The endocrine role of the skeleton: background and clinical evidence

Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, β-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated.     

Circadian regulation of glucose,lipid, and energy metabolism in humans

The circadian system orchestrates metabolism in daily 24-hour cycles. Such rhythms organize metabolism by temporally separating opposing metabolic processes and by anticipating recurring feeding-fasting cycles to increase metabolic efficiency. Although animal studies demonstrate that the circadian system plays a pervasive role in regulating metabolism, it is unclear how, and to what degree, circadian research in rodents translates into humans. Here, we review evidence that the circadian system regulates glucose, lipid, and energy metabolism in humans. Using a range of experimental protocols, studies in humans report circadian rhythms in glucose, insulin, glucose tolerance, lipid levels, energy expenditure, and appetite. Several of these rhythms peak in the biological morning or around noon, implicating earlier in the daytime is optimal for food intake. Importantly, disruptions in these rhythms impair metabolism and influence the pathogenesis of metabolic diseases. We therefore also review evidence that circadian misalignment induced by mistimed light exposure, sleep, or food intake adversely affects metabolic health in humans. These interconnections among the circadian system, metabolism, and behavior underscore the importance of chronobiology for preventing and treating type 2 diabetes, obesity, and hyperlipidemia.     

Regulation of glucose metabolism and the skeleton

Complex interactions occur among adipose tissue, the central nervous system, bone and pancreas to integrate bone remodelling, glucose, lipid and energy metabolism. Data obtained largely from the judicious use of gain-of-function and loss-of-function genetic mouse models show that leptin, an adipocyte-secreted product, indirectly inhibits bone accrual through a central pathway comprising the hypothalamus and central nervous system. Increased sympathetic output acting via β2-adrenergic receptors present in osteoblasts decreases bone formation and causes increased bone resorption. Insulin is a key molecular link between bone remodelling and energy metabolism. Insulin signalling in the osteoblasts increases bone formation and resorption as well as the release of undercarboxylated osteocalcin. An increase in the release of bone-derived undercarboxylated osteocalcin into the systemic circulation enables it to act as a circulating hormone to stimulate insulin production and secretion by pancreatic β-cells and adiponectin by adipocytes. Insulin sensitivity increases, lipolysis and fat accumulation decreases while energy expenditure increases. Whether this model of integrative physiology involving the skeleton, pancreas and adipose tissue, so elegantly demonstrated in rodents, is applicable to humans is controversial. The mouse Esp gene, encoding an intracellular tyrosine phosphatase that negatively regulates insulin signalling in osteoblasts, is a pseudogene in humans, and a homolog for the Esp gene has so far not been identified in humans. A close homologue of Esp, PTP1B, is expressed in human osteoblasts and could take the role of Esp in humans. Data available from the limited number of clinical studies do not provide a sufficient body of evidence to determine whether osteocalcin or undercarboxylated osteocalcin affects glucose metabolism in humans.     

Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options

Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.     

Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options.

Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.     

Adiponectin: Systemic contributor to insulin sensitivity

Adipocyte-specific secreted molecules, termed adipokines, have dispelled the notion of adipose tissue as an inert storage depot for lipids, and highlighted its role as an active endocrine organ that monitors and alters whole-body metabolism and maintains energy homeostasis. One of these adipokines, adiponectin (also known as Acrp30, AdipoQ, and GBP28), has gained significant attention recently as a mediator of insulin sensitivity. Many clinical reports and genetic studies over the past few years demonstrate decreased circulating levels of this hormone in metabolic dysfunction, such as obesity and insulin resistance, in both humans and animal models. Pharmacologic adiponectin treatments in rodents increase insulin sensitivity, although the primary site and detailed mechanism of action is yet to be determined. The phenotypes of adiponectin-deficient and transgenic adiponectin-overproducing animal models underscore the role of adiponectin in the maintenance of glucose and lipid homeostasis.     

Osteocalcin and glucose metabolism in postmenopausal women subjected to aerobic training program for 8 weeks

Results of animal studies suggest that osteocalcin (OC) plays an important role in the regulation of carbohydrate metabolism. The aim of the present study was to assess the relationship between biochemical indices of bone turnover and carbohydrate metabolism in postmenopausal women subjected to aerobic training for 8 weeks. The study was conducted on 44 postmenopausal women: 27 of them participated in the training program, and 17 did not undertake any additional physical activity during the study period (control group). Subjects performed a cycle-ergometer physical workout at a level of 70% to 80% of ventilatory threshold intensity for 8 weeks (40-minute sessions, 3 times per week). Serum concentrations of OC, C-terminal telopeptide of type I collagen, osteoprotegerin (OPG), insulin, and glucose were measured; and the homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated before and after the 8-week training program. The training program caused significant decrease in levels of OC (P < .05), HOMA-IR (P < .05), and waist-to-hip ratio (P < .05). No significant changes were observed in C-terminal telopeptide of type I collagen, OPG, insulin, and glucose concentrations. Pretraining OC levels inversely correlated with concentrations of OPG (P < .05), glucose (P < .05), and insulin (P < .05) and with HOMA-IR values (P < .05). Our study revealed an association between serum OC concentrations and metabolic markers in postmenopausal women. Regular physical activity was associated with decrease in central adiposity and OC levels and slight reduction of insulin resistance. However, no direct relationships between training-related changes in OC concentrations and metabolic markers were observed.     

Myocardial fatty acid metabolism and cardiac performance in heart failure

It is well established that cardiac metabolism is abnormal in heart failure (HF). Experimental studies suggest that in severe HF, cardiac metabolism reverts to a more fetal-like substrate use characterized by enhanced glucose and downregulated free fatty acid (FFA) metabolism. Correspondingly, in humans, when FFA levels are similar, myocardial glucose metabolism is increased, and FFA metabolism is decreased. However, depression of left ventricular function and insulin resistance induces a shift back to greater FFA uptake and oxidation by increasing circulating FFA availability. Myocardial insulin resistance may further impair myocardial glucose uptake and lead to an energy depletion state. Experimental and preliminary clinical studies suggest that metabolic modulators enhancing myocardial glucose oxidation may improve cardiac function in patients with chronic HF. However, it has been found that acute FFA deprivation is harmful to the cardiac performance. Optimizing myocardial energy metabolism may serve as an additional approach for managing HF, but further studies are warranted.     

Nonischemic heart failure in diabetes mellitus

PURPOSE OF REVIEW: Diabetic patients with heart failure have a poor prognosis. Although it has been demonstrated in animal models that metabolic maladaptation plays a pivotal role in contractile dysfunction of the heart, the understanding of 'diabetic cardiomyopathy' and its treatment in humans remains incomplete. RECENT FINDINGS: Epidemiological studies show that structural changes in the left ventricle can be demonstrated before onset of clinical diabetes. Diastolic dysfunction is the earliest manifestation that is associated with increasing level of serum-free fatty acids and worsening glycemic control. Spectroscopic and histologic evidence in the human myocardium indicates a maladaptive metabolic response in diabetes, characterized by intramyocellular triglyceride accumulation. Studies also suggest a link between myocardial isoform switching, calcium homeostasis and altered metabolism in the development of heart failure. However, treatment directed at deranged metabolic control in diabetes is effective only in animals, and not in humans. SUMMARY: Although clinical studies suggest the existence of 'diabetic cardiomyopathy', it is still difficult to prove causality. However, animal models and human studies suggest that systemic metabolic derangements may lead to metabolic, functional and structural maladaptation of the heart. The exact mechanisms of heart failure in diabetes remain elusive.     

Bone: Another potential target to treat,prevent and predict diabetes

Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone‐derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone‐derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ‐B ligand, neuropeptide Y, and other known and unidentified bone‐derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.     

Review: efficacy of alginate supplementation in relation to appetite regulation and metabolic risk factors: evidence from animal and human studies

This review provides a critical update on human and animal studies investigating the effect of alginate supplementation on appetite regulation, glycaemic and insulinemic responses, and lipid metabolism with discussion of the evidence on potential mechanisms, efficacy and tolerability. Dependent on vehicle applied for alginate supplementation, the majority of animal and human studies suggest that alginate consumption does suppress satiety and to some extent energy intake. Only one long‐term intervention trial found effects on weight loss. In addition, alginates seem to exhibit beneficial influence on postprandial glucose absorption and insulin response in animals and humans. However, alginate supplementation was only found to have cholesterol‐lowering properties in animals. Several mechanisms have been suggested for the positive effect observed, which involve delayed gastric emptying, increased viscosity of digesta and slowed nutrient absorption in the small intestine upon alginate gel formation. Despite reasonable efficacy and tolerability from the acute or short‐term studies, we still realize there is a critical need for development of optimal alginate types and vehicles as well as studies on further long‐term investigation on alginate supplementation in humans before inferring that it could be useful in the management of obesity and the metabolic syndrome.     

Mechanisms of insulin resistance in hypertensive rats

Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. Recent evidence indicates that these impairments in glucose metabolism may play a role not only in the development of type 2 diabetes, but also in the onset and persistence of hypertension, dyslipidemia, and abdominal obesity. The accumulation of these risk factors constitutes a high-risk group of cardiovascular diseases, the so-called metabolic syndrome. Insulin resistance has also been reported in several animal models for hypertension, including the spontaneously hypertensive rat (SHR) and the fructose-fed rat (FFR). SHRs and FFRs have been employed in many studies to investigate the mechanisms and pathophysiology of insulin resistance and hypertension, but the precise mechanism of insulin resistance remains to be clarified. In this review, the possible mechanisms of insulin resistance in SHRs and FFRs are summarized.     

Mitochondrial dysfunction in pancreatic beta-cells in Type 2 diabetes

Mitochondrial metabolism controls insulin secretion from the pancreatic beta-cell. Type 2 Diabetes evolves when the beta-cells fail to release appropriate amounts of insulin, causing metabolic dysregulation and hyperglycemia. It is attractive to assume that mitochondrial dysfunction plays a decisive role in these processes. Indeed, while being a rare condition, genetically determined dysfunction of mitochondria causes a Type 2 Diabetes-like syndrome. Here, we review what is known about mitochondrial dysfunction in the beta-cell in Type 2 Diabetes. The focus is on observations in humans but relevant studies in animal models of the disease are discussed. A particular emphasis is placed on changes in metabolic enzymes and function in beta-cell mitochondria and how altered structure of the organelle appears to facilitate its function. These molecular processes are subject to tight genetic as well as epigenetic control. Variations and implications of these mechanisms are reviewed. The emerging picture is that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in Type 2 Diabetes. Such processes may prove to be targets for therapeutic interventions in the disease.     

The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis.

Homeostatic mechanisms normally maintain the plasma glucose concentration within narrow limits despite major fluctuations in supply and demand. There is increasing evidence that the growth hormone (GH)-insulin-like growth factor (IGF) axis may play an important role in glucose metabolism. GH has potent effects on intermediary metabolism, some of which antagonize the actions of insulin. In contrast, IGF-I has insulin-like actions, which are, in the case of glucose metabolism, opposite to those of GH. There is often deranged glucose metabolism in situations where GH is deficient or in excess. The clinical administration of GH or IGF-I results in altered glucose metabolism and changes in insulin resistance. Despite these observations, the precise role of GH and IGF-I and their interactions with insulin in controlling normal glucose homeostasis are unknown. In diabetes, GH secretion is abnormally increased as a result of reduced portal insulin resulting in impaired hepatic IGF-I generation. Evidence suggests that this may contribute to the development of diabetic microvascular complications. IGF-I 'replacement' in diabetes is under investigation and new methods of delivering IGF-I as a complex with IGFBP-3 offer exciting new prospects.     

Glucose‐dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity‐associated disorders

Glucose‐dependent insulinotropic polypeptide (GIP) is a hormone secreted from the intestinal K‐cells with established insulin‐releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the adipose tissue, gut, bone and brain, where GIP modulates energy intake, cell metabolism and proliferation, and lipid and glucose metabolism, eventually promoting lipid and glucose storage. In diabetes and obesity, the incretin effect of GIP is blunted, while the extrapancreatic tissues keep a normal sensitivity to this hormone. As GIP levels are normal or elevated in obesity and diabetes, mounting evidence from chemical or genetic GIP deletion in animal models of obesity‐related diabetes suggests that GIP may have a pro‐obesogenic action and that a strategy antagonizing GIP action may be beneficial in these conditions, clearing triglyceride deposits from adipose tissue, liver and muscle, and restoring normal insulin sensitivity. Emerging evidence also suggests that the metabolic benefits of bypass surgery are mediated, at least in part, by surgical removal of GIP‐secreting K‐cells in the upper small intestine.     

Mechanisms of Insulin Resistance in Hypertensive Rats

Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. Recent evidence indicates that these impairments in glucose metabolism may play a role not only in the development of type 2 diabetes, but also in the onset and persistence of hypertension, dyslipidemia, and abdominal obesity. The accumulation of these risk factors constitutes a high-risk group of cardiovascular diseases, the so-called metabolic syndrome. Insulin resistance has also been reported in several animal models for hypertension, including the spontaneously hypertensive rat (SHR) and the fructose-fed rat (FFR). SHRs and FFRs have been employed in many studies to investigate the mechanisms and pathophysiology of insulin resistance and hypertension, but the precise mechanism of insulin resistance remains to be clarified. In this review, the possible mechanisms of insulin resistance in SHRs and FFRs are summarized.     

Adiponectin and bone metabolism markers in female rowers: eumenorrheic and oral contraceptive users

This study investigated whether adiponectin, bone formation (osteocalcin) and bone resorption [type I carboxyterminal telopeptide (ICTP)] values are influenced by menstrual cycle phase and oral contraceptive use in female rowers. Twenty-four rowers divided into normally cycling athletes (NOC; no.=15) and athletes taking oral contraceptive pills (OC; no.=9) participated in this study. Fasting blood samples, body composition and aerobic capacity measurements were taken during the follicular (FP) and the luteal (LP) phases of the menstrual cycle. Adiponectin, insulin, glucose, insulin resistance, body composition and aerobic capacity did not fluctuate significantly during menstrual cycle in both groups. Osteocalcin and ICTP were lower (p<0.05) in OC compared with NOC, but did not change significantly across menstrual cycle phases in both groups. Estradiol and progesterone were not related to adiponectin, osteocalcin or ICTP (r<0.147; p>0.05). Adiponectin was correlated (p<0.05) with osteocalcin (r=0.452) and fat free mass (r=0.428), and osteocalcin was related (p<0.05) to insulin (r=-0.413), glucose (r=-0.486) and insulin resistance (r=-0.528). In conclusion, adiponectin was not affected by menstrual cycle phase and OC use in female rowers, while bone metabolism markers were lower in OC compared to NOC groups. Adiponectin and osteocalcin were interrelated and may characterise energy homeostasis in female athletes.     

The mitochondrial citrate carrier (CIC) is present and regulates insulin secretion by human male gamete

The mechanisms through which sperm manage their energy metabolism are poorly understood. The present study provides biochemical and morphological evidence that mitochondrial citrate carrier (CIC) is present in ejaculated human sperm and is restricted to the midpiece. The inhibition of CIC with the specific substrate analog 1,2,3-benzenetricarboxylate resulted in the reduction of cholesterol efflux, protein tyrosine phosphorylation, phospho-AKT, phospho-p60src, hyperactivated motility and acrosome reaction, suggesting a role for this mitochondrial carrier in sperm physiology. Furthermore, inhibition of CIC by 1,2,3-benzenetricarboxylate resulted in a reduction of glucose-stimulated insulin secretion and autocrine insulin secretion by sperm. Remarkably, blocking CIC also reduced glucose-6-phosphate dehydrogenase activity, probably in accordance with its regulation on insulin secretion. Capacitation and glucose metabolism were stimulated by glucose as well as citrate, the specific substrate of CIC, implying a similar action because glucose and citrate both induced insulin secretion by sperm. In the present finding, we discovered a new site of action for CIC in the regulation of metabolism, and it may be assumed that CIC works with other factors in the regulation of sperm energy metabolism to sustain capacitation process and acrosome reaction.     

Carbohydrate metabolism and the skeleton: picking a bone with the beta-cell

Novel data show that the bone protein, undercarboxylated osteocalcin, increases islet cell growth and insulin and adiponectin synthesis and enhances glucose metabolism in mice. Human studies, in which undercarboxylated osteocalcin concentrations have been perturbed, show no effect (or a very minor effect) on fasting glucose or insulin concentrations. More extensive and detailed experiments in humans are needed to definitively establish the role of undercarboxylated osteocalcin in human carbohydrate metabolism.