Insulin Sensitivity In Obese Individuals Research Articles

Will melatonin supplementation become a new form of obesity treatment? A review of recent literature.

Background: In 2020, the World Health Organization (WHO) estimated that 650 million adults worldwide are obese, and 2.8 billion individuals struggle with overweight. Obesity is associated with an increased risk of cardiovascular diseases, type 2 diabetes, heart disease, adverse effects on mental health, the development of certain cancers, and other conditions. In recent years, there has been growing interest in the role of melatonin, which has therapeutic potential in the treatment of obesity. Studies suggest that melatonin supplementation may lead to weight reduction and improvement in metabolic parameters, significantly reduce cardiovascular disease risk factors, and enhance insulin sensitivity in obese individuals. Aim of study: This review aims to present the latest scientific findings on the impact of melatonin supplementation on the development of obesity and its complications. We focus primarily on the mechanisms of melatonin's action in the context of obesity, particularly on potential pathways that have not yet been thoroughly explored. Our aim is to provide deeper insights into research on obesity and its prevention. Materials and Methods: Search was conducted using PubMed and Google Scholar databases, utilizing the keywords "obesity," "melatonin," and "weight loss" in various configurations. The review primarily considers studies published after 2016 that are available online. Summary Melatonin supplementation leads to a statistically significant reduction in blood glucose levels and an increase in cellular insulin sensitivity. Its promising properties in the treatment of obesity have been demonstrated through the reduction of oxidative stress, indicating a potential adjunct for weight loss. Based on the cited studies, the beneficial effects of melatonin supplementation on cardiovascular risk factors have been confirmed. Melatonin could be considered as an adjunctive therapy for obese individuals who do not respond to other treatment modalities.

Impact of physical exercise on metabolic dysfunction-associated fatty liver disease (MAFLD)

Obesity is a chronic multifactorial disease characterized by excess adiposity. Adipose tissue hypertrophy favors lipid deposition in ectopic tissues, such as the liver, which favors the development of the metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by excessive accumulation of lipids in the cytoplasm of hepatocytes (fatty liver). Triglyceride overload in hepatocytes observed in obesity is associated with inflammation and insulin resistance status. Non-pharmacological strategies, such as the practice of physical exercise, seem to be an effective in reducing inflammatory markers and improving insulin sensitivity in obese individuals with MAFLD attenuating hepatocellular steatosis. Thus, this review aims to demonstrate the factors involved in the development of hepatic steatosis, as well as investigate the impact of physical exercise on insulin sensitivity and inflammatory markers in the condition of obesity-associated MAFLD.

Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties.

Neurological diseases such as stroke and multiple sclerosis are associated with high morbidity and mortality, long-term disability, and social and economic burden. Therefore, they represent a major challenge for medical treatment. Numerous evidences support the beneficial effects of polyphenols from olive trees, which can alleviate or even prevent demyelination, neurodegeneration, cerebrovascular diseases, and stroke. Polyphenols from olive oils, especially extra virgin olive oil, olive leaves, olive leaf extract, and from other olive tree derivatives, alleviate inflammation and oxidative stress, two major factors in demyelination. In addition, they reduce the risk of stroke due to their multiple anti-stroke effects, such as anti-atherosclerotic, antihypertensive, antioxidant, anti-inflammatory, hypocholesterolemic, hypoglycemic, and anti-thrombotic effects. In addition, olive polyphenols have beneficial effects on the plasma lipid profiles and insulin sensitivity in obese individuals. This review provides an updated version of the beneficial properties and mechanisms of action of olive polyphenols against demyelination in the prevention/mitigation of multiple sclerosis, the most common non-traumatic neurological cause of impairment in younger adults, and against cerebral insult with increasing incidence, that has already reached epidemic proportions.

Role of Hypovitaminosis D in the Pathogenesis of Obesity-Induced Insulin Resistance.

Obesity and type 2 diabetes have both rapidly increased during the last decades and are continuing to increase at an alarming rate worldwide. Obesity and impaired glucose homeostasis are closely related, and during the last decades of investigation about vitamin D, several clinical and epidemiological studies documented an inverse correlation between circulating vitamin D levels, central adiposity and the development of insulin resistance and diabetes. The insufficient sun exposure and outdoor activities of obese individuals, the storage of vitamin D in adipose tissue, because of its lipophilic properties, and the vitamin D-mediated modulation of adipogenesis, insulin secretion, insulin sensitivity and the immune system, are the main reasons for the close relationship between obesity, glucose homeostasis and hypovitaminosis D. Then objective of this review is to explore the pathophysiological mechanism(s) by which vitamin D modulates glycemic control and insulin sensitivity in obese individuals.

Adipose tissue macrophages: going off track during obesity.

Inflammation originating from the adipose tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a plethora of different immune cells shapes adipose tissue inflammation, this review is specifically focused on the contribution of macrophages that reside in adipose tissue in lean and obese conditions. Both conventional and tissue-specific functions of adipose tissue macrophages (ATMs) in lean and obese adipose tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and adipose tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect adipose tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals. Highlights • Macrophages play a significant role in regulating adipose tissue functioning during health and disease• In addition to conventional functions such as clearing cellular debris and participating in tissue immune surveillance, lipid buffering is an important function of ATMs• Obesity-induced inflammation, characterised by an elevated number of proinflammatory macrophages in adipose tissue, has been suggested to contribute to systemic insulin resistance• Their origin, as well as a combination of peripheral changes and adipose tissue-derived stressors, probably contribute to ATM dysfunction and inflammatory traits during obesity• Identification of transcriptional differences between ATMs from lean vs obese adipose tissue at several key points during the development of obesity and insulin resistance may reveal upstream triggers, regulatory factors and intracellular pathways that shape ATM function• Targeting metabolic capacity rather than the inflammatory phenotype of ATMs may hold potential to restore ATM function and adipose tissue homeostasis in obese individuals

Skeletal muscle salt inducible kinase 1 promotes insulin resistance in obesity.

ObjectiveInsulin resistance causes type 2 diabetes mellitus and hyperglycemia due to excessive hepatic glucose production and inadequate peripheral glucose uptake. Our objectives were to test the hypothesis that the proposed CREB/CRTC2 inhibitor salt inducible kinase 1 (SIK1) contributes to whole body glucose homeostasis in vivo by regulating hepatic transcription of gluconeogenic genes and also to identify novel SIK1 actions on glucose metabolism.MethodsWe created conditional (floxed) SIK1-knockout mice and studied glucose metabolism in animals with global, liver, adipose or skeletal muscle Sik1 deletion. We examined cAMP-dependent regulation of SIK1 and the consequences of SIK1 depletion on primary mouse hepatocytes. We probed metabolic phenotypes in tissue-specific SIK1 knockout mice fed high fat diet through hyperinsulinemic-euglycemic clamps and biochemical analysis of insulin signaling.ResultsSIK1 knockout mice are viable and largely normoglycemic on chow diet. On high fat diet, global SIK1 knockout animals are strikingly protected from glucose intolerance, with both increased plasma insulin and enhanced peripheral insulin sensitivity. Surprisingly, liver SIK1 is not required for regulation of CRTC2 and gluconeogenesis, despite contributions of SIK1 to hepatocyte CRTC2 and gluconeogenesis regulation ex vivo. Sik1 mRNA accumulates in skeletal muscle of obese high fat diet-fed mice, and knockout of SIK1 in skeletal muscle, but not liver or adipose tissue, improves insulin sensitivity and muscle glucose uptake on high fat diet.ConclusionsSIK1 is dispensable for glycemic control on chow diet. SIK1 promotes insulin resistance on high fat diet by a cell-autonomous mechanism in skeletal muscle. Our study establishes SIK1 as a promising therapeutic target to improve skeletal muscle insulin sensitivity in obese individuals without deleterious effects on hepatic glucose production.

Hypothalamic inflammation in the control of metabolic function.

Diet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues. We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.

Higher circulating leukocytes in women with PCOS is reversed by aerobic exercise

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, elevated circulating leukocytes, and hypothesized to have higher adipose tissue inflammation. Aerobic exercise reduces circulating leukocytes and improves insulin sensitivity in obese individuals, but the effect of exercise on inflammation in PCOS is not known. We investigated circulating leukocytes, insulin sensitivity by euglycemic-hyperinsulinemic clamp, serum pro- and anti-inflammatory markers (hsCRP, TNF-α, total and high molecular weight adiponectin), and abdominal subcutaneous adipose tissue (SAT) gene expression of proinflammatory markers in 8 PCOS women and 8 obese control females matched for BMI. Additionally, in a prospective study, the 8 women with PCOS underwent a 16-week aerobic exercise regimen with the same measures performed post-intervention. Compared to controls, white blood cell counts (WBC) were 30% higher (p=0.04) and circulating total adiponectin levels were 150% lower (p=0.03) in women with PCOS at baseline/pre-exercise conditions. SAT gene expression of macrophage migration inhibitory factor (MIF, p<0.01) and interleukin-6 (IL-6, p<0.05) were also lower in women with PCOS. In response to 16 weeks of aerobic exercise, insulin sensitivity improved (p<0.01) and WBC counts decreased (p=0.02). The exercise-induced change in WBC and circulating neutrophils correlated inversely with changes in glucose disposal rate (r=-0.73, p=0.03; and r=-0.82, p=0.01, respectively). Aerobic exercise reduced serum leptin (p<0.05) after 4 weeks, trended to reduce the ratio of leptin-to-high molecular weight adiponectin (p<0.1) by the 8th week, and significantly increased serum dehydroepiandrosterone sulfate (DHEA-S, p<0.001) after 16 weeks. In conclusion, women with PCOS have higher circulating leukocytes compared to controls, which can be reversed by aerobic exercise and is associated with improvements in insulin sensitivity.

Independent positive association of plasma β-carotene concentrations with adiponectin among non-diabetic obese subjects.

Many epidemiological studies find an inverse correlation between carotenoids intake or carotenoids plasma concentrations and body mass index (BMI), insulin resistance or metabolic syndrome in the general population. However, it is not clear whether these relationships occur in obese population. We conducted a cross-sectional study in 108 obese non-diabetic patients. There was an inverse correlation between plasma levels of pro-vitamin A carotenoids (α-carotene, β-carotene and β-cryptoxanthin) and both BMI and insulin resistance (estimated by the HOMA-IR). No correlation between plasma concentrations of lycopene or lutein/zeaxanthin and BMI or insulin resistance was found. The inverse association between the three pro-vitamin A carotenoids and HOMA-IR disappeared after adjustment for BMI and waist circumference. Interestingly, we identified a positive association between concentrations of β-carotene and adiponectin in plasma that was independent of sex, age, smoking status, BMI and waist circumference. To our knowledge, such association has never been described in obese patients. These results suggest the existence of a favourable effect of β-carotene on insulin sensitivity in obese individuals that could involve a positive regulation of adiponectin, either directly or via its pro-vitamin A activity. The demonstration of the potential benefits of β-carotene towards insulin sensitivity would open the way to dietary strategies to prevent metabolic syndrome.

Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity

The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.

B cell activating factor in obesity is regulated by oxidative stress in adipocytes

Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, and plays a key role in the integration of systemic metabolism. We have previously shown that B cell activating factor is produced mainly in visceral adipose tissue and affects insulin sensitivity in obese individuals. In this study, we identified the signals that lead to production of B cell activating factor in adipocytes. 3T3-L1 and C3H/10T 1/2-clone 8 cells showed increased B cell activating factor expression upon exposure to hydrogen peroxide, and these changes were inhibited by treatment with the antioxidant N-acetyl-cysteine. B cell activating factor levels in both serum and visceral adipose tissue were increased in high fat diet-fed mice, and these increases were correlated with oxidative stress. In addition, serum BAFF levels in high fat diet-fed mice were reduced by N-acetyl-cysteine treatment. We also found that oxidative stress-induced B cell activating factor expression in adipocytes was regulated by NF-κB activation. These data indicate that control of the redox state in visceral adipose tissue is a potentially useful target for treating metabolic syndromes through regulation of adipokine production.

The effect of acute exercise on undercarboxylated osteocalcin in obese men

The purpose of this study was to examine if the reduction in glucose post-exercise is mediated by undercarboxylated osteocalcin (unOC). Obese men were randomly assigned to do aerobic or power exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC. Osteocalcin (OC) in its undercarboxylated (unOC) form may contribute to the regulation of glucose homeostasis. As exercise reduces serum glucose and improves insulin sensitivity in obese individuals and individuals with type 2 diabetes (T2DM), we hypothesised that this benefit was partly mediated by unOC. Twenty-eight middle-aged (52.4 ± 1.2 years, mean ± SEM), obese (BMI = 32.1 ± 0.9 kg m(-2)) men were randomly assigned to do either 45 min of aerobic (cycling at 75% of VO(2peak)) or power (leg press at 75% of one repetition maximum plus jumping sequence) exercises. Blood samples were taken at baseline and up to 2 h post-exercise. At baseline, unOC was negatively correlated with glucose levels (r = -0.53, p = 0.003) and glycosylated haemoglobin (HbA1c) (r = -0.37, p = 0.035). Both aerobic and power exercises reduced serum glucose (from 7.4 ± 1.2 to 5.1 ± 0.5 mmol L(-1), p = 0.01 and 8.5 ± 1.2 to 6.0 ± 0.6 mmol L(-1), p = 0.01, respectively). Aerobic exercise significantly increased OC, unOC and high-molecular-weight adiponectin, while power exercise had a limited effect on OC and unOC. Overall, those with higher baseline glucose and HbA1c had greater reductions in glucose levels after exercise (r = -0.46, p = 0.013 and r = -0.43, p = 0.019, respectively). In a sub-group of obese people with T2DM, the percentage change in unOC levels was correlated with the percentage change in glucose levels post-exercise (r = -0.51, p = 0.038). This study reports that the reduction in serum glucose post-acute exercise (especially aerobic exercise) may be partly related to increased unOC.

Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals

Circulating soluble transferrin receptor (sTfR) has been recently found to be associated negatively with insulin sensitivity. To evaluate circulating sTfR concentration after changing insulin sensitivity in obese individuals. Circulating sTfR concentration was evaluated after diet-induced weight loss in obese women (diet (D) group, n=8); after diet-induced weight loss plus resistance training (D+RT group, n=11); and after follow-up without weight loss (control (C) group, n=7). After 16 weeks, insulin sensitivity (HOMA (Homeostasis Model Assessment) value) significantly improved in parallel to weight loss (-7.3%) and reduced total fat mass (evaluated using magnetic resonance imaging) in the D group. Thigh muscle mass decreased significantly (P=0.03). Serum sTfR concentration did not change significantly. In the D+RT group, weight loss (-8.7%) and improvement of insulin sensitivity were of similar magnitude. Thigh muscle mass was preserved (P=0.8). Serum sTfR concentration decreased significantly (P=0.001). Interestingly, higher the thigh muscle volume after weight loss, higher the decrease in circulating sTfR concentration. We also found that higher the increases in leg force at week 16, higher the decrease in circulating sTfR concentration in all individuals as a whole. No significant changes were observed in insulin sensitivity, sTfR concentration or thigh muscle mass in the C group. These findings suggest a long-term regulation of serum sTfR concentration by exercise-induced improvement of insulin sensitivity in obese individuals.

Adipose Tissue Macrophages, Low Grade Inflammation and Insulin Resistance in Human Obesity

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.

Improvements in glucose tolerance in obese males with abnormal glucose tolerance following 10 days of aerobic exercise

Background. Aerobic exercise training has been shown to produce beneficial changes in glucose tolerance and insulin sensitivity in obese individuals if performed at high enough intensities and/or durations. We examined the effects of a moderate intensity, short-term exercise training protocol on glucose tolerance in obese males with glucose intolerance. Methods. Fourteen abdominally obese, sedentary males with normal glucose tolerance (NGT; n = 7) and abnormal glucose tolerance (AGT; n = 7) completed 40 min of exercise bouts for 10 consecutive days at approximately 75% of age-predicted maximum heart rate. Fasting glucose and insulin levels, and glucose tolerance and insulin response to glucose were measured before and after the training period. Results. Participants did not experience significant mass loss during the 10-day investigation. Individuals in the AGT group experienced significant ( P < 0.05) improvement in glucose tolerance [glucose area: 1,763.67 (255.98) mmol L −1 × 120 min −1 vs. 1,682.98 (266.91) mmol L −1 × 120 min −1] and fasting insulin levels [44.57 (7.58) μU mL −1 vs. 36.14 (3.97) μU mL −1] as a result of training. Significant ( P < 0.05) reductions in fasting glucose concentrations [5.82 (0.19) mmol L −1 vs. 5.42 (0.18) mmol L −1] and a decrease in fasting insulin concentrations [44.71 (9.39) μU mL −1 vs. 35.0 (7.15) μU mL −1; P = 0.064] were observed in the NGT group following the training period. Conclusions. The data suggest that moderate, short-term exercise without concomitant mass loss is effective in improving glucose tolerance and insulin response to a glucose load in obese males with abnormal glucose tolerance.

Effects of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity in obese individuals

To evaluate the effect of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity we studied 12 obese subjects (body mass index 33.4 +/- 1.1) before and after 6 wk of a very-low-calorie diet (VLCD) with euglycemic insulin clamp in combination with indirect calorimetry. Body weight decreased from 105.3 +/- 4.6 to 94.1 +/- 4.0 kg (P less than 0.001) and fat mass from 47.2 +/- 3.6 to 37.7 +/- 3.0 kg (P less than 0.001). Total glucose disposal during insulin clamp increased from 30.4 +/- 4.3 to 38.4 +/- 4.4 mumol.kg lean body mass (LBM)-1.min-1 (P less than 0.05), insulin-stimulated glucose oxidation from 14.3 +/- 4.6 to 19.1 +/- 1.4 mumol.kg LBM-1.min-1 (P less than 0.05), and non-oxidative glucose metabolism from 16.0 +/- 3.8 to 19.3 +/- 3.6 mumol.kg LBM-1.min-1 (NS). Lipid oxidation decreased in the basal state (P less than 0.05) and during the insulin clamp (P less than 0.01). The basal rate of energy expenditure decreased from 99.1 +/- 4.6 to 88.5 +/- 2.7 kJ.kg LBM-1.min-1 (P less than 0.05) after weight reduction. A reduction in fat mass achieved by VLCD is associated with reduced lipid oxidation and, because of substrate competition, enhanced glucose oxidation. The physiological consequence is improved insulin sensitivity.