Insulin effects are transmitted by insulin binding to a specific transmembrane insulin receptor. The receptor belongs to the family of tyrosine kinase receptors, like the receptors for many growth factors. The active receptor is a dimer of two combined subunits. Insulin effects in the intact organism are mediated almost exclusively through the insulin receptor but can also be mediated by hybrid receptors that are formed by one subunit of the insulin receptor and another subunit of the receptor for insulin-like growth factor (IGF-1). Insulin binds with high affinity to its own receptor and with a 100 to 150 times lower affinity to the IGF-1 receptor. Therefore insulin binding to the IGF-1 receptor does not play a notable role at physiologic insulin plasma concentrations compared with IGF-1 effects at its own receptor. The affinity toward insulin-IGF-1 hybrid receptors lies between that for the insulin receptor and that for the IGF-1 receptor. The binding of insulin to its receptor leads to a cascade of cellular signals that are mostly phosphorylation and dephosphorylation events. The docking proteins IRS-1 to IRS-4 (insulin receptor substrates) have been detected as primary intracellular substrates for postreceptor signaling. These transmit the insulin signal downstream into different cellular compartments after phosphorylation by the activated insulin receptor. There are two distinctly different pathways in the intracellular insulin signal transmission. One pathway conveys the metabolic effects of insulin via the signaling molecules AKT/protein kinase B (PKB), and the other pathway transmits the mitogenic effects of insulin via the signaling proteins Ras/Raf/MAP kinase ( Fig. 2.2 ). Insulin resistance can, therefore, lead to a reduction of metabolic and mitogenic effects. Because redundancies and compensation mechanisms are present throughout the entire system of the intracellular signal transduction of the insulin signal, a disturbance of a single transmission element does not necessarily result in insulin resistance. Depending on the defects of the insulin signal transduction, metabolic and mitogenic effects of insulin may be affected to varying degrees.

Insulin signaling: modulation and target cell-stroma interaction.

Critical nodes form an important part of the signaling network that functions downstream of the insulin receptor ( IR ) and the insulin-like growth factor 1 ( IGF-1 ) receptor ( IGF-1R ). The important metabolic and mitogenic pathways are shown. Three important nodes in the insulin pathway are the IR and the IR substrates ( IRS ) 1 to 4 (node 1), the phosphatidylinositol 3-kinase ( PI3K ) with its several regulatory and catalytic subunits (node 2), and the three AKT/protein kinase B (PKB) isoforms (node 3). Downstream or intermediate effectors, as well as modulators, of these critical nodes include atypical protein kinase C ( aPKC ), AKT substrate of 160 kDa ( AS160 ), Cas-Br-M (murine) ecotropic retroviral transforming sequence homologue ( Cbl ), Cbl-associated protein ( CAP ), cell-division cycle 42 ( CDC42 ), extracellular signal-regulated kinase 1 and 2 ( ERK1 and ERK2 ), forkhead box O1 ( FOXO1 ), glycogen synthase kinase 3 ( GSK3 ), Janus kinase ( JAK ), c-Jun- N -terminal kinase ( JNK ), mammalian target of rapamycin ( mTOR ), p90 ribosomal protein S6 kinase (p90RSK), phosphoinositide-dependent kinase 1 and 2 ( PDK1, 2 ), phosphatase and tensin homologue ( PTEN ), protein tyrosine phosphatase-1B ( PTP1B ), Ras, Rac, Src-homology-2-containing protein ( Shc ), suppressor of cytokine signaling ( SOCS ), signal transducer and activator of transcription ( STAT ), and Ras homologue gene family, member Q (ARHQ; also called TC10). IL , Interleukin; TNF α _, tumor necrosis factor α; TNFR , TNF-α receptor.

Modified from Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–95.

Numerous investigations have been carried out to investigate possible mutations in the gene for the insulin receptor in T2DM. Only very few mutations have been found that are associated with the development of insulin resistance or T2DM. Furthermore, most studies have not shown a significant reduction in insulin receptor molecules in peripheral target tissues and organs for insulin action. Therefore quantitative changes in insulin receptor expression and insulin receptor mutations are not responsible for the development of insulin resistance in T2DM. It is interesting to note that a reduction in insulin receptor autophosphorylation was detected in vitro in tissues from patients with T2DM in numerous former investigations. It is hypothesized that the reduced autophosphorylation of the insulin receptor is responsible for disturbed insulin signal transduction and consequently the development of insulin resistance. The reduction in autophosphorylation and autoactivation of the insulin receptor is partially caused by modifications in the receptor molecule by an increased phosphorylation of serine residues. The changes in insulin receptor activity are most likely secondary phenomena resulting from the metabolic changes in T2DM (e.g., hyperglycemia, dyslipidemia). Studies demonstrating normalization of the insulin receptor activity after lifestyle interventions support this hypothesis. Only in rare patients with severe insulin resistance syndromes have insulin receptor mutations been detected that are associated with a reduced binding affinity of insulin to the insulin receptor or to a diminished autophosphorylation and autoactivation of the insulin receptor. These severe insulin resistance syndromes, also referred to as type A insulin resistance , most often lead to glucose metabolism disorders during adolescence and are often associated with acanthosis nigricans and hyperandrogenism in females. Other very rare insulin receptor mutations involving a complete loss of function lead to severe diseases such as leprechaunism.

Functional studies on the activation of the IRSs and the phosphatidylinositol 3-kinase (PI 3-kinase) that binds to the IRS were performed predominantly in muscle cells and adipocytes of patients with T2DM. These in vitro studies revealed reduced activation of IRS-1 and IRS-2 as well as reduced PI 3-kinase/PKB activity in T2DM. Defects in the insulin signaling cascade are therefore already present in the first steps of the signal transmission in insulin resistance and T2DM. Apart from these findings, genetic polymorphisms in the genes for the IRS proteins and the PI 3-kinase/PKB/AKT complex were found in T2DM—for example, Gly972Arg for IRS-1 and Met326Iso for PI 3-kinase. The incidence and the functional relevance of these polymorphisms are very heterogeneous in different populations. These studies suggest that the diminished activation of IRS-1, IRS-2, and PI 3-kinase/AKT in muscle cells, hepatocytes, and adipocytes may be secondary to regulatory signal changes in metabolic disturbances. It is interesting to note that a disturbance of the metabolic signal pathway via IRS/PI 3-kinase/AKT is present in insulin resistance in T2DM, whereas the mitogenic pathway of the insulin signal via MAP kinase is not affected. In summary, in insulin resistance, a reduced cellular action of insulin is found concerning the metabolic but not the mitogenic effects of insulin.

Skeletal muscle plays an important role in glucose uptake. Approximately 80% of the glucose is transported into the skeletal muscle in an insulin-dependent manner. In this respect, the skeletal muscle is an important organ involved in the development of insulin resistance. This was demonstrated in glucose clamp experiments and positron emission tomography (PET) scan investigations that showed that in insulin resistance and T2DM, insulin-dependent glucose uptake into the skeletal muscle is significantly reduced. Ectopic fat deposition also seems to be highly important for the development of insulin resistance of skeletal muscle. Increased intramyocellular fat depositions are found in insulin resistance and T2DM. The ectopic fat deposition creates an altered metabolic atmosphere with increased free fatty acid concentrations and increased adipokines that lead to enhanced lipid oxidation and an increase in chronic inflammation, resulting in the development of insulin resistance and diminished glucose uptake into the skeletal muscle. The cause of increased intramyocellular fat deposition in insulin resistance and T2DM is most likely a genetic disposition. The triglyceride accumulation in skeletal muscle in obesity derives from a reduced capacity for fat oxidation. An inflexibility in regulating fat oxidation, rather than a defect in fatty acid uptake, is related to insulin resistance and T2DM. On the other hand, elevated circulating free fatty serum concentrations may secondarily lead to an increase in intramyocellular triglyceride accumulation.

The humoral cross talk between skeletal muscle and liver seems to be of interest and importance; in animal studies, an acute increase in physical activity quickly and strongly regulates the expression of a large number of genes in the liver.

In humans, aerobic fitness specifically regulates liver fat content but not total or visceral obesity. Whether myokines are involved in this important cross talk between skeletal muscle and liver in humans needs to be further investigated and characterized.

In addition to insulin-dependent glucose uptake, the transport of glucose into the skeletal muscle can also be mediated by physical activity in an insulin-independent manner. This insulin-independent glucose uptake is mainly mediated by an increase in the 5ʹ-AMP-kinase concentration with the consecutive activation of the 5ʹ-AMP-activated protein kinase (AMPK). Most data indicate that this pathway, activated by physical activity, is not altered in insulin resistance and in T2DM, in contrast to perturbations of insulin-dependent glucose transport.

In this respect, interleukin-6 (IL-6) produced in the working muscle during physical activity could act as an energy sensor by activating AMP-activated kinase and enhancing glucose disposal, lipolysis, and fat oxidation. In addition to the numerous positive effects of physical activity on all aspects of the metabolic syndrome and beyond, physical fitness and training improve glucose uptake into the skeletal muscle via the AMPK pathway.

The role of central and visceral obesity in the development of insulin resistance was described previously. On a molecular level, the mediators secreted by the adipocytes in dependence of fat mass and fat distribution play an important role in the development of insulin resistance. In addition to the free fatty acids, adiponectin and numerous inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), IL-6, and transforming growth factor beta (TGF-β), are secreted by the adipocytes. These inflammatory cytokines cause insulin resistance via an inhibition of the intracellular insulin signaling. In addition, they lead to inflammatory processes that are frequently observed in insulin-resistant patients. The visceral fat stores, therefore, mediate insulin resistance and chronic inflammation, as well as arteriosclerotic development, through their secretory capacity of adipokines and cytokines.

One of the most important physiologic functions of the liver in glucose metabolism is to make glucose available for other organs in the fasting state, especially during the night. The regulation of hepatic glucose production is mediated by the influence of insulin on gluconeogenesis. In the postprandial state, the plasma glucose concentration rises, as do the concentrations of the incretin hormones (mainly glucagon-like peptide-1 [GLP-1]) that stimulate insulin secretion. Insulin reaches the liver directly in high concentrations via the portal vein system and physiologically suppresses hepatic glucose production, which would be counterproductive in the postprandial state, when plasma glucose is elevated already. Only during the fasting state with low glucose and insulin concentrations do low insulin concentrations disinhibit hepatic gluconeogenesis, leading to sufficiently high glucose concentrations in the circulation in the fasting state. In insulin resistance and T2DM, an increased hepatic glucose production is observed that is caused by a diminished hepatocyte response to insulin failing to suppress gluconeogenesis. Insulin resistance of the liver is typically detected in the clinical setting through elevated fasting glucose concentration, which is caused by the increased hepatic glucose production. Different mechanisms that lead to an increased hepatic gluconeogenesis are discussed: the insensitivity of the liver toward insulin itself on the one hand, but also elevated free fatty acid concentrations, as well as hyperglucagonemia, and increased activity of phosphoenolpyruvate-carboxykinase, a key enzyme of gluconeogenesis. One important trigger for insulin resistance of the liver is the fat accumulation in this organ. Different studies have shown a correlation between triglyceride content in hepatocytes and insulin resistance within the liver. Patients with T2DM frequently also have nonalcoholic steatohepatosis (MASH) or nonalcoholic fatty liver disease (MASLD), which are tightly correlated with insulin resistance. Successful implementation of a lifestyle intervention may reduce liver fat mass and may improve insulin resistance. The insulin-sensitizing effect of metformin and glitazones is partially explained by the reduction of the triglyceride content in the liver. MASLD is the most common liver disease, and along with the worldwide increase in the prevalence of general and abdominal obesity, MASLD has become a prevalent general health problem in many industrialized countries. MASLD represents a continuum of liver disease from simple steatosis to MASH and cirrhosis. Up to 20% of patients with simple steatosis will develop MASH, and in a subgroup of these patients, MASH can progress further to MASH with fibrosis and cirrhosis. Cirrhosis is the main risk factor for the development of hepatocellular carcinoma. In addition, MASLD was identified as a strong and independent predictor of T2DM and cardiovascular disease. Thus much effort is currently focused worldwide on precisely quantifying liver fat content in humans for predictive and therapeutic purposes. However, this endeavor might not be sufficient to completely understand the pathophysiology of MASLD.

During conditions of a positive energy balance, subcutaneous and visceral adipose tissues expand in a manner that is predominantly genetically determined. Subcutaneous obesity is not strongly associated with metabolic diseases, whereas visceral obesity is a strong predictor of these diseases. Increased availability of fatty acids (resulting from increased lipolysis), increased subclinical inflammation, and dysregulation of adipokine production and release are thought to promote insulin resistance, atherosclerosis, and beta-cell dysfunction. Accumulation of lipids in the liver is also largely genetically determined, and two distinct phenotypes have been identified. When hepatic detoxification processes are active, storage of lipids in the liver is not associated with metabolic diseases. By contrast, when lipotoxicity is present, hepatic glucose production increases, and lipids are released with an atherogenic profile. Dysregulated hepatokine production also contributes to the development of metabolic diseases. The important heptokines are listed in Table 2.3 , and Fig. 2.5 shows a schematic diagram of the putative roles of liver and adipose tissue in the development of metabolic diseases.

Novel roles of liver and adipose tissue in the development of metabolic diseases.

During conditions of a positive energy balance, subcutaneous and visceral adipose tissues expand in a manner that is predominantly genetically determined. Subcutaneous obesity is not strongly associated with metabolic diseases, whereas visceral obesity is a strong predictor of these diseases. Increased availability of fatty acids (resulting from increased lipolysis), increased subclinical inflammation, and dysregulation of adipokine production and release are thought to promote insulin resistance, atherosclerosis, and beta-cell dysfunction. Accumulation of lipids in the liver is also largely genetically determined, and two distinct phenotypes have been identified. When hepatic detoxification processes are active, storage of lipids in the liver is not associated with metabolic diseases. By contrast, when lipotoxicity is present, hepatic glucose production increases and lipids are released with an atherogenic profile. Dysregulated hepatokine production also contributes to the development of metabolic diseases.

Modified from Stefan N, Häring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;9:144.

The glycoprotein fetuin-A is an important hepatokine. It is a natural inhibitor of the insulin-stimulated insulin receptor tyrosine kinase and induces insulin resistance in rodents. In humans, circulating fetuin-A levels are positively associated with fat accumulation in the liver, insulin resistance, metabolic syndrome, and type 2 diabetes mellitus. In addition to inducing insulin resistance, fetuin-A is involved in subclinical inflammation and correlates positively with high-sensitive C-reactive protein levels in humans. It also induces cytokine expression in human monocytes and reduces the expression of the atheroprotective adipokine adiponectin in animals. Taken together, fetuin-A may represent a pathway linking fatty liver with cardiovascular events by inducing insulin resistance and inflammation. Indeed, an investigation in the cohort of the EPIC study (European Prospective Investigation into Cancer and Nutrition; EPIC-Potsdam) revealed a link between high plasma fetuin-A levels and an increased risk of myocardial infarction (MI) and ischemic stroke. High fetuin-A plasma concentrations led to a threefold to fourfold increased risk for MI and ischemic stroke.

During the past years, an increasingly important role of the brain in the development of insulin resistance and obesity has been found. The brain is not only an important organ for glucose disposal but has recently also been recognized as an insulin-sensitive organ. IRs are expressed in brain tissue. A high degree of insulin sensitivity of the human brain facilitates the loss of body weight and body fat during a lifestyle intervention.

Furthermore, insulin has important functions in regulating satiety signals and energy expenditure within the central nervous system and therefore has an influence on the development of obesity. Intracerebroventricular application of insulin promotes satiety in experimental models in animals and human studies. Neutralizing insulin effects in the brain in animal experiments leads to hyperphagia and obesity and a reduced peripheral action of insulin in the liver. The results of these experiments point to insulin effects in the brain that most likely lead to a neurotransmitter response that has an influence on hepatic glucose production. The brain is therefore an important central regulator for peripheral insulin action in the liver. Brain insulin resistance in humans has been associated with long-term adiposity and an unfavorable adipose tissue distribution, thus implicating it in the pathogenesis of subgroups of obesity and (pre)diabetes that are characterized by distinct patterns of body fat distribution. Encouragingly, emerging evidence suggests that brain insulin resistance could represent a treatable entity, thereby opening up novel therapeutic avenues to improve systemic metabolism and enhance brain functions, including cognition.

Regarding interventions, two clinical trials showed that brain insulin resistance appears to be treatable. A nonpharmacological intervention with 8 weeks of exercise in obese subjects improved insulin responsiveness in the dorsal striatum (putamen) to a level similar to that seen in lean individuals. Another study evaluated pharmacological treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in subjects with prediabetes and overweight or obesity. Empagliflozin over 8 weeks restored hypothalamic insulin sensitivity independently of body weight loss. Further analyses indicated that this improvement in hypothalamic insulin responsiveness seems to trigger the reduction of liver fat content and enhancement of fasting blood glucose levels that were also achieved with the SGLT2 inhibitor intervention.

Improving and developing therapeutic methods for brain insulin resistance could potentially lead to novel preventative or therapeutic options for obesity and metabolic disorders on the one hand and perhaps also for related neurological and psychiatric conditions. Progress in this central and important promising area requires a multidisciplinary effort to translate research findings into clinical practice and improvement of therapeutic options.

Disturbed beta-cell function and a loss of beta-cell mass of the pancreatic islets play important pathogenetic roles in the development and progression of T2DM. Regarding the beta cell, a loss of insulin secretion and defects in the early phase of insulin secretion are important in the pathogenesis of T2DM. As diabetes progresses, a loss of beta-cell mass is also observed. In addition, a disturbance in glucagon secretion from the pancreatic alpha cells in the islet with hyperglucagonemia also contributes to the disorder of glucose metabolism. Although insulin resistance is relatively stable in the course of T2DM, the defects in beta-cell function and the loss of beta-cell mass are responsible for the progressive nature of the disease.

Insulin secretion is regulated through a complex interplay of glucose, hormones, incretins, amino acids, and neuronal signals, among other factors. Physiologic insulin secretion follows a pulsatile pattern; in healthy individuals, every 5 to 10 minutes insulin is secreted in a pulse. These short-lasting insulin pulses add up to an insulin secretion profile that is repeated every 80 to 150 minutes. The pulsatile secretion of insulin is significantly more effective in lowering plasma glucose concentrations than continuous secretion. Patients with T2DM already show defective pulsatile insulin secretion even before the clinical manifestation of their diabetes. This defect is characterized by a reduction in pulse frequency as well as lower amplitudes of the insulin pulses. These disturbances can be observed in glucose-dependent as well as glucose-independent fashion. Insulin secreted from the beta cells reaches the liver via the portal system in the described pulsatile manner. It is degraded by approximately 60% in the liver and not distributed in the same pulsatile fashion into the systemic circulation. As a consequence of the defective pulsatile insulin secretion, hepatic glucose production is elevated.

The insulin secretion response after glucose administration in healthy individuals has a typical biphasic pattern, with an immediate insulin secretion peak approximately 3 to 5 minutes after an intravenous glucose bolus and approximately 20 minutes after oral glucose administration, which lasts for around 10 minutes. This acute or first phase of insulin secretion is followed by a second phase with a slower and more sustained elevation of plasma insulin concentrations. The duration of the second phase of insulin secretion is dependent on the elevation of plasma glucose. The first phase of insulin secretion results from the liberation of insulin from the fast recruitable secretory vesicles that are close to the plasma membrane of the beta cell. The second phase of insulin secretion is recruited from a less readily recruitable reserve pool of insulin vesicles. This reserve pool comprises newly synthesized insulin vesicles and so-called storage vesicles and is located further away from the outside cell membrane of the beta cell. In T2DM as well as in the prediabetic state of impaired glucose tolerance ( Table 2.4 for classification), a significantly reduced or even absent first phase of insulin secretion is observed after a glucose stimulus. This defect in the first phase of insulin secretion especially has an impact on the postprandial glucose concentrations. Several mechanisms have been reported to cause the defect in the first phase of insulin secretion: chronic hyperglycemia, elevated free fatty acid plasma concentrations, and a reduction in beta-cell mass. Some studies indicate that the first phase of insulin secretion can be restored by normalizing glucose metabolism. In addition to the described changes in the first phase of insulin secretion, the second phase is also changed in T2DM. Because of persistent hyperglycemia, the second phase of insulin secretion is often prolonged and more pronounced compared with the second phase in healthy individuals. There is a reciprocal nonlinear hyperbolic relationship between insulin secretion and insulin resistance. Insulin secretion can therefore be evaluated only with respect to the amount of peripheral insulin resistance. In insulin-resistant patients with T2DM, elevated plasma insulin concentrations may be observed compared with healthy controls, but these may be inappropriately low in relation to the degree of insulin resistance or to the elevation of plasma glucose concentrations during chronic hyperglycemia and may not be sufficient to normalize the plasma glucose. The insulin secretion in T2DM is, therefore, insufficient and often inadequate to cover the actual demand for glucose normalization. In addition to the disturbed insulin secretion, a defect in glucagon secretion is found in T2DM. Usually an inappropriately high glucagon secretion is observed that mediates increased hepatic glucose production. This hyperglucagonemia is partially caused by the lack of the tonic inhibition of glucagon secretion by insulin and beta-cell activity.

Table 2.4

Classification and Detection of T2DM and Prediabetic States With a Standardized Oral Glucose Tolerance Test (OGTT, 75 g Glucose)

Data from American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36(suppl 1):S67.

Time Point of Glucose Measurement	Normoglycemia	Impaired Fasting Glucose (IFG)	Impaired Glucose Tolerance (IGT)	T2DM
Fasting (0 min)	<100 mg/dL<5.6 mmol/L	100–125 mg/dL 5.6–6.9 mmol/L		≥126 mg/dL ≥7.0 mmol/L
2-Hour postglucose	<140 mg/dL<7.8 mmol/L		140–199 mg/dL7.8–11.0 mmol/L	≥200 mg/dL ≥11.1 mmol/L

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