Insulin Resistance: Pathophysiology, Molecular Mechanisms, Genetic Insights

Genetic Factors

Type 2 diabetes is a polygenetic disease with heterogeneous phenotypes and different gene-environment interactions. A high genetic predisposition for type 2 diabetes has been shown in population studies (e.g., the Pima Indians) and in family studies. First-degree relatives of type 2 diabetic patients have a significantly higher risk for type 2 diabetes than persons without a hereditary or genetic risk. Twin studies revealed a much higher diabetes concordance in homozygous twins compared with heterozygous twins. Although the existence of these genetic factors has been known for a considerable time, it was difficult to identify specific type 2 diabetes genes until recently, when genome-wide analyses and the human genome project led to progress in this field. ^,

The greatest success in type 2 diabetes genetics arose from the development and use of high-density single-nucleotide polymorphism (SNP) arrays in large case-control cohorts. Most of the gene variants could be confirmed in many ethnicities, whereas others, probably because of divergent risk allele frequencies, may have higher relevance for certain ethnic groups.

Recent studies also provided evidence that SNPs associated with diabetes risk act in an additive manner to increase the diabetes risk. Although significantly contributing to the type 2 diabetes risk, these gene-gene interactions do not yet allow a substantially better disease prediction than clinical risk factors (e.g., body mass index [BMI], age, sex, family history of diabetes, fasting glucose level, blood pressure [BP], plasma triglycerides), ^, nor do they explain the heritability of type 2 diabetes. ^,

Beyond that, some of the diabetes-relevant genes are susceptible to persistent and partly inheritable epigenetic regulation—that is, DNA methylation and histone modifications—so gene-environment interactions are additional important factors that contribute to the complexity of type 2 diabetes genetics. ^,

Genome-wide association studies identified a series of type 2 diabetes risk loci that are for the most part associated with impaired pancreatic beta cell function. ^,

Although the underlying mechanisms by which common genetic variations within these loci affect beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, ^{, , , ,} proinsulin conversion, ^, and incretin secretion or incretin action. Table 2-1 summarizes the most important diabetes genes and their functional roles.

It has further become evident in recent studies that genetic variants in several diabetes risk genes may predict treatment outcome of glucose-lowering drugs. Response to thiazolidinedione therapy has been associated with peroxisome proliferator-activated receptor gamma (PPAR-γ) variations ^{, ,} in some but not all studies. ^{, ,} The genetic variants of the transcription factor 7-like 2 (TCF7L2, a transcription factor involved in the Wnt-signaling pathway and the most important genetic marker associated with type 2 diabetes) have been reported to influence disease severity and therapeutic control, ^, including lifestyle intervention, ^, and the response to sulfonylureas and possibly incretin-based therapies. ^,

Insulin Resistance

Type 2 diabetes, according to our present understanding, is a multifactorial disease characterized by insulin resistance of various degrees in different organs. Insulin resistance is in most patients further accompanied by central obesity, arterial hypertension, dyslipidemia, and other risk factors for cardiovascular disease. The joint presence of these risk factors with or without manifest type 2 diabetes is summarized by the term “metabolic syndrome.” The metabolic syndrome is a multifactorial metabolic disorder with a twofold to fourfold increased risk for cardiovascular disease (see Chapter 4 ).

The hormone insulin has a number of cellular effects and regulates not only glucose metabolism but also lipid and protein metabolism, as well as DNA synthesis and lipolysis ( Fig. 2-1 ). Any defect of these different cellular effects of insulin action can be seen as insulin resistance. In experimental medicine, the gold standard for measuring and quantifying insulin resistance is the euglycemic glucose clamp technique. This technique is too complicated and time- and personnel-consuming for everyday clinical practice; therefore a number of simpler tests for determining insulin resistance were developed. These are basically based on the assumption that a curvilinear relationship between insulin sensitivity and insulin secretion exists. In healthy patients it is possible to calculate the insulin sensitivity from the fasting plasma glucose concentration with a special formula for a hyperbolic relationship. However, this formula is not applicable for patients with a disturbance of glucose tolerance and diabetes because they show a disturbance in insulin secretion of varying degree in addition to being insulin resistant. The presently available simple tests to determine insulin resistance in patients with diabetes are based on the measurements of the fasting plasma glucose and insulin concentrations (homeostatic model assessment [HOMA]) or on the completion of an oral glucose tolerance test (OGTT) with measurements of plasma glucose and insulin concentrations (e.g., HOMA-IR [HOMA model for insulin resistance], insulin sensitivity index [ISI][0,120], Matsuda index, and the Stumvoll index). Whereas the glucose-clamp technique is a reliable method for the quantification of insulin resistance, the previously mentioned simple tests do not allow an exact quantification for a single individual. Therefore the determination of insulin resistance with these tests in an individual clinical setting is feasible only in special situations. Frequent sources of error include, for example, the incorrect performance of the OGT that will eventually lead to wrong conclusions in determining insulin resistance. In everyday clinical practice, insulin resistance can be more easily detected with symptoms such as central obesity or other factors of the metabolic syndrome. Therapeutic decisions are mainly based on these clinically visible characteristics and will lead to recommendations of lifestyle changes, body weight reduction, and pharmacologic interventions with oral glucose-lowering drugs such as metformin. It should be mentioned that insulin resistance may vary considerably depending on the patient’s level of physical fitness and activity, body weight, and overall health (e.g., acute and chronic infections, tumors). Insulin resistance is a common and important risk factor for development of type 2 diabetes and cardiovascular disease. However, insulin resistance does not always lead to diabetes even though obesity is the most important risk factor. Only patients with a disturbance in insulin secretion or other risk factors will develop diabetes.

Insulin Signaling and Cellular Mechanisms of Insulin Resistance

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 the 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/PKB; 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 effects as well as 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. ^,

Glucose Transport

The activation of the insulin signal transduction cascade leads to glucose transport into the cell. The insulin effect on the glucose transport system is mediated by a translocation of glucose transporters from the intracellular pools to the plasma membrane on the one hand, and by the activation of the transporters in the plasma membrane on the other. ^, There are at least 12 different glucose transporter proteins in different tissues. The insulin-dependent glucose transporter GLUT-4 is the most widely expressed glucose transporter and is responsible for the largest proportion of glucose transport in muscle and adipose tissue. In addition to that, glucose-dependent glucose transporters such as GLUT-1 in the brain, GLUT-2 in the liver, and sodium-dependent transporters such as GLUT-3 in the gastrointestinal tract are also known. Investigations in muscle cells and adipocytes have been performed to elucidate whether a defect in the insulin-dependent glucose transporter GLUT-4 is responsible for the development of insulin resistance in type 2 diabetes. The results from these experiments were relatively heterogeneous and revealed a reduced expression of GLUT-4 in some studies, a defect in the translocation and activation of GLUT-4 in others, as well as an unchanged GLUT-4 expression in type 2 diabetes. ^, It is interesting to note that in studies of patients with type 2 diabetes, a reduced translocation of glucose transport vesicles to the plasma membrane was found, whereas GLUT-4 expression was unchanged. ^, In studies investigating possible mutations of GLUT-4 in type 2 diabetes, no functionally relevant defects were found. In summary, in type 2 diabetes, a reduced capacity of insulin-dependent translocation of GLUT-4 vesicles to the plasma membrane is observed as a consequence of insulin resistance ( Fig. 2-3 ).

The Role of the Adipocyte and Obesity in Type 2 Diabetes

Obesity is one of the most important predisposing factors for the development of insulin resistance and type 2 diabetes. In the past two decades, we have learned to discriminate which fat compartments contribute substantially to this development. Patients with an increased visceral (mesenteric and omental) fat mass, as well as persons with increased liver fat mass, have an increased risk for insulin resistance and type 2 diabetes. This explains why measuring the waist circumference and the waist-to-hip ratio (WHR) predicts diabetes incidence more reliably than measuring the BMI. Increased subcutaneous fat depots in the hip, thigh, or gluteal region do not increase the risk for insulin resistance as long as there is no accompanying increase in visceral fat. An increased subcutaneous fat accumulation around the hip and thigh is often observed in women and is termed gynoid fat distribution, whereas central obesity is more common in men and is termed android fat distribution. The causes of predominantly subcutaneous or visceral fat storage are genetic and also dependent on sex hormone concentrations and additional endocrine influences. The understanding of genetic causes for central obesity is just being unraveled, but hormones such as cortisol and androgens have already been identified as being important for the development of central obesity. Visceral fat cells express a higher number of cortisol receptors and are therefore more sensitive to react to increased plasma cortisol concentrations. One hypothesis is that insulin resistance–induced obesity is caused by an overactivity of the neuroendocrine hormonal axes as well as by genetic predisposition. ^, One rare example of an extreme cause of central obesity and in this case a secondary cause of diabetes development is Cushing syndrome. Furthermore, hyperandrogenism in women predisposes them to central obesity. These women frequently have polycystic ovary syndrome (PCOS) and an increased risk for the development of type 2 diabetes during middle age and later.

Visceral adipose tissue is now seen as an endocrine organ with respect to special functions concerning activation and secretion of numerous hormones and cytokines that mediate insulin resistance and chronic inflammation ( Fig. 2-4 ). Not only omental adipose tissue, but also an increased fat content in hepatocytes, muscle cells, and even intrapancreatic fat play an important role in the development of insulin resistance and even in a decrease in insulin secretion (caused by intrapancreatic fat). ^{, , ,} Free fatty acids are important mediators in central obesity. Elevated free fatty acid concentrations in plasma are found in insulin resistance and in type 2 diabetes. These free fatty acids are most likely liberated by an increased lipolytic activity of the central and visceral fat depots and facilitate insulin resistance through an increased rate of fatty acid oxidation of the involved organs. Insulin and the sympathetic nervous system are important regulators of lipolysis. In central obesity, the increased sympathetic activity and a reduced insulin action mediate the rate of lipolysis, which results in an increase of free fatty acids. ^{, ,}

In addition to free fatty acids, numerous other factors play a role in the development of insulin resistance. In patients with insulin resistance, the insulin-sensitizing hormone adiponectin has gained much attention in the past few years, not only because circulating levels of this adipokine are markers of type 2 diabetes and an elevated risk for cardiovascular disease, but also because adiponectin is involved in the progression of these diseases. ^, Adiponectin is a protein that is synthesized and secreted by fat cells. In obese individuals, significantly reduced adiponectin plasma concentrations are observed compared with lean persons. Adiponectin is present in serum in relative high concentrations, and the serum concentrations show a negative correlation with BMI and a positive correlation with insulin resistance and even with the incidence of cardiovascular diseases. ^, The exogenous application of adiponectin under experimental conditions leads to an improvement in insulin sensitivity, a reduction in plasma glucose concentrations because of the activation of 5’AMP-kinase (AMP = adenosine mono-phosphate), and anti-inflammatory effects. These effects may also be responsible for the antidiabetic and antiarteriosclerotic properties of adiponectin. Adiponectin is therefore thought to be a protective protein that is not sufficiently synthesized and secreted by adipocytes in insulin-resistant patients and patients with type 2 diabetes. Other known adipokines (e.g., leptin, resistin, retinol-binding protein, glypican-4) are currently being evaluated to determine whether they might serve as important targets for the prevention and treatment of type 2 diabetes and cardiovascular disease. ^{, ,}

Adipokines presently are the best-known “organokines”, although several other classes of organokines have been identified (including myokines, lipokines, and hepatokines). Organokines are proteins exclusively or predominantly produced by and secreted from a specific tissue, but they are not simply markers of the function of their source tissue. All organokines have paracrine or endocrine actions or both ( Table 2-2 ). ^{, ,}

Tissue- and Organ-Specific Contribution to Insulin Resistance