Insulin resistance (IR) manifests itself from the clinical point of view in various ways, involving various organs and systems, including metabolic syndrome and TD2M, nonalcoholic fatty liver disease (NAFLD), the syndrome of polycystic ovary disease (PCOS), obstructive sleep apnea syndrome (OSAS), atherosclerosis, cardiovascular disease, some neurodegenerative diseases, and neoplastic diseases (Table 1). This polyvalence in determining rather different pathologies is attributable to the fact that insulin exerts physiological effects on lipid and protein metabolism and participates with its anabolic function in the division and proliferation of the cell without neglecting the fact that its receptors are distributed in various organs and tissues of the body ^[1][41]. Although IR is typically a male condition, the study of gender-specific differences has become important since the protective role of estrogens, which reduce the risk of this disorder among women, was discovered ^[2][3][4][42,43,44].

Metabolic syndrome (MS) is classically associated with obesity and insulin resistance contributing to a series of cardiometabolic alterations that result in increased cardiovascular risk due to the fact that visceral adipose tissue produces a greater amount of proinflammatory adipokines that induce a permanent inflammatory state in this tissue by reducing its sensitivity to insulin ^[5][6][7][45,46,47]. Plasma glucose and triglycerides are diverted to other organs (pancreas, liver, kidney, blood vessels, skeletal muscle, heart, and epicardial adipose tissue, EAT), altering their insulin sensitivity ^[5][6][7][45,46,47]. Proinflammatory cytokines produced by the adipocytes play a crucial role in the development of fatty liver disease. In fact, they reduce hepatocyte insulin sensitivity by favoring the deposition of lipids in the liver, fibrosis, and steatosis (nonalcoholic fatty liver disease, NAFLD), which in turn worsens the state of insulin resistance ^[8][48]. Metabolic syndrome (MS) is a critical factor related to NAFLD, to the extent that NAFLD has been considered by many to be the hepatic manifestation of this syndrome ^[9][49]. A higher prevalence is known of NAFLD in men, associated with visceral obesity, IR, and dyslipidemia ^[10][50]. Although NAFLD is a condition more frequent in males with IR and dyslipidemia, rwesearchers found that there is a gender-specific association between these variables and the female population ^{[11][12][13][14]}[51,52,53,54]. Women tend to have more subcutaneous adipose tissue, higher basal leptin levels, and elevated estrogen levels, while less thick adipose tissue in the visceral compartment. On the contrary, males have higher peripheral IR and a higher content of fatty acids at the level of the portal and enterohepatic circulation and this favors the development of metabolic syndrome, NAFLD, and cardiovascular consequences ^{[15][16][17][18][19]}[55,56,57,58,59]. A particular role in the evolution of MS has been recognized for androgens. Studies show that excess female androgens and male androgen deficiency have similar metabolic phenotypes, showing the complexity of androgens’ role in metabolism ^{[20][21][22][23]}[60,61,62,63]. In NAFLD, females show greater IR, hypertriglyceridemia, and visceral adiposity, while in males it is conceivable that there are factors that go beyond IR. In particular, rwesearchers  focused on the lipid metabolism in the lipolytic capacity of both sexes. These studies demonstrate that females have more lipolysis while males show prolonged de novo lipogenesis, which may be associated with the damage to lipid storage typical of NAFLD ^[24][64]. Beta-oxidation during fasting in men is also less efficient than in females ^[24][64]. It would seem that such metabolic disturbances occur until attenuated with the exogenous administration of androgens and estrogens ^[25][26][27][65,66,67]. Srinivas et al. ^[25][65] investigated, from a gender perspective, the association of NAFLD with the risk factors of the components of MS and found that the components related to this disorder in women were hyperglycemia and hypertriglyceridemia, while in men only the BMI was related. In another study, the risk component among males was the indirect measure of adiposity (WC), while in females it was low HDL levels and hypertriglyceridemia ^[26][66]. From a practical point of view, the presence of MS seen from a gender perspective cannot be diagnosed only with the measurement of fasting blood sugar but must be correlated with a more in-depth metabolic study ^[27][67]. The prevalence of glucose metabolism disorder differs between genders, giving rise to different clinical implications: men more often develop abnormal fasting glucose levels, while women more often show elevated glucose levels after meals. Fasting glucose elevation is characterized by increased hepatic glucose production and decreased early insulin secretion, whereas postprandial hyperglycemia is mainly due to peripheral IR ^[28][68]. Postprandial hyperglycemia carries a higher risk of mortality since it is more strictly a cause of increased cardiovascular risk, therefore, if initial MS is suspected, oral glucose tolerance tests should be performed to screen, especially in women ^[29][30][69,70]. WAs we have already mentioned, women enjoy particular protection against MS from estrogen and this lasts until menopause unless there is a hypoestrogenic state or a prolonged anovulatory condition ^[29][69]. Together with estrogen, vitamin D can also directly stimulate the expression of the insulin receptor, thus improving the transport of glucose into human cells ^[30][70]. A significant interaction between sex and vitamin D is evidenced by the fact that low levels of 25(OH) of vitamin D3 are associated with T2DM in women but not in men ^[31][71]. We have also seen how there is an interchange between vitamin D and estrogen; on the one hand, vitamin D increases the bioavailability of estrogens and, on the other, the latter is able to increase the efficiency of absorption, transport systems, and affinity with its receptor ^[32][72]. The important role of the composition of the intestinal microbiota has also been established both in promoting the production of intestinal estrogens with a systemic function and, with them, greater absorption of vitamin D ^[33][73]. The effect of estrogen deficiency in menopausal women is associated with an increased risk of T2DM and manifests itself through three different mechanisms including impaired insulin secretion by pancreatic beta cells, reduced sensitivity to insulin by the target organs and tissues, and increased sensitivity to glucose by the main organs involved in diabetes-related pathology ^[34][35][74,75].

We observed that insulin resistance is related to an alteration of the lipid characterized by hypertriglyceridemia, increased concentration of very low-density lipoprotein (VLDL), decreased concentration of high-density lipoprotein (HDL), and formation of low-density lipoprotein (LDL) ^[36][37][38][76,77,78]. Insulin regulates lipid metabolism through the PI3K pathway, promoting the degradation of apoprotein B and hindering the production of VLDL by the liver. In the presence of insulin resistance, on the contrary, there is both increased production and reduced clearance of VLDL ^[39][79]. The hepatic protein CEPT instead intervenes in promoting the transfer of triglycerides from VLDL to LDL and HDL, increasing the overall triglyceride content of these particles ^[40][41][80,81]. Triglyceride-rich LDL and HDL become the substrate of liver lipase, which promotes the removal of triglycerides from these lipoproteins, thereby transforming LDL into sdLDL and reducing apoprotein A (apo-A) concentration, increasing the catabolism of HDL ^[40][41][80,81]. This transfer process of fatty acids is strongly atherogenic since sdLDL fills the vascular wall more diffusely than LDL, has a longer half-life, is more oxidizable than LDL macroparticles, and has a lower affinity for the LDL receptor ^[1][41]. It is therefore clear that IR intervenes synergistically with vascular blood flow disturbances in damaging endothelial function and altering the existing balance of the endothelial barrier linked to the production of nitric oxide (NO) ^[42][43][44][82,83,84]. This damaging activity of the endothelial barrier is also linked to the hyperactivation of the renin–angiotensin–aldosterone system promoted by hyperglycemia since the MAP kinase (MAPK) system is a signal transduction pathway common to insulin and aldosterone and its activation induces proliferation and contractility of vascular myocytes and proinflammatory activity of endothelial cells ^[45][46][47][85,86,87]. This mechanism would reduce the production of NO, the most powerful vasodilator in the body and the main indicator of endothelial well-being ^{[41][42][43][44][48]}[81,82,83,84,88]. NO plays a crucial role in vessel protection, limiting platelet aggregation and inhibiting the recruitment and adhesion of leukocytes on the damaged vascular surface. In insulin-resistant patients, NO synthesis is compromised and is therefore associated with a greater cardiovascular risk. As IR acts in contributing to endothelial damage, it also contributes to inducing a proinflammatory state and endothelial dysfunction at the level of renal microcirculation and vascular damage, favoring the deposition of matrix by the mesangial cells, inducing glomerulosclerosis ^[49][50][89,90]. BAs we have already said, before interacting with cellular receptors, LDL can undergo modifications mainly linked to the activity of the cholesterol ester transfer protein (CETP), which mediates the transfer of triglycerides and esterified cholesterol between lipoproteins ^[50][51][90,91]. In particular, triglycerides from VLDL are transferred to LDL and HDL in exchange for cholesterol esters. These interchanges decrease the cholesterol ester content of LDL and increase the triglyceride content, making these particles more susceptible to lipolytic action on the part of hepatic lipase (HL). The end result is the formation of smaller, denser LDLs that are thought to be more atherogenic than normal LDLs. Significant gene–gender interactions have also been reported for the gene that codes for the cholesterol ester transfer protein in its variant TaqIB (CETP) ^[50][51][90,91]. Proatherogenic CETP activity depends on various factors, primarily genetic polymorphisms, but also depends on age, physical activity, alcohol consumption, obesity, and lipid balance, in particular, the concentration of triglycerides, LDL cholesterol, and HDL cholesterol. Villard et al. ^[52][92] showed that high-risk cardiovascular patients have increased CETP activity in comparison to lower-risk patients. In particular, the isoform of CEPT derived from the heterozygous B2 allele was associated with larger particle size for HDL and LDL in men, while in women there was only an increase in HDL particle size. However, the protective association of this genetic variant with cardiovascular risk was present in men but not in women ^[52][92]. A polymorphism (I405V) of the CETP gene leading to lower serum C-LDL levels has also been linked to exceptional longevity ^[53][93]. The effect of this polymorphism was low for diabetic women who showed significant interactions with the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and concentrations of triglycerides ^[54][55][94,95]. Endothelial damage depends largely on estrogen’s influence. In females, estrogen promotes the release of NO and, on the other hand, prevents the production of oxygen free radicals and the chronic inflammatory state deriving from the metabolism of uric acid. Moreover, estrogens play a major role in regulating serum levels of uric acid, resulting in less accumulation in the walls of blood vessels and therefore limiting endothelial damage compared to men. Estrogen activity is the major determinant of gender difference when rwesearchers associate atherogenesis and endothelial damage and IR, contributing to the damage of the microvessel environment ^[54][55][94,95].

Insulin also has a role in some neuronal functions and is particularly involved in the processes of maintaining the integrity of neurons and increasing the production and sensitivity of some neurotransmitters ^[56][57][96,97]. In general, therefore, it is capable of positively affecting nerve transmission and synapse function. Recently, it has been hypothesized that IR can interfere with the production of some neurotransmitters such as dopamine and is also implicated in a greater deposition of amyloid substances which, associated with a chronic inflammatory state, contribute to the pathogenesis of both Parkinson’s disease and Alzheimer’s disease ^[58][59][60][98,99,100].

In women, the presence of estrogenic activity slows down the progression of Parkinson’s disease, as the hormone gives these subjects high levels of physiological dopamine at the nigro-striatal level ^[61][101]. This suggests that estrogens may have a role in preventing the disease itself due to their anti-inflammatory activity, which counteracts the chronic inflammatory state induced by IR ^[62][63][102,103]. Overall, therefore, women show a mild course in terms of symptom progression although the clinical severity of symptoms is greater than in their male counterparts ^[64][104]. Furthermore, the role of IR in sleep disorders has been hypothesized ^[65][66][105,106]. The discontinuity of sleep has been compared independently from obesity to the syndrome of sleep apnea (OSAS) and as a consequence of the onset of insulin resistance ^[65][66][67][105,106,107]. Furthermore, it has been shown that the severity of apneas inversely correlates with insulin sensitivity ^[68][69][70][108,109,110] while nocturnal ventilation enhanced by c-PAP improves insulin sensitivity ^[71][111]. At the basis of the association between insulin resistance, sleep disturbances, and OSAS is hypoxia which occurs during the apnea phases, increases by the discharge of the sympathetic nervous system, simultaneously inhibits insulin secretion, and reduces the availability of glucose to the arrangement of neurons ^[71][111]. Finally, it is hypothesized that sleep disturbances could increase cortisol secretion, and this negatively affects peripheral insulin sensitivity by further amplifying IR ^[72][112]. Conflicting data regarding gender exist for the relationship between headaches and IR. In particular, migraine is usually more frequent in women, and in particular, migraine with aura also has an association with metabolic syndrome and cardiovascular risk ^[73][74][75][113,114,115]. In two cohort studies, no significant association was observed between migraine and diabetes ^[74][75][114,115]. Studies conducted on animal models have provided a possible link between IR and migraine, considering that several vascular mediators, interleukins or cytokines (TNF-α, C-reactive protein, IL-1β, IL-6, and IL-8), have an important role in both IR and migraine ^[76][77][116,117]. Furthermore, numerous neuropeptides such as substance P, neuropeptide Y, and calcitonin gene related-peptide (CGRP) and some adipokines such as leptin and adiponectin are altered in both conditions ^[78][79][118,119]. On the other hand, population-based and clinical studies have reported that the prevalence of migraine in diabetic patients, particularly in women, is lower than ^[80][81][120,121], similar to ^[82][122], or higher than ^[83][123] that in nondiabetic patients. Actually, the presence of diabetes-related vascular changes may potentially increase the risk of migraines or affect the severity of migraines in diabetic women. The use of certain medications for diabetes management may have an impact on migraines. For instance, some medications like metformin and GLP-1 receptor agonists have been reported to potentially reduce the frequency and severity of migraines ^[84][85][124,125]. In migraine-affected women, increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance due to specific alterations in energy intake and sympathetic–adrenal system activation ^{[83][84][85][86]}[123,124,125,126].

Recent evidence underlines the association between IR and neoplastic risk, particularly in breast, colorectal, pancreas, and liver cancer ^{[87][88][89][90][91][92]}[127,128,129,130,131,132]. Several pathways have been proposed through which IR may have pro-oncogenic, mitogenic, and antiapoptotic effects ^[93][94][133,134]. In fertile women, insulin and IGF-1 inhibit the hepatic synthesis of sex hormone-binding globulin (SHBG), increasing the bioavailability of estrogen, which may account for the increased risk of breast cancer ^[95][96][135,136]. The proinflammatory state and the consequent increased production of free oxygen radicals (ROS) represent a favorable environment for the development and progression of neoplasms inducing mutagenesis and carcinogenesis ^[97][137].

Polycystic ovary syndrome (PCOS) unites hyperandrogenism and IR, occurring in patients who are not exclusively obese but who nonetheless have peripheral IR, albeit variable. PCOS is a condition affecting young patients characterized by marked hyperandrogenism, ovulatory dysfunction, morphological alterations of the ovary, and IR ^[98][138]. From the data available in the literature, it has been observed that these conditions are associated with a moderate risk of venous thromboembolism, especially in women with higher estrogen levels ^{[99][100][101]}[139,140,141]. The resulting compensatory hyperinsulinemia is caused largely by phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), which reduces the efficiency of insulin signaling. At the ovarian level, excess insulin stimulates the expression of luteinizing hormone (LH) receptors, making these cells more active and thus promoting the production of androgenic-type sex steroids, leading to anovulation ^[102][103][142,143]. Conversely, all treatments that reduce IR improve ovulation and hyperandrogenism ^[103][143].