The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

The worldwide prevalence of obesity has increased more than 2-fold since 1980. In 2014, WHO global estimates suggested that more than 1.9 billion adults, 18 years and older, were overweight. Of these, over 600 million are obese. In humans, obesity is defined as having excess body fat and a body mass index of >30. The increased incidence of obesity in many modernized countries has caused comorbidities such as type 2 diabetes mellitus (T2DM) to have negative impacts on public heath globally [1,2,3]. Known factors for the transition between normality and obesity-associated T2DM include: (1) visceral obesity; (2) hyperleptinemia; (4) hyperinsulinemia; (5) insulin resistance; (6) impaired glucose tolerance; and (7) impaired fasting glucose. Of these diabetogenic factors, the common link between obesity and the development T2DM is insulin resistance. In a prospective study of 208 healthy and nonobese individuals, Facchini et al. [4] identified insulin resistance as a strong predictor of not only T2DM, but also other diseases such as hypertension, cancer, coronary heart disease, and stroke.

T2DM is diagnosed when fasting glycemia is >7 mmol/L. Recent evidence has put forward a 2-stage development of type 2 diabetes [5]. During the first stage, impaired glucose tolerance is developed with insulin resistance as the primary feature. In the second stage, impaired glucose tolerance progresses to type 2 diabetes in association with a progressive deterioration in both insulin sensitivity in tissues and insulin secretion by pancreatic β-cells [5].

Insulin resistance is a hallmark characteristic of obesity-associated T2DM. It is a “classic” physiological phenomenon where tissues such as the liver, skeletal muscle, and adipose tissue have a reduced responsiveness to insulin. However, over the last decade, the brain has been identified as an insulin-responsive organ, and the role of insulin signaling in brain for glucose metabolism has become recognized. In contrast to the prevailing view that assigns a dominant role to insulin resistance in the periphery, in this review we summarize the current findings surrounding the action of insulin in the brain and peripheral organs such as the skeletal muscles, liver, and adipose tissue. Additionally, we discuss how the exposure to obesogenic environment (hyperinsulinemia and hyperleptinemia) leads to insulin resistance in individual tissues (with focus on the brain) and ultimately the perturbation of systemic glucose homeostasis. Here, we integrated the central and peripheral roles of insulin signaling to provide insights for developing new approaches to combat both central and peripheral insulin resistance in obesity.

Insulin receptor (IR) can regulate its activity through a negative feedback loop that is associated with a decrease in receptor affinity to insulin, and a reduction in IR translocation to the target cell surface. These events in turn negatively regulate the activation of IR and its downstream activators. In this section, we focus on the impact of insulin on its own sensitivity with emphasis on homologous desensitization, i.e. the dampening effects produced by continuous exposure of the target cells to stimulatory levels of insulin. IR has 2 heterogeneous binding sites for insulin, where the first insulin molecule binds at high affinity and the second insulin binds at a lower affinity [6]. The affinity to insulin decreases with increased occupancy of the receptor sites when insulin levels are elevated. The phenomenon is referred to as “negative cooperativity” [7].

IR structure has been well described [8,9]. Constant exposure to insulin has been shown to reduce the ratio of higher affinity (short) to lower affinity (long) IR isoforms [10]. Additionally, high concentration of insulin exposure drives internalization and degradation of insulin-occupied receptors, resulting in a reduction of IR expressed on the cell surface [11]. Upon the activation of the IR, the intrinsic tyrosine kinases undergo autophosphorylation, leading to the recruitment and phosphorylation of the IR substrate (IRS) protein-1, 2, and 3 [12,13]. The phosphorylation of IRS proteins on serine residues has a heterogeneous role, which either enhances or inhibits insulin actions. On one hand, the activation of protein kinase B in response to IR stimulation drives the phosphorylation of IRS proteins on serine residues creating a positive-feedback loop for insulin action. In contrast, insulin also activates the downstream phosphoinositide 3-kinase (PI3K) signaling cascade leading to activation of Akt and other downstream transmitters such as IκB kinase, ERK, JNK, protein kinase C (PKC), and mTOR, which negatively phosphorylate IRS proteins on specific sites and inhibit the activity (negative-feedback loop) [14,15,16,17,18,19]. Ultimately, these intracellular signaling events will lead to the translocation of GLUT4 in the plasma membrane [20,21], allowing glucose uptake into insulin-responsive cells. IR activation also stimulates glycogen synthesis through the inhibition of glycogen synthase kinase 3 [22,23]. Thus, there is a fine balance between the positive phosphorylation of IRS tyrosine/serine residues and the negative phosphorylation of IRS serine residues in the regulation of IRS function. Notably, continuous exposure to insulin diminishes the receptor tyrosine kinases activity. This event not only reduces the capabilities of IRS proteins to activate downstream elements, but also negatively regulates upstream mediators, resulting in the inhibition of IR [24,25,26,27,28].

In essence, chronic high plasma levels of insulin may lead to the desensitization of IR and dysregulation of insulin signaling in IR-expressing tissues, ultimately causing insulin resistance. Of note, IR are expressed in most tissues of the body, including classic insulin-sensitive tissues (pancreas, liver, muscle, fat), as well as “insulin-insensitive” tissue, such as the brain, macrophages, and vascular endothelial cells [29].

Historically, the discovery of leptin and its actions in the central nervous system (CNS) has identified the brain as an essential regulator of body adiposity [30,31]. The “classic” view of plasma glucose regulation is commonly attributed to the changes in insulin-mediated glucose fluxes in peripheral tissues such as the liver, skeletal muscle, and adipose tissue; the brain is only involved under circumstances where plasma blood glucose levels are critically low. However, emerging evidence has showed that the 2 systems work in concert to maintain normal glycemia. Whether the lack of insulin responses at the level of CNS or the dysregulation of neuronal circuits during obesity contributes to the poor glucose homeostasis remains a key question to investigate.

Although the brain is the major site of glucose utilization, it is not classically considered as an insulin-sensitive organ, as it was thought that the transport of glucose from the blood into the brain is an insulin-independent process [32,33]. Interestingly, García-Cáceres et al. [34] have recently revisited this concept and showed that intact insulin signaling in astrocytes is required for brain glucose uptake and insulin transport across the blood-brain barrier (BBB). In fact, both astrocytic IR (GFAP-IR) and hypothalamus-specific astrocytic IR (Hyp-GFAP-IR) knockout mice showed a decrease in glucose availability in the CNS, which consequently impaired systemic glucose homeostasis [34]. Noteworthy, this study has provided compelling evidence to prove that glucose transport across the brain is at least in part dependent on astrocytic insulin signaling and nutrient availability. IR is expressed in many brain regions, including the medial and lateral portions of the arcuate nucleus of the hypothalamus (ARH), the olfactory tract, the cerebellum, and others [35,36,37,38]. Questions surrounding the presence of IR in the brain are how much circulating insulin reaches the brain and the mechanism associated with insulin transport. The presence of insulin in the cerebrospinal fluid (CSF) suggests that insulin can cross the BBB and exert its action in brain regions, which are insulin-responsive [39]. Indeed, studies have demonstrated that 25% of circulating insulin is detected in the CSF, and the level increases proportionally with peripheral insulin infusion or postprandially. Additionally, a portion of plasma insulin crosses the BBB through a saturable IR-mediated transport process [40,41]. Further support came from a recent study [34], in which it was elegantly demonstrated that the increase in CSF insulin levels was completely blunted in GFAP-IR knockout mice following a glucose challenge. This indicates that insulin uptake into the brain is mediated by IR-expressing astrocytes.

The recurring question of whether insulin synthesis occurs in the brain remains controversial. Neurons in lower organisms such as Caenorhabditis elegans and Drosophila have been shown to be the primary production site for insulin-like peptides [33]. An older study by Havrankova et al. [42] detected a high concentration of insulin in whole rat brains relative to plasma. In contrast, others have showed evidence of insulin synthesis and secretion by cultured mammalian neuronal cells [43], and the transcription of INS2 gene instead of INS1 gene in the CNS of rodents [44,45]. Importantly, the INS2 gene in rodents is equivalent to the human INS gene, and it is detected in several regions of the human brain [44]. Nevertheless, no evidence has definitively demonstrated the physiological relevance of insulin synthesis in the brain in rodents or humans. However, it is possible that insulin production in the brain plays a crucial role in specific brain regions.

The positive correlation between adiposity and basal plasma insulin level helped to put forward a hypothesis that insulin in the brain regulates energy homeostasis [46,47]. Consistent with this notion, neuron-specific IR knockout (NIRKO) mice exhibit mild obesity, insulin resistance, hypertriglyceridemia, reproductive dysfunction, and neuronal growth deficiency [48]. This was achieved by expressing the cre recombinase under the promoter for nestin, a neural stem cell marker. From this seminal study, it was evident that insulin in the brain plays an important role in the regulation of energy and glucose homeostasis. Even mild impairments of insulin release may have central effects on metabolic homeostasis. For example, the reduction in insulin release upon the loss of β-cell dysfunction may result in decreased insulin action in brain regions that are associated with controlling energy balance and insulin sensitivity.

The transport of metabolic hormones from the periphery to the brain may modulate their action at the level of the CNS. Several decades ago, King and colleagues [49,50] demonstrated that insulin is transported across the blood vessels. Essentially, they showed that insulin is internalized in endothelial cells and rapidly released without being degraded with the use of iodine-125-labeled insulin. This process was blocked by insulin-receptor antibody, suggesting that insulin transport across endothelial cells is receptor-mediated. However, the study was performed on bovine aortic endothelial cells, and it is not known whether similar mechanisms exist in the endothelial cells of the BBB. Later, Banks et al. [51] provided evidence of insulin transport from the blood to the brain by peripherally infusing mice with increasing doses of human insulin. The increasing concentration of human insulin detected in the brain and circulation of the mice suggested that a saturable transport system exists to transport insulin from the periphery to the brain. However, the precise mechanism remains unknown. It has been suggested that insulin transport occurs via transcytosis across the endothelial cells of the BBB [39]. Furthermore, IR is expressed on capillary endothelial cells in the brain [52,53]. Therefore, we cannot exclude other mechanisms such as transport across tanycytes that are known to take up leptin from the blood to the hypothalamus [54]. Given the fact that tanycytes express nestin [55,56], the metabolic syndrome phenotype observed in NIRKO mice could be a result of IR deletion in tanycytes. Recently, García-Cáceres et al. [34] revealed the importance of insulin signaling in astrocytes in transporting glucose and insulin across the BBB. This concept is relevant in the context of hypothalamic insulin resistance because the perturbation in tanycytic or astrocytic insulin signaling could potentially decrease glucose and insulin availability in the brain, which may explain the alterations in systemic glucose homeostasis in T2DM individuals. Moreover, it was recently demonstrated that astrocytic IR deficiency decreases nutrient availability in the CNS, impairing systemic glucose homeostasis through the reduction in glucose-induced activation of glucose-sensing neurons [34]. Several studies have proposed that insulin transport into the brain is impaired in obesity and diabetes [51,57,58]. However, the lower rate of radiolabeled insulin transport observed in obese mice could be a result of hyperinsulinemia in these animals. Given that a high level of endogenous insulin can interfere with the uptake of exogenous insulin in the brain, the use of labeled insulin will be required in future studies.

IR was first detected and quantified in the CNS using radiolabeled 125I-insulin binding assay in 1978 [36]. Accordingly, membrane preparations from the monkey and pig hypothalami showed higher 125I-insulin-binding activity in the anterior rather than the posterior parts of the hypothalamus [59]. High 125I-insulin-binding activity was also detected all olfactory areas, limbic regions, neocortex and accessory motor areas of the basal ganglia, hippocampus, cerebellum, and choroid plexus, which suggested a regulatory role of insulin in the brain [60]. The notion was further supported by autoradiography and computerized densitometry, revealing that the highest concentrations of IR were in the brain regions which control olfaction, appetite, and autonomic functions [61]. In situ hybridization performed on rat brains also showed that IR mRNA was most abundant in the granule cell layers of the olfactory bulb, cerebellum, dentate gyrus, in the pyramidal cell body layers of the piriform cortex, hippocampus, in the choroid plexus, and in the ARH [38]. Importantly, these studies have consistently demonstrated similar expression profiles of IR in the CNS.

Recently, the insulin action in the limbic system has also been shown to regulate food preference through IR signaling in the ventral striatum [62]. Notably, the role of central insulin action is highlighted by the NIRKO mice; these mice recapitulated similar phenotypes such as insulin resistance, hyperinsulinemia, and hypertriglyceridemia observed in mice fed a high-fat diet [48]. Interestingly, the selective decrease in IR expression (antisense oligodeoxynucleotide directed against IR) in the hypothalamus resulted in an increase in food intake and body weight, and the development of insulin resistance [63]. In the ARH, there are 2 distinct populations of well-studied neurons, namely the pro-opiomelanocortin (POMC) neurons and the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons (Fig. 1). Importantly, these 2 populations of neurons have opposing effects on food intake and body weight; the activation of POMC neurons results in reduced food intake and weight loss, whereas the activation of NPY/AgRP neurons results in increased food intake and weight gain. Direct delivery of insulin into the brain increases the expression of anorexigenic peptides α-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and decreases the expression of the orexigenic peptides NPY and AgRP [64,65,66]. Accordingly, central and intranasal delivery of insulin resulted in reduced food intake in rats, baboons, and humans [67,68,69]. The anorexigenic effect of central insulin occurs via PI3K/Akt signaling, demonstrated by the loss of insulin effect on food intake in the presence of PI3K inhibitor [70]. In contrast, central administration of insulin promoted lipogenesis [71], suggesting that the acute effect of central insulin could differ from its long-term metabolic actions.

Fig. 1

Central leptin and insulin actions and the regulation of systemic glucose homeostasis. The arcuate nucleus of the hypothalamus (ARH) contains two primary populations of neurons that either express pro-opiomelanocortin (POMC) or co-express agouti-related protein (AGRP) and neuropeptide Y (NPY). Both populations of neurons express leptin receptors (OBRs) and insulin receptors (IRs). Leptin action on POMC neurons and its effect on glucose production are partially mediated by second-order melanocortin receptor 4 (MC4R) expressing neurons in extra-arcuate nuclei. On the other hand, insulin acts on NPY/AGRP neurons to regulate hepatic glucose output; this effect is independent of MC4Rs. Importantly, leptin and insulin signaling in the ARH use both divergent and overlapping circuits and mechanisms. Recently, central insulin action has been shown to mitigate hepatic vagal activation via the α7-nicotinic acetylcholine receptor (α7-nAchR) to reduce hepatic glucose production. This may also involve the regulation of sympathetic branch of the autonomic nervous system, ultimately affecting muscle glucose uptake and hepatic glucose production. However, the neural regulation of skeletal glucose uptake remains to be determined. Note: IR is expressed on POMC neurons; however, it appears that insulin signaling in POMC regulates insulin secretion instead of hepatic glucose production. SNS, sympathetic nervous system.

Fig. 1

Central leptin and insulin actions and the regulation of systemic glucose homeostasis. The arcuate nucleus of the hypothalamus (ARH) contains two primary populations of neurons that either express pro-opiomelanocortin (POMC) or co-express agouti-related protein (AGRP) and neuropeptide Y (NPY). Both populations of neurons express leptin receptors (OBRs) and insulin receptors (IRs). Leptin action on POMC neurons and its effect on glucose production are partially mediated by second-order melanocortin receptor 4 (MC4R) expressing neurons in extra-arcuate nuclei. On the other hand, insulin acts on NPY/AGRP neurons to regulate hepatic glucose output; this effect is independent of MC4Rs. Importantly, leptin and insulin signaling in the ARH use both divergent and overlapping circuits and mechanisms. Recently, central insulin action has been shown to mitigate hepatic vagal activation via the α7-nicotinic acetylcholine receptor (α7-nAchR) to reduce hepatic glucose production. This may also involve the regulation of sympathetic branch of the autonomic nervous system, ultimately affecting muscle glucose uptake and hepatic glucose production. However, the neural regulation of skeletal glucose uptake remains to be determined. Note: IR is expressed on POMC neurons; however, it appears that insulin signaling in POMC regulates insulin secretion instead of hepatic glucose production. SNS, sympathetic nervous system.

Close modal

Neurons in the ARH also have a role in the regulation of systemic glucose levels. For instance, insulin action on POMC neurons is required to maintain glucose homeostasis [72]. Insulin action on POMC neurons is likely to occur via Akt signaling as the genetic suppression of PI3K in these neurons blunted the acute response to insulin and impaired glycemic responses. In contrast, an increase in PI3K activity in POMC neurons led to an increase in systemic insulin sensitivity [73]. AgRP neurons in the ARH also express IR, and insulin signaling in this neuronal population has been shown to play a role in the long-term regulation of blood glucose [74]. Recently, using chemogenetic and optogenetic stimulation, Steculorum et al. [75] demonstrated that AgRP neurons control insulin sensitivity in peripheral tissues. Importantly, they showed that acute activation of AgRP neurons decreases sympathetic-driven glucose uptake in brown adipose tissue through the reduction in myostatin expression, which led to the development of insulin resistance in mice.

The central action of insulin, in particular insulin signaling in the hypothalamus, is required for the maintenance of glucose homeostasis (Fig. 1). Indeed, in rodent models central insulin delivery decreased glucose production by the liver (Fig. 1) [76]. In contrast, the inhibition of hypothalamic insulin signaling failed to reduce hepatic glucose production (HGP) in the presence of exogenous insulin, thus impairing glucose regulation in rats [76]. The respective role played by POMC and AgRP neurons in the suppression of HGP in response to central insulin was investigated using genetic models. The selective inactivation of IR in AgRP neurons left mice unable to suppress HGP during a hyperinsulinemic-euglycemic clamp, which uncovered the importance of AgRP neurons in glucose regulation. Interestingly, the lack of insulin signaling in POMC neurons alone did not affect blood glucose levels, whereas mice lacking both leptin and IRs in POMC neurons (Pomc-Cre, Leprflox/flox IRflox/flox mice) displayed systemic insulin resistance [72]. This study put forward a direct synergistic action of insulin and leptin on POMC neurons to maintain glycemic control. Previous electrophysiological studies have also implicated ATP-sensitive potassium channels (K(ATP) channels) in mediating insulin action on hypothalamic neurons [77]. In essence, neuronal K(ATP) channels are required to modulate hypothalamic insulin action. Later, Pocai et al. [78] showed the involvement of K(ATP) channels in the suppression of HGP exerted by hypothalamic insulin signaling. In this study, the authors showed that the pharmacological activation of K(ATP) channels in the mediobasal hypothalamus (MBH) of rats was sufficient to reduce HGP, and consequently decreases blood glucose levels. Importantly, the blockade of K(ATP) channels in the MBH blunted the effect of central insulin infusion on HGP [78]. The action of hypothalamic insulin signaling on HGP was attributed to the direct vagal output to the liver as hepatic denervation of the vagus nerve suppresses the ability of central insulin to decrease HGP [78]. This notion is further delineated by a recent study, which showed that the neural control of insulin-mediated suppression of HGP involves a series of downstream events, which include hepatic vagal output, expression of interleukin-6 (IL-6), and the activation hepatic STAT3 signaling to regulate glucose output [79]. These events eventually reduce HGP via the STAT3-mediated downregulation of genes such as glucose-6-phosphatase (G6pc), a gluconeogenic enzyme [79,80]. Recently, Kimura et al. [81] demonstrated that the inhibition of hepatic gluconeogenic enzymes in response to central insulin signaling is mediated by the α7-nicotinic acetylcholine receptor (Fig. 1). Altogether, these studies have provided compelling evidence that the brain plays an integral role in mediating central insulin actions to regulate HGP. In summary, the activation of hypothalamic IR leads to neuronal K(ATP) channel activation, which increases hepatic IL-6/STAT3 signaling through the vagus nerve to downregulate gluconeogenic enzyme activity.

Although the marked regulatory effect of central insulin on HGP could not be replicated in dogs, the difference in methods and animal models employed can largely elucidate the disparity in the findings [82]. Under normal physiological conditions, insulin and glucagon are readily released into the portal vein and taken up by the liver. Of note, hepatic insulin levels are typically ∼3-fold higher than insulin levels detected in extrahepatic tissues such as the brain [83,84]. It was proposed that peripheral vein insulin infusion reduces hepatic insulin level by blunting endogenous insulin secretion, and causing hepatic insulin deficiency [85]. Therefore, it is thought that hepatic insulin deficiency is likely to overstate the importance of central insulin mechanisms in regulating HGP. In a canine study, Cherrington and colleagues [86] assessed the contribution of hepatic and extrahepatic (including the brain) effects of insulin on HGP. They found that switching the insulin infusion from the portal vein to the leg vein resulted in a 2-fold increase in arterial insulin and a 50% decrease in hepatic insulin levels. This reduction in hepatic insulin levels led to a marked decrease in suppression of HGP. Therefore, they pinned the effect on hepatic insulin deficiency instead of suppression by the increase in extrahepatic (including the brain) insulin levels [86]. In another study, they performed a basal intraportal pancreatic clamp with central infusion of insulin at the same dose that suppresses HGP in rats [76]. Despite the increase in hypothalamic pAKT, hepatic pSTAT3, and a decrease in mRNA expression of pyruvate carboxylase, G6pc, and PEPCK, intracerebroventricular insulin did not affect hepatic glucose output over a 4-h period [87].

Despite the conflicting results, the role of central insulin action cannot be ignored as the brain readily senses insulin levels and signals to the liver. Importantly, there are known species differences in terms of glucose metabolism. In rodents, hepatic glycogen stores are rapidly depleted after an acute fast, whereas in humans and dogs, hepatic glycogen and the rate of glycogenolysis are maintained after a 42-h fast [88,89]. Therefore, this is an important factor to consider when extrapolating results from rodent studies. Collectively, the gluconeogenic pathway may be more important in maintaining glucose homeostasis in rodents than humans during fasting. Noteworthy, the increase in gluconeogenic drive in rodents could be explained in part by the species-dependent differences in hepatic innervation between rodents and humans [90].

In rodents, the progression of obesity after high-fat feeding is associated with a loss of central insulin action. Metabolic insults can reduce the ratio of insulin uptake into the brain, and it is thought that insulin transport is impaired under those circumstances [51,57,58]. However, in obese animals, brain insulin resistance is also observed at the level of hypothalamic signaling pathways with a decrease in PI3K-Akt response following insulin administration [91]. In parallel, the activation of K(ATP) channels is blunted in obese animals in response to insulin [77].

Central resistance to metabolic hormones can be a consequence of impaired transport systems between the blood circulation and the brain [92]. Therefore, the delivery of insulin directly into the brain represents a viable technique to investigate the systemic effects resulting from IR activation within the brain, without interferences from systemic insulin. In rodent models, brain insulin delivery is mainly achieved through lateral ventricle injection, whereas in humans insulin is shown to reach the brain and induce physiological responses through the intranasal route, which preferentially targets the brain [93]. Nonetheless, the hypothesis that a defect in insulin uptake into the brain causes central insulin resistance remains to be determined since central and intranasal delivery of insulin did not reverse the metabolic dysregulation in both obese rodents and humans, respectively [91,94,95,96]. In particular, central and intranasal delivery of insulin failed to exert physiological changes in food intake and glycemia following the loss of IR activation in the hypothalamus in vivo [94,95].

In rodents, insulin action in the hypothalamus promotes the suppression of HGP and contributes to whole-body glucose homeostasis. However, it was not known, until recently, whether blood glucose regulation is similar in humans. In human subjects with intranasal insulin, Heni et al. [96] demonstrated that they require a higher glucose infusion rate to maintain normal glycemia during hyperinsulinemic-euglycemic clamps, indicating a decrease in HGP and/or an increase in glucose disposal. Importantly, the effect observed on blood glucose is associated with a change in hypothalamic activity measured by functional magnetic resonance imaging [96]. Interestingly, the beneficial effect of intranasal insulin on glucose management was only seen in lean, and not in obese individuals [96]. Of note, it was suggested that a small portion of intranasal insulin may have been absorbed into the blood; therefore, it is possible that the improved peripheral insulin sensitivity seen in humans was partly due to the leaking of intranasal insulin into the systemic circulation [97]. In two other studies where insulin spillover was controlled with a lower dose of intranasal insulin, Gancheva et al. [98] did not observe any effects of intranasal insulin on systemic lipolysis, while Dash et al. [99] found that intranasal insulin suppresses HGP without altering venous insulin concentrations. In a separate study, serum levels of insulin were shown to be lower after a meal following intranasal insulin application compared to placebo [100]. The reduction in insulin levels suggests that insulin action in the brain is required to improve whole-body insulin sensitivity in humans. Whilst evident in rodents that central insulin action is required for the regulation of HGP, the challenge to dissect the central and peripheral effects of insulin in humans persists.

Hyperinsulinemia, insulin resistance, and the impairment of glucose-stimulated insulin secretion (GSIS) are tightly connected biologically, and hyperinsulinemia can result in sustained insulin resistance, regardless of where the pathology originated. There are several factors that contribute to insulin release following weight gain. Basal insulin level is an important determinant of insulin sensitivity; therefore, it is worth understanding the elements that may contribute to hyperinsulinemia in the basal state.

Free Fatty Acids

There is a strong association between obesity and insulin resistance and high levels of circulating free fatty acids (FFAs) [101]. This hypothesis is further supported by the demonstration that elevated levels of circulating FFA can cause peripheral insulin resistance in both animals and humans [102,103]. In addition, most obese individuals have elevated plasma FFA levels, which are known to cause peripheral (muscle) insulin resistance [104]. The role of circulating FFA during obesity and its association with the development of insulin resistance has been discussed extensively in another review [105].

Apart from the insulin-stimulated glucose uptake and glycogen synthesis, FFA also acts through GPR40 to regulate insulin secretion from pancreatic β-cells [106]. Fasted rats deprived of FFA display blunted GSIS; however, GSIS was rapidly restored by the infusion of exogenous FFA [107]. Although elevated plasma FFA has been shown to potently augment GSIS [108,109], if the increase in FFA is chronically sustained coupled with elevated glucose levels, it can not only significantly decrease insulin biosynthesis and secretion [25,110,111], but also induce β-cell death [112]. In obese insulin-resistant states, increased plasma FFA levels may accentuate insulin secretion from pancreatic β-cells and consequently contribute to hyperinsulinemia.

Hyperleptinemia

Leptin is a 16-kDa protein hormone secreted by adipocytes. Plasma leptin concentration increases in proportion to body fat mass, and regulates food intake and energy expenditure to maintain body fat stores [30,113,114,115,116,117]. Data in humans showed that plasma leptin level is highly correlated with insulin concentration [118,119] and hyperleptinemia is associated with hyperinsulinemia in obesity [120,121]. Upon the onset of obesity pancreatic β-cells increase in numbers and hypersecrete insulin in parallel to weight gain to compensate for the elevated levels of plasma FFA and glucose [122,123]. Under normal conditions, leptin acts directly on leptin receptors expressed in pancreatic β-cells to inhibit insulin production [124], while augmenting skeletal muscle glucose disposal and oxidation [116,125] and suppressing HGP [126]. Mice with specific β-cell leptin receptor deletion displayed hyperinsulinemia and developed insulin resistance [127]. Hyperinsulinemia observed in leptin-deficient (ob/ob) mice [115], leptin receptor-deficient (db/db) mice [128], and leptin-resistant humans [129,130] are additional evidence to support leptin's interaction with insulin secretion. In addition, hyperleptinemia in obesity can result in leptin resistance in β-cells, and contribute to the overproduction of insulin by β-cells [127].

In accordance with the proposed bidirectional adipoinsular axis, both insulin and glucose are capable of driving leptin secretion in adipocytes [131,132,133]. In fact, patients with insulinoma have increased leptin levels [134]. Furthermore, leptin monotherapy has been shown to normalize a wide array of diabetic complications in mice which include hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency [135,136,137]. However, leptin therapy has not been successful in treating obesity-associated T2DM, although it has improved diabetic measures in children [129,130] and adults [138] with familial leptin deficiency and in patients with lipoatrophic diabetes [139]. Taken together, these data put forward a series of sequential events; lipid accumulation during obesity (weight gain) causes an increase in FFA and leptin levels (hyperleptinemia), leading to the development of leptin resistance followed by an increase in insulin secretion. Chronically, these events can induce tissue-specific insulin resistance, which will be discussed in detail in the following section.

Hyperglycemia

Progressive hyperglycemia is associated with glucotoxicity and worsening of insulin resistance in T2DM. During the initial transition from prediabetes to diabetes, the pancreas compensates by increasing insulin secretion to offset insulin resistance, and glucose levels remain normal. After chronic hyperglycemia, the β-cells fail to keep up with the high rate of insulin secretion, and eventually it leads to “exhaustion” of the pancreas and insulinopenia. Different stages and degrees of glucose intolerance and type 2 diabetes result in an inverted U-shaped insulin secretion pattern which is termed as the “Starling curve of the pancreas” [140]. In the later stage of diabetes, when β-cells fail to compensate, hyperglycemia per se can impair insulin secretion [141,142] and cause apoptosis of β-cells [143]. More importantly, chronic small fluctuations in glucose levels in prediabetic individuals before overt T2DM can induce glucotoxicity in pancreatic β-cells [144]. Chronic exposure to hyperglycemia in rat in vivo also promotes insulin resistance [145]. Additional evidence in humans with type 1 diabetes has provided further support that glucotoxicity can induce insulin resistance [146]. In the study of Yki-Jarvinen et al. [146], type 1 diabetes patients received constant co-infusion of insulin and glucose to either maintain euglycemia or hyperglycemia for a period of 24 h. After that, insulin sensitivity was assessed using the glycemic clamp technique. The results indicate that patients exposed to hyperglycemia required less glucose compared to patients exposed to euglycemia [146]. In this study, the deficiency in endogenous insulin production in these patients suggests that hyperglycemia per se can impair insulin sensitivity.

Hyperinsulinemia is defined as sustained high levels of plasma insulin during fasting from either hypersecretion or decreased clearance of insulin. The balance of insulin production and insulin clearance determines plasma insulin level. The average half-life of insulin is about 3 min in the blood. The liver and kidney are the primary sites for insulin clearance; through the binding of insulin to IR, and the action of insulin degrading enzyme after internalization [147]. When these 2 mechanisms are deficient due to gene inactivation in mice, insulin clearance is impaired and mice develop insulin resistance and type 2 diabetes as a consequence of hyperinsulinemia [148,149,150]. These studies strongly suggest that hypersecretion of insulin is not the only cause of hyperinsulinemia. Impairment of insulin clearance may also cause insulin resistance by causing constant high levels of insulin in the blood.

Additional in vivo studies have demonstrated that insulin administered at high levels to mimic insulin levels similar to those found in insulin-resistant states can lead to insulin resistance. Rats given increasing doses of neutral protamine Hagedorn insulin have decreased IR expression in target tissues parallel to a decrease in insulin sensitivity [151,152]. Healthy humans infused with insulin at submaximal and maximal doses for 40 h were hyperinsulinemic and displayed significantly reduced glucose utilization and overall glucose metabolism [153]. In essence, these studies recapitulate the notion that constant hyperinsulinemia similar to those observed in many insulin-resistant states can induce insulin resistance.

It is noteworthy that one of the characteristics of hyperinsulinemic states, specifically in obesity-associated T2DM individuals, is the elevation of inflammatory markers, including C-reactive protein (CRP), haptoglobin, fibrinogen, plasminogen activator inhibitor and serum amyloid A and sialic acid, as well as cytokines and chemokines [154,155,156]. Furthermore, inflammatory markers like IL-1β, IL-6, and CRP can predict the development of T2DM [155,157]. Thus, it is possible that hyperinsulinemia can exacerbate insulin resistance through the increase in inflammation associated with obesity. Importantly, hyperinsulinemia can increase inflammation in the brain, and therefore it may be a contributor to central insulin resistance relating to obesity-associated T2DM [158].

Conversely, whether inflammation precedes hyperinsulinemia in the development of T2DM remains unclear. Nevertheless, there are studies showing that chronic low-grade tissue inflammation, specifically in the liver and adipose tissue can cause insulin resistance in rodents [159,160]. Although less evident in humans, similar inflammatory alterations resulted from obesity were observed in some human populations [161,162]. Seminal studies from Hotamisligil et al. [163,164] in the 1990s have showed that tumor necrosis factor-α (TNF-α) concentration is significantly elevated in obese mice and humans. In addition, neutralization and deletion of TNF-α in mice improved and protected them from obesity-induced insulin resistance [164,165]. The role of inflammatory mediators and immune cells in the regulation of metabolism has been extensively reviewed elsewhere [166,167,168,169,170]. Moreover, there are 2 recent reviews describing possible immunotherapies targeting inflammation in the treatment of T2DM [171,172]. Overall, the development of insulin resistance is not limited to hyperinsulinemia alone as chronic tissue inflammation may also be a contributor.

While dissecting the complex mechanisms underpinning obesity-associated insulin resistance can be difficult, it is crucial to recognize that insulin resistance is tightly linked to the changes in glucose homeostasis. The assessment of insulin resistance usually involves the measurements of glucose and insulin concentrations, glucose uptake, insulin's ability to regulate the synthesis and storage of fat, protein synthesis, and nonmetabolic processes such as cell growth and differentiation. However, alteration in glucose homeostasis is only one aspect of insulin resistance. The second concept we should account for is that not all insulin-mediated processes and tissues become equally resistant to insulin. Furthermore, we should carefully consider the impact of hyperinsulinemia that evolves with insulin resistance, which may lead to increased insulin action in tissues or pathways that are not as resistant as those related to glucose metabolism. In the following sections, we aim to discuss the development of insulin resistance in peripheral tissues associated with obesity.

The liver is known to have a pivotal role in glucose and lipid metabolism, and hepatic insulin resistance is thought to be primarily responsible for fasting hyperglycemia. It is well established that obesity can cause ectopic accumulation of fat in the liver, and it is highly associated with the development of insulin resistance in nonalcoholic fatty liver disease (NAFLD) [173]. NAFLD can affect up to 75% of an obese population [174]. In an obese state, the liver exhibits selective insulin resistance; an impaired ability of insulin to suppress endogenous glucose production while the synthesis of fatty acids and triglycerides is enhanced, resulting in chronic hyperglycemia and hypertriglyceridemia [175,176]. Hyperinsulinemia is thought to contribute to fatty acid and very low-density lipoprotein biosynthesis through the activation of transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) that ultimately enhances the transcription of genes such as acetyl-coenzyme A carboxylase and fatty acid synthase [177,178]. This promotes an influx and deposition of triglycerides in muscle and adipose tissue, which lead to insulin resistance. The resultant effect of insulin resistance in adipose tissue is a blunted response to fatty acid uptake and oxidation, which corresponds to decreased FFA uptake and glucose utilization [179]. These findings suggest that the reduced insulin-mediated fatty acid uptake and oxidation at the level of the adipose tissue may exacerbate hepatic steatosis by increasing FFA flux to the liver. Excessive oxidation of FFA enhances glucose production by increasing hepatic acetyl-CoA content to activate pyruvate carboxylase needed for gluconeogenesis. A large body of work has also documented the role of hepatic diacylglycerol (DAG) accumulation and PKCε, a predominant PKC isoform in the liver, upon high-fat feeding in rodents [180,181]. Reduced PKCε expression and PKCε deletion protected rodents against diet-induced insulin resistance [182,183]. Since this discovery, hepatic DAG content and PKCε activation have emerged to be the strongest predictors of hepatic insulin sensitivity in obese humans [184,185].

In obesity, the excess influx of circulating nutrients into the liver triggers various molecular pathways and alters hepatic glucose metabolism. There is a preponderance of evidence in rodents and humans showing that the accumulation of nutrient-derived metabolites in obesity leads to endoplasmic reticulum stress and chronic metabolic inflammation, which collectively impedes hepatic insulin signaling [186]. Yang et al. [187] recently described that S-nitrosylation of hepatic proteins is responsible for obesity-induced inflammation with elevated nitric oxide synthase expression in the liver of rodents. The precise mechanism involves the suppression in ribonuclease activity of inositol-requiring protein 1α following an increase in S-nitrosylation of hepatic proteins, which resulted in decreased X-box-binding protein 1 splicing activity [187]. Under these circumstances, it increases endoplasmic reticulum stress, leading to the impediment of hepatic insulin action and whole-body glucose tolerance.

To date, numerous studies have emerged showing that forkhead box protein O1 (FOXO1) in the liver regulates both glucose production and lipogenesis by driving the expression of G6pc and suppressing the expression of glucokinase (Gck) during refeeding. Liver-specific deletion of 3 FOXOs (L-FOXO1, 3, 4-/-) increased de novo lipogenesis (DNL) that was attributed to the elevated expression of Gck, which ultimately increased liver glucose uptake and utilization [188]. Notably, hepatic insulin signaling remained intact with liver-specific deletions of Akt1/Akt2/FOXO1-/-[189] or FOXO1-/-[190]. Two independent studies have also recently demonstrated that liver-specific IR-/- mice have blunted glucoregulatory response during refeeding and insulin-mediated suppression of HGP. However, these impairments were completely reversed in the dual liver-specific IR-/-, FOXO1-/- mice [191]. These studies have provided evidence that hepatic insulin signaling is dispensable for the suppression of glucose production in a postprandial state or under hyperinsulinemic state, indicating that HGP can be regulated by an extrahepatic insulin-responsive tissue. On the other hand, hepatic insulin signaling is still necessary for nutrient sensing (refeeding) and lipogenesis as liver-specific Akt1/Akt2/FOXO1-/- mice displayed defective lipogenesis with concomitant decrease in lipogenic enzymes such as Srebp1c, Gck, and Fas [192]. Collectively, these findings have presented 2 schools of thought. First, in insulin-resistant states, hyperinsulinemia can lead to excess DNL as hepatic insulin signaling remains intact, which consequently increases circulating FFA, leading to uncontrolled glucose production by the liver [192]. Second, the fact that insulin-mediated suppression of HGP was restored in liver-specific InsR-/-, FOXO1-/- mice suggested that intact insulin signaling in extrahepatic tissues (including the brain) may be involved. In line with the notion that intact insulin signaling in the brain regulates HGP in rodents and humans [76,193], these studies underscore the involvement of hypothalamic insulin signaling in controlling hepatic glucose release in both postprandial and insulin-resistant states.

Skeletal muscle is the primary target organ for glucose uptake in humans, and it accounts for 80% of glucose disposal under hyperinsulinemic euglycemic conditions [194]. Upon glucose uptake in skeletal muscle, glycogen synthesis occurs as the principal pathway of glucose disposal in both normal and diabetic patients [195]. Based on the tenet formulated by Randle and colleagues [196], obesity-associated insulin resistance could be due to increased FFA oxidation and the accumulation of citrate, resulting in the inhibition of an essential glycolytic enzyme, phosphofructokinase, thereby reducing glucose utilization. Defective glycogen synthesis has a prominent role in the development of insulin and T2DM [197]. Insulin action is blunted in T2DM, and it does not increase glucose-6-phosphate to mediate glucose transport and glycogen synthesis. This suggests a possible association of T2DM with either decreased glucose transport activity or decreased hexokinase activity. Cline et al. [198] have elegantly demonstrated that glucose transport is the rate-controlling step in insulin-stimulated glycogen synthesis. Therefore, impaired insulin-stimulated glucose transport may be responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in T2DM patients. In addition, exogenous delivery of FFAs in humans increases intramyocellular lipid metabolism coupled with a ∼50% decrease in insulin-stimulated glycogen synthesis in muscle [199]. Collectively, these studies have demonstrated that the influx of FFAs and triglycerides from liver metabolism can accumulate in muscle and compromise the intrinsic insulin-mediated glucose metabolism. These events can facilitate the progression of insulin resistance into glucose intolerance and hyperglycemia causing greater insulin secretion from the pancreas forming a vicious cycle.

Similar to the liver, many studies have implicated other lipid species such as DAGs in the development of insulin resistance. In the skeletal muscles of humans and rodents, lipid infusion acutely impaired insulin-mediated tyrosine phosphorylation of IRS-1 and downstream PI3K activation [200]. To further support the deleterious effect of lipid accumulation, rodents and humans subjected to lipid infusion displayed a transient increase in muscle DAG content and activation of 2 separate isoforms of PKC (PKCδ and PKCθ), which provoked muscle insulin resistance [201,202]. These studies support a mechanistic model in which muscle DAG accumulation activates PKCθ, which impairs insulin signaling. Interestingly, muscle insulin resistance can divert glucose to the liver for hepatic DNL, as mice with muscle-specific deletions of the IR and GLUT4 have increased susceptibility to hepatic steatosis and weight gain [203,204].

White adipose tissue (WAT) is classically considered as a depot for lipid storage following excess energy intake, and nutrient deprivation will trigger the mobilization of these energy stores [205]. Glucose uptake in WAT is to a large extent dependent on insulin although quantitatively only accounts for ∼5-10% of whole-body glucose uptake [206,207]. Notwithstanding, glucose metabolism in fat cells can impact other tissues with its extra-adipose actions. For instance, adipose-specific GLUT4-/- mice exhibited insulin resistance in skeletal muscle and liver without affecting adiposity [208]. Furthermore, mice with adipose-specific Rab10 deletion, a GTPase required for insulin-stimulated GLUT4 translocation, displayed hepatic insulin resistance despite normal insulin suppression of plasma FFAs [209].

Fat within the intra-abdominal region has been strongly associated with insulin resistance, T2DM, and cardiovascular disease compared to other fat depots such as the gluteal and subcutaneous fat depots [210]. Although glucose transport is impaired in obesity and insulin-resistant states, the insulin-mediated antilipolytic pathway in adipocytes is preserved; thus, the differentiation or expansion of adipocytes is sustained [211]. The enlargement of adipocytes releases more FFA into the intraportal vein, which can directly impair insulin signaling or indirectly activate inflammatory pathways promoting insulin resistance [212,213]. Concomitant with decreased insulin secretion by the pancreas in the insulin-resistant state, it can result in increased lipolysis of adipocytes, which compounds the insulin resistance in skeletal muscle and drives HGP by magnifying FFA influx [214].

In the recent years, studies have shown that the activation of carbohydrate response element-binding protein (ChREBP) upon glucose uptake into adipocytes can impact adipose lipid metabolism by regulating lipogenic and glycolytic genes [215]. Interestingly, adipose ChREBP expression has been implicated in systemic insulin sensitivity in rodents and humans [215]. Owing to the fact that WAT is a major endocrine organ, it can secrete proteins that have metabolic effects on distant tissues. In the last decade, adipocytes have been found to secrete specific fatty acids such as palmitoleate [216,217] and monomethyl branched-chain fatty acids [218] that correlated positively with increased insulin sensitivity in humans. Adipose tissue has also recently been shown to synthesize fatty acid esters of hydroxyl fatty acids, particularly palmitic-acid-9-hydroxy-stearic acid (9-PAHSA), which is dependent on ChREBP expression [219]. In addition, PAHSA levels are closely associated with insulin sensitivity as exogenous PAHSA administration improved glucose tolerance and inflammation in insulin-resistant mice [219].

Recently, Chopra and colleagues [220] identified a new hormone, asprosin, which is secreted by WAT and acts primarily on the liver to drive glucose release. They showed that plasma asprosin peaks during fasting and induces HGP through the activation of cAMP-PKA pathway [220]. In addition, they reported that insulin-resistant mice and prediabetic humans displayed elevated levels of asprosin [220]. Blocking asprosin using an antiasprosin monoclonal antibody dampened HGP and normalized glucose and insulin levels in insulin-resistant mice [220].

WAT drives the development of obesity-induced inflammation by increasing the synthesis and secretion of various adipocytokines such as IL-6, IL-1β, and TNF-α, which aggravated insulin resistance [164,221,222]. These adipocytokines have been shown to enhance lipolysis by lowering perilipin [223,224] and fat-specific protein 27 [225] expression as these lipid-associated proteins function to stabilize lipid droplets through limiting lipase access to triglycerides. Elevated WAT lipolysis can indirectly induce hepatic insulin resistance through the increase in FFA flux to the liver, which augmented hepatic Acetyl-CoA content and the activation of pyruvate carboxylase, consequently raising the rate of hepatic glucose release [226,227]. Additionally, WAT lipolysis also increased the rate of glycerol delivery to the liver, which further increased hepatic gluconeogenesis via a substrate push mechanism (e.g., dihydroxyacetone phosphate) [226,227]. These indirect mechanisms are dependent on insulin signaling in the adipocyte instead of hepatic insulin signaling. WAT may not be the first tissue to develop insulin resistance, but as soon as insulin signaling in WAT is impeded, it can have pronounced negative impact on glucose metabolism in other tissues by increasing substrate availability. Importantly, adipocytes display exquisite sensitivity to insulin [228].

In addition to the proinflammatory mediators, leptin is proposed to have proinflammatory effects owing to its cytokine-like structure and the large degree of sequence homology between leptin receptor (LRb) and gp130Rβ; activation of both receptors stimulates the JAK/STAT and ERK signaling pathways [229]. Leptin not only drives the production of the other proinflammatory mediators like IL-2 and IFN-γ, but also blocks the production of the anti-inflammatory cytokine IL-4 by T cells or mononuclear cells [230]. The interaction between leptin and inflammation is bidirectional as leptin secretion was increased in response to proinflammatory cytokines (TNF-α, IL-1) and endotoxin (lipopolysaccharide, LPS), which perpetuated the chronic inflammatory state in obesity [231]. All these events progressively contribute to β-cell failure, and consequently give way to frank T2DM.

As mentioned previously, sustained WAT expansion is also involved in the development of obesity-induced insulin resistance. Lipid deposition in ectopic sites such intra-abdominal/visceral regions, liver, heart, and skeletal muscles occurs when the ability to expand and storage capacity is exceeded in WAT, a phenomenon known as “lipid spillover.” Recently, the association between impaired fat expansion and insulin resistance in humans has been extensively reviewed [232,233]. Noteworthy, numerous studies in humans and animals have shown that hypertrophic expansion of fat cells (subcutaneous fat) increases tissue fibrosis, infiltration of immune cells, and lipolysis, and exacerbates systemic insulin resistance [234]. As such, hypertrophic obesity is highly associated with many aspects of the metabolic syndrome [234,235,236] and the development of T2DM [237,238]. Interestingly, obese individuals without insulin resistance displayed smaller subcutaneous adipocytes, higher secretion of adiponectin, and reduced WAT inflammation [239]. Altogether, insulin resistance can manifest itself in the presence of hyperinsulinemia, dyslipidemia, and impaired adipogenesis.

An obesogenic environment promoted by sedentary lifestyles and calorie imbalance has promoted an epidemic of obesity. Obesity can result in the hypersecretion of insulin by β-cells and chronic low-grade tissue inflammation, which consequently causes insulin resistance in peripheral tissues such as the liver, skeletal muscles, and WAT. Importantly, insulin resistance is not limited to peripheral tissues as hyperinsulinemia can also cause insulin resistance in the brain. Insulin resistance can be exacerbated by the increase in FFA flux, hyperleptinemia, and hyperglycemia causing lipotoxicity and glucotoxcity, leading to β-cell failure and eventually T2DM. Despite the differences between some animal models, there is good evidence showing that central insulin resistance contributes to the development of obesity and T2DM. In this regard, we should acknowledge the invaluable knowledge and underst

anding gained over the past few decades relating to the central effects of insulin on HGP in mice and humans. However, there is a need for future studies to incorporate a refined insulin dose that does not affect systemic insulin levels in order to better elucidate the central actions of insulin in humans. In addition, the intranasal route represents an effective way to deliver drugs that target the human brain. Ultimately, it opens up new therapeutic avenues to target central and peripheral mechanisms as an integrative approach to suppress HGP and improve glucose homeostasis in obese patients with T2DM.

The authors declared that no conflict of interest exists.

W.C. and E.B. wrote the manuscript. W.C., E.B., and M.A.C. edited the manuscript.

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