms are mostly unknown. Insulin resistance (IR), which is a hallmark of T2D, also afflicts up to 50% of the elderly without T2D. IR has been associated with impaired recovery after stroke. However, the causative role of IR in impaired stroke recovery has not been demonstrated. By using different mouse models of early IR, we investigated the potential crosstalk between IR and stroke recovery as well as some of the cellular mechanisms possibly involved.
Methods
We used three different models of IR. Early IR with or without fasting hyperglycaemia was respectively induced by 4 months of high fat diet or by 30% sucrose supplementation in the drinking water. In addition, we used 10-month-old mice that spontaneously develop IR, but not hyperglycaemia, and where IR was targeted pharmacologically pre-stroke with 10 mg/kg/day Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and neuroplasticity mediated by cholinergic interneurons were assessed by immunohistochemistry/quantitative microscopy.
Results
The induction of IR before stroke, with or without hyperglycaemia, impaired post-stroke neurological recovery. Moreover, the results indicate the involvement of increased neuroinflammation and decreased cholinergic interneuron-mediated neuroplasticity in the recorded effects. Importantly, the pharmacological normalization of IR, significantly improved post-stroke neurological recovery.
Conclusion
The global diabetes epidemic and world population aging are dramatically increasing the percentage of people in need of post-stroke treatment and care. Targeting hyperglycaemia acutely post-stroke has so far provided negative results to improve stroke outcome and new targets are highly needed. The results of our study suggest that future clinical studies should focus on the specific targeting of pre-stroke IR to reduce the sequelaeof stroke in both diabetic patients and the elderly suffering from prediabetes.
Enteral feedings are safely tolerated by most patients. When complications occur, gastrointestinal disturbances are most frequently encountered, followed by mechanical and metabolic complications. Nurses can prevent many of the problems associated with enteral feeding through careful monitoring. Based on the current literature, the authors make the following recommendations:
1.All patients receiving tube feedings should be placed on a protocol that provides guidelines for (a) confirming correct tube placement; (b) preventing/managing tube obstruction; (c) handling and selecting formulas; (d) administering formulas; and (e) monitoring patients.
2.Fine-bore tubes are easily misplaced or dislodged; ensure correct positioning both before and during feeding. Food coloring should be added to all feedings to help detect aspiration/tube displacement.
3.Multiple factors can cause diarrhea in tube-fed patients and, therefore, require periodic assessment. These factors include concomitant drug therapy; malnutrition/hypoalbuminemia; formula-related factors (for example, lactose content, osmolality); and bacterial contamination.
4.Urine sugar and acetone levels should be checked every 6 hours (until stable). Vital signs and fluid intake and output should be determined every 8 hours, and weight should be measured on a daily basis. Serum electrolytes, blood urea nitrogen, and glucose levels should be determined daily, until serum levels stabilize. Weekly measurements of trace elements should be made to ensure adequate mineral replacement.
5.Use a controller pump to administer continuous feedings at a constant rate or to administer formulas that are viscous. Flush feeding tubes with water every 4 hours during continuous feedings, after giving intermittent feedings, after giving medications, and after checking for gastric residuals. If tube obstruction occurs, attempt to irrigate the tube with either water or cola.
6.Select feedings that contain appropriate nutrient sources, caloric density, and osmolality; handle feedings in a way that minimizes bacterial contamination.
While glucose tolerance is widely known to deteriorate with age, there are individuals whose borderline elevated glucose does not presage development of diabetes, but there are people who do develop overt diabetes. In addition, elevated glucose may also presage other morbidities, particularly for those who show progressive deterioration in glucose control over time. This concept of the glucose trajectory has taken on recent significance with sophisticated mathematical modeling that can identify several different arcs, primarily based on longitudinal changes in fasting plasma glucose. Other trajectories, calculated on changes in glycated hemoglobin, or integrated responses to oral glucose tolerance tests, are less well characterized. The author has reviewed the literature in an attempt to clarify these different themes of age-related deterioration in glucose control, highlight conflicting definitions of glucose trajectory, and potentially identify avenues of further investigation. Genetic contributions to the risk of development of type 2 diabetes, artificial intelligence and mathematical models of diabetes risk, and the discrepancy between fasting glucose and postprandial measures, including glycated hemoglobin, in risk prediction are also considered.
Background:
Ageing is accompanied by muscle loss and fat gain, which may elevate the risk of type 2 diabetes (T2D). However, there is a paucity of data on the distribution of regional lean and fat tissue in older adults with T2D or prediabetes compared with healthy controls. The objective of this study was to compare regional body composition [by dual-energy x-ray absorptiometry (DXA)], muscle and subcutaneous adipose tissue (SAT) thicknesses (by ultrasound), and ultrasound-based muscle texture features in older adults with T2D or prediabetes compared with normoglycaemic controls.
Methods:
Eighteen adults > 60 years with T2D or prediabetes (T2D group) were individually matched to normoglycaemic participants [healthy matched (HM) group] for age (±5 years), sex, and body fat (±2.5%). In a single study visit, all participants received a whole-body DXA scan and ultrasound assessment of the abdomen and anterior thigh. At these two landmarks, we used ultrasound to measure muscle and SAT thickness, as well as texture features of the rectus femoris and rectus abdominis. We also conducted an exploratory subanalysis on a subset of participants (n = 14/18 in the T2D group and n = 10/18 in the HM group) who underwent additional assessments including strength testing of the knee extensors (using a Biodex dynamometer), and a fasting blood sample for the measurement of circulating markers of glucose metabolism [glucose, insulin, c-peptide, and the homoeostatic model assessment of insulin resistance (HOMA-IR)].
Results:
The T2D group was 72 ± 8 years old (mean ± SD), predominantly male (n = 15/18; 83%), and overweight (BMI: 27.8 ± 4.2 kg/m2 , 33.2 ± 5.3% body fat). DXA-derived upper arm lean mass was 0.4 kg greater (P = 0.034), and leg fat mass was 1.4 kg lower (P = 0.048), in the T2D vs. HM group. Ultrasound-based texture features were distinct between the groups [rectus abdominis blob size: 0.07 ± 0.06 vs. 0.30 ± 0.43 cm2 , P = 0.045; rectus femoris local binary pattern (LBP) entropy: 4.65 ± 0.05 vs. 4.59 ± 0.08 A.U., P = 0.007]. When all participants who underwent additional assessments were pooled (n = 24), we observed that certain ultrasound-based muscle texture features correlated significantly with muscle strength (rectus abdominis histogram skew vs. power during an isokinetic contraction at 60°/s: r = 0.601, P = 0.003) and insulin resistance (rectus femoris LBP entropy vs. HOMA-IR: r = 0.419, P = 0.042).
Conclusions:
Our findings suggest a novel body composition phenotype specific to older adults with T2D or prediabetes. We are also the first to report that ultrasound-based texture features correspond with functional outcomes. Future larger scale studies are needed to uncover the mechanisms underpinning these regional body composition differences.
Ageing is the prime risk factor for the development of type 2 diabetes. We investigated the role of the Interleukin-1 system on insulin secretion in aged mice. During ageing, expression of the protective IL-1 receptor antagonist decreased in islets, while IL-1beta gene expression increased specifically in the CD45+ islet immune cell fraction. 1-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during ageing while it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2 and of the cell cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2 and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.
A single high-fat, high-carbohydrate meal (HFHC) results in elevated postprandial glucose (GLU), triglycerides (TRG) and metabolic load index (MLI; TRG (mg/dL) + GLU (mg/dL)) that contributes to chronic disease risk. While disease risk is higher in older adults (OA) compared to younger adults (YA), the acute effects of exercise on these outcomes in OA is understudied. Twelve YA (age 23.3 ± 3.9 yrs, n = 5 M/7 F) and 12 OA (age 67.7 ± 6.0 yrs, n = 8 M/4 F) visited the laboratory in random order to complete a HFHC with no exercise (NE) or acute exercise (EX) condition. EX was performed 12 hours prior to HFHC at an intensity of 65% of maximal heart rate to expend 75% of the kcals consumed in HFHC (Marie Callender’s Chocolate Satin Pie; 12 kcal/kgbw; 57% fat, 37% CHO). Blood samples were taken at 0, 30, 60, 90 minutes, and then every hour until 6 hours post-meal. TRG levels increased to a larger magnitude in OA (Δ˜61 ± 31%) compared to YA (Δ˜37 ± 34%, p < 0.001), which were attenuated in EX compared to NE (p < 0.05) independent of age. There was no difference in GLU between OA and YA after the HFM, however EX had attenuated GLU independent of age (NE: Δ˜21 ± 26%; EX: Δ˜12 ± 18%, p = 0.027). MLI was significantly lower after EX compared to NE in OA and YA (p < 0.001). Pre-prandial EX reduced TRG, GLU and MLI post-HFHC independent of age.
Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.
Background
Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored.
Objectives
This study sought to determine the association between brain metabolism, subclinical atherosclerosis, and CVRFs in middle-aged asymptomatic individuals.
Methods
This study included 547 asymptomatic middle-aged participants (50 ± 4 years, 82% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study with evidence of subclinical atherosclerosis. Participants underwent ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomography. Global brain FDG uptake and voxel-wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3-dimensional vascular ultrasound.
Results
Global FDG uptake showed an inverse correlation with 30-year Framingham Risk Score (FRS) (β = −0.15, p < 0.001). This association was mainly driven by the presence of hypertension (d = 0.36, p < 0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β = −0.16, p < 0.001), even after adjusting for 30-year FRS. Voxel-wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30-year FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus.
Conclusions
In asymptomatic middle-aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include those known to be affected in dementia. These data reinforce the need to control CVRFs early in life in order to potentially reduce the brain’s midlife vulnerability to future cognitive dysfunction.
Calorie restriction (CR), the reduction of dietary intake below energy requirements while maintaining optimal nutrition, is the only known nutritional intervention with the potential to attenuate aging. Evidence from observational, preclinical, and clinical trials suggests the ability to increase life span by 1–5 years with an improvement in health span and quality of life lived. CR moderates intrinsic processes of aging through cellular and metabolic adaptations and reducing risk for the development of many cardiometabolic diseases. Yet, implementation of CR may require unique considerations for the elderly and other specific populations. The objectives of this review are to summarize the evidence for CR to modify primary and secondary aging; present caveats for implementation in special populations; describe newer, alternative approaches that have comparative effectiveness and fewer deleterious effects; and provide thoughts on the future of this important field of study.
Please see http://www.annualreviews.org/page/journal/pubdates for expected final online publication date for the Annual Review of Nutrition, Volume 40. 2020
Laboratory data often plays a significant role in the care of older adults. However, the interpretation of laboratory data in older adults is complicated by a number of factors including lack of representation of older adults in populations sampled to determine the reference ranges for laboratory tests, misconceptions regarding the meaning of laboratory reference ranges, normal physiologic changes with aging which influence results of some tests, difficulty distinguishing normal changes with aging from pathologic changes, and the frequent presence of chronic conditions and use of medications which may alter test results. Lack of awareness of the above issues can lead to misinterpretation of laboratory tests and result in overtreatment as well as missed diagnoses.
Although the brain is the master regulator of all bodily functions, peripheral nerves provide a means by which the brain communicates to all tissues, regulates organ function, and maintains systemic homeostasis. Metabolic homeostasis relies on the maintenance of energy balance which is governed in large part by the brain and adipose tissue. Disruption of communication between these two organs can lead to a metabolic state of energy excess or insufficiency, i.e. energy imbalance. Energy balance is maintained when energy intake, governed by appetite, food intake and nutrient absorption, equates energy expenditure, which is influenced by physical activity, basal metabolic rate, and thermogenesis. Over the last few decades, surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and ‘browning’ of white adipose tissue (the process by which energy iv storing adipose tissue becomes thermogenically active and expends energy). However, the factors that regulate peripheral nerve health and remodeling, defined to include neuropathy (nerve death) and plasticity (neurite outgrowth), within the adipose organ have not been well explored. Peripheral neuropathy is a condition of nerve die-back that begins in the skin and travels inwards. Here we have shown that underlying subcutaneous adipose tissues also display peripheral neuropathy with conditions that range from obesity and diabetes to aging and certain diets. Under all aforementioned conditions the tissue also exhibited a loss of locally produced neurotrophic factors, which we have now implicated in the mechanism of adipose neuropathy. Exercise is able to at least partially reverse adipose neuropathy, and is associated with an increase in local neurotrophic factor expression. Furthermore, AAV-mediated gene delivery of this neurotrophic factor was shown to increase innervation in subcutaneous adipose tissue in a murine model of diabetic peripheral neuropathy. Interestingly, exercise and cold stimulation are both able to increase gene and protein expression of pan-neuronal and synaptic markers in adipose tissue, suggesting increased innervation of the tissue. We have also demonstrated that in adipose tissue, a neurotrophic factor is produced by immune cells in the stromovascular fraction, under stimulation from noradrenergic signaling. Deletion of this neurotrophic factor from myeloid lineage immune cells leads to a striking and specific ‘genetic denervation’ of white adipose tissue only, sparing the spinal nerves, neuromuscular junction, brain, and brown adipose tissue. Therefore, we believe we have uncovered a novel mechanism for how adipose tissue metabolic health is regulated through remodeling of the tissue’s peripheral nerve network.
There seems little doubt that the disposal of a glucose load is progressively impaired during aging. The mechanism(s) for this alteration remains unclear. Five possibilities have been raised: (1) poor diet, (2) physical inactivity, (3) decreased lean body mass in which to store the carbohydrate load, (4) decreased insulin secretion, and (5) insulin antagonism. Although poor diet and physical inactivity may contribute to some of the abnormal glucose tolerance tests of the older population, these two factors do not provide a full explanation. Diminished lean body mass may play some role but there is almost certainly an additional effect due to aging. A few papers have suggested that glucose-induced insulin secretion may be impaired as the population ages, but the bulk of studies in this area conclude that normal or increased amounts of insulin are released by the pancreatic beta-cell during aging. If abnormalities of insulin secretion exist, either in degree or timing, they are subtle and would not seem sufficient to account for the great number of older subjects who manifest impaired glucose tolerance. The evidence for insulin antagonism seems the strongest but the data are certainly not conclusive. In actuality, the aging effect on carbohydrate metabolism may be heterogeneous in nature. Either some or all of these five factors may contribute to the aging effect to varying degrees in individual subjects. Alternatively, the glucose intolerance of aging may represent a heterogeneous group of disorders. In any event, until better methods to identify possible subgroups of these subjects and/or a marker for diabetes mellitus independent of glucose concentration become available, this problem will remain difficult to resolve. Based on the currently available data, it seems prudent to diagnose diabetes mellitus only if fasting hyperglycemia is present.
The total plasma insulin and proinsulin-like material after oral glucose was studied in 68 lean subjects of varying ages with normal glucose tolerance tests. Although each subject had a normal test, the mean glucose levels increased with increasing age. When younger subjects (ages 15 to 44) were compared with older (45 to 74), no significant differences in total insulin responses were seen, but plasma proinsulin-like material was significantly higher in the older age subjects. All values after stimulation were significantly greater in subjects 45 to 74 years of age than in those 15 to 44 years of age (p less than 0.01). A significant correlation between the amount of proinsulin and the age of the subject was seen. These findings may reflect a decreased conversion of proinsulin to insulin in the aging pancreas or could reflect decreased clearance of proinsulin in older subjects.
In an effort to determine the possible relationship between changes in insulin-receptor binding and the glucocorticoid-induced insulin-resistant state, we studied insulin binding to specific receptors located on isolated adipocytes and hepatocytes obtained from dexamethasone (D)-treated rats. Three groups of D-treated rats were studied: (1) acute high-dose treatment (1.5 mg/kg/6 days), (2) acute low-dose treatment (0.125 mg/kg/6 days), and (3) chronic low-dose treatment (0.125 mg/kg/21 days). When insulin binding to isolated hepatocytes was studied, we found that binding to isolated hepatocytes was studied, we found that binding was only 30%-50% of control values when cells from the D-treated animals were used. This decrease in binding was greatest for cells from the acute high-dose group, indicating a dose-response effect, and least for cells from the chronic group, suggesting a tendency toward return of insulin-receptor binding during chronic treatment. When insulin binding to isolated adipocytes was studied, binding was 50%-60% of control values when cells from both acute D-treated groups were used. While the magnitude of the decrease in insulin binding was not as great as that seen with hepatocytes, the decrease was still greatest using cells from the acute high-dose group as compared to the acute low-dose group. Thus, a dose-response effect was suggested in both tissues. On the other hand, the effects of chronic D treatment on insulin binding were strikingly different in the two cell systems. After chronic D treatment, insulin binding to adipocytes returned to near-normal levels, while a 55% decrease in binding to hepatocytes persisted. Thus, the tendency toward return of insulin binding after chronic D treatment seen with hepatocytes was almost fully expressed by adipocytes. This might be related to the amelioration of the corticosteroid-induced insulin-resistant state which has been reported after chronic corticosteroid administration to humans. In conclusion, (1) a decrease in insulin binding is associated with corticosteroid excess, and it is possible that this decreased binding is related to the insulin resistance which results from corticosteroid administration; (2) the return of insulin binding toward normal after chronic D treatment could well be related to the improvement in insulin resistance seen during chronic corticosteroid administration to humans; and (3) the difference in effects of chronic D treatment on insulin binding to hepatocytes versus adipocytes indicates that changes in insulin binding can be tissue specific.
Summary Glucose tolerance, plasma FFA and insulin response following an oral glucose load (1 g/kg body weight) were studied in normal
healthy subjects of different age groups. Although there was no obvious loss of glucose tolerance, the peak and 120 min blood
glucose levels, and the glucose area under the glucose curve in the sixth decade were significantly higher than in the other
decades. Fasting plasma FFA levels were also significantly elevated in the sixth decade but the insulin response was normal.
The subtle degree of loss of glucose tolerance observed in the sixth decade could be either due to decreased sensitivity to
insulin produced by elevated plasma FFA or atherosclerotic changes interfering with ready availability of circulating insulin
to the tissues.
In 707 non‐obese female adults with unimpaired glucose tolerance, the fasting blood glucose levels of those in the fourth, fifth and sixth decades of life exceeded the levels found in those of the third decade (20–29 years), but there was no evidence of a progressive increase in successive age decades. The slightly greater fasting glycemia in the later age decades was accompanied by higher increments in blood glucose in the first half hour of the glucose tolerance test. These higher levels of glucose during the fasting state and in the first half hour after oral administration of glucose were not associated with increments in serum insulin greater than those recorded for the third age decade. This age‐related increase in fasting and post‐glucose blood sugar levels without an increase in serum insulin could result from the age‐related increase in the thickness of capillary basement membranes. The higher levels of glucose could then serve to restore glucose transport and cell glucose metabolites to normal without evoking a rise in serum insulin.
In 479 obese women with unimpaired glucose tolerance, there was no evidence of the age‐related increase in fasting blood glucose nor the slightly exaggerated hyperglycemia found early in the test in non‐obese subjects with normal glucose tolerance. The relative fasting hyperinsulinemia and the increased insulin responses to induced hyperglycemia known to characterize obese persons were present in all age decades but the hyperinsulinemia was less marked in subjects older than 30. In these obese subjects with unimpaired glucose tolerance, there was no evidence of any delay in the insulin response to the induced hyperglycemia.
Abstract In 29 healthy young adults and 22 ambulatory elderly subjects, a study was made of the effects of an oral glucose load on the levels of serum immunoreactive insulin (IRI), free fatty acids (FFA), growth hormone (HGH) and blood glucose. In the elderly, the pre-load blood glucose and serum IRI levels were higher than in the younger group, reached the peak more gradually, and took longer to return to the baseline values. There was no significant difference in the serum FFA levels between the two groups until 3 hours after the glucose load, at which time the FFA values had returned to the fasting level in the young subjects but remained depressed in the elderly subjects. Serum HGH fasting levels in the elderly males were significantly higher than in the younger males and remained so at 1-2 hours after the glucose load. For the females, the numbers were too small and the intragroup variability too great to permit drawing conclusions. The total findings lend support to Dilman's hypothesis of a genetically programmed elevation of the hypothalamic threshold to feedback suppression, with age.
. Radioactivity in adipose tissue triglycerides was followed after giving an intravenous injection of 25 g of glucose with 50 μCi of U-14C-glucose to 12 obese and 7 control patients. Seventy-five minutes after injection the radioactivity could be measured with sufficient precision. Recirculation of label was probably small during this period. Total adipose tissue glucose uptake could therefore be estimated knowing the variation of adipose tissue triglyceride radioactivity in different selected regions, and total body fat, and was found to be only a few per cent of all assimilated glucose in the body. Triglyceride radio-activity per gram of adipose tissue was similar in obese subjects and controls. Consequently total adipose tissue label was higher in the obese. Triglyceride radioactivity per fat cell correlated positively with fat cell size which in turn correlated positively with plasma insulin concentration. During the two first weeks after injection adipose tissue triglyceride radioactivity increased after which it began to fall in some patients.
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- D Fedele
- A Valerio
- M Molinari
- Glucose Intolerance And Aging / Ralph A
- Defronzo
- H P Himsworth
- R B Kerr
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Glu-cose kinetics in obesity Age and the kinetics of re-sponse to sugars and insulin Adre-nocortical responsivity in old age Glucose tolerance and insulin sensitivity Growth hormone response to insulin hypoglycemia in the el-derly
- J R M Franckson
- W Malaisse
- E Arnould
- E Rasio
- H A Ooms
- E Balasse
- V Conrad
- P A Bastenie
- N O Galloway
- R Kujak
- B B Hochstaedt
- M Schneebaum
- M Shadel
- F I R Martin
- M J Pearson
- A E Stocks
- W J Kalk
- A I Vinik
- B L Pimstone
- W P U Jackson
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In-sulin sensitivity and insulin binding to monocytes in maturity-onset diabetes Effect of age on glucose utilization and responsiveness to insulin in forearm muscle
- R A Defronzo
- D Diebert
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- P Felig
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- D Leiborici
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DeFronzo, R. A., Diebert, D., Hendler, R., and Felig, P.: In-sulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J. Clin. Invest. 63: 939-46, 1979. 46 Kalant, N., Leiborici, D., Leibovici, T., and Fukushima, N. : Effect of age on glucose utilization and responsiveness to insulin in forearm muscle. J. Am. Gerontol. Soc. 28: 304-307, 1980.
T h e ef-fect of age on the in vitro response to insulin in the rat. 1. Glucose metabolism o n t h e diaphragm Reduced insulin action in vitro and binding of 125 I-insulin to cultured human skin fibro-blasts with aging
- M B M Davidson
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- H Shimoda
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In-sulin a n d epidermal growth factor. Receptors in cultured skin fibro-blasts from young a n d old adult males Insulin binding to cul-tured human fibroblasts increases with normal and precocious aging
- M D Hollenberg
- E Schneider
- J H A Goldstein
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- H P Himsworth
- R B Kerr
- R A Silverstone
- M Brandfonbrener
- N W Shock
- M J Franckson
- J R M Malaisse
- W Arnould
- E Rasio
- E Ooms
- H A Balasse
- E Conrad
- V Bastenie
- P A Galloway
- N O Kujak
- R Hochstaedt
- B B Schneebaum
- M Shadel
37 Himsworth, H. P., and Kerr, R. B.: Age and insulin sensitivity. Clin. Sci. 4: 153-57, 1939-42.
38 Silverstone, R. A., Brandfonbrener, M., Shock, N. W., and
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39 Franckson, J. R. M., Malaisse, W., Arnould, E., Rasio, E.,
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40 Galloway, N. O., and Kujak, R.: Age and the kinetics of response to sugars and insulin. J. Am. Geriatr. Soc. 19: 122-30,
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41 Hochstaedt, B. B., Schneebaum, M., and Shadel, M.: Adrenocortical responsivity in old age. Gerontol. Clin. 3: 239-46,
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42 Martin, F. I. R., Pearson, M. J., and Stocks, A. E.: Glucose
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43 Kalk, W. J., Vinik, A. I., Pimstone, B. L, and Jackson, W.
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