Insulin Resistance and Metabolic Syndrome

　　There are many causes of insulin resistance, including genetic factors or primary insulin resistance such as abnormal insulin structure, the presence of insulin antibodies, gene mutations in insulin receptors or post-insulin receptor genes (such as mutations in the Glut4 gene, glucose kinase gene, and insulin receptor substrate gene, etc.). The vast majority (more than 90%) of primary insulin resistance is caused by polygene mutations and often results from the synergistic effect of polygene mutations leading to insulin resistance. In addition to the above genetic factors, many environmental factors are also involved or cause insulin resistance, known as secondary insulin resistance, such as obesity (the main cause of insulin resistance, especially central obesity, which is mainly related to insufficient physical activity and excessive dietary energy intake, with 80% of type 2 diabetes patients diagnosed with obesity), long-term hyperglycemia, hyperlipidemia, certain drugs (such as glucocorticoids), certain trace element deficiencies (such as chromium and vanadium deficiencies), pregnancy, and an increase in insulin antagonistic hormones in the body.

　　An increase in tumor necrosis factor alpha (TNF-α) and enhanced TNF-α activity can promote fat decomposition, leading to an increase in plasma FFA levels. It also inhibits the activity of tyrosine kinase in insulin receptors of muscle tissue, inhibits the phosphorylation of IRS-1 and the expression of Glut4, resulting in insulin resistance and hyperinsulinemia. In recent years, it has also been found that adipocytes can secrete resistin, which can reduce glucose uptake after insulin stimulation and increase tissue glucose uptake after resistin neutralization. Other factors such as leptin resistance and decreased levels or activity of adiponectin are also related to insulin resistance. An increase in triglyceride (TG) content in skeletal muscle cells is also considered one of the causes of insulin resistance, and excessive accumulation of TG in B cells can lead to a decrease in their function.

　　The main complications caused by insulin resistance and metabolic syndrome include hyperglycemia, hyperinsulinemia, dyslipidemia (increased blood free fatty acids, cholesterol, triglycerides, and low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol), overweight or obesity (body mass index over 25), hypertension, and so on.

　　The traditional components of metabolic syndrome mainly include central obesity, diabetes or impaired glucose tolerance, hypertension, dyslipidemia, and cardiovascular disease. However, with the in-depth study of this syndrome, its components have been expanding. Currently, in addition to the above components, it also includes polycystic ovary syndrome, hyperinsulinemia or hyperinsulininemia, hyperfibrinogenemia, and increased plasminogen activator inhibitor-1 (PAI-1), hyperuricemia, endothelial cell dysfunction-microalbuminuria and inflammation (increased blood CRP, IL-6, and matrix metalloproteinase-9, etc.), and constipation, lumbar and knee weakness, dizziness, tinnitus, palpitations, fatigue, overweight or obesity, and body mass index ≥ 25 are common in patients.

　　Enhance exercise, control diet, and reduce weight: Emphasize a reasonable diet plan for overweight individuals, and carry out long-term, scientific, and regular exercise to reduce weight and maintain weight within an ideal range, which is the basis for reducing insulin resistance and treating metabolic syndrome. In addition, exercise itself can also enhance the body's sensitivity to insulin, especially in skeletal muscles, which is helpful for correcting various metabolic disorders and is beneficial for reducing blood sugar and blood pressure, as well as improving lipid metabolism.

　　Insulin sensitivity exists with physiological variation, and the time and degree of insulin resistance in different tissues of the same individual are different. The physiological neuroendocrine rhythm of androgens, such as corticosteroids, prolactin, sex hormones, sex hormone-binding globulin, and androgens, is related to the daily variation of insulin sensitivity. The action of insulin decreases by 27% at night, peripheral insulin sensitivity in the elderly decreases, and in healthy individuals, insulin sensitivity does not change seasonally. The variation range within a certain period is very small, and the variation between individuals and within individuals themselves is also small. Compared with individuals of the same weight without type 2 diabetes, individuals with type 2 diabetes have higher insulin resistance. The methods and indicators for evaluating insulin resistance are all related to glucose metabolism.

　　Firstly, estimate the insulin resistance status by using fasting blood glucose and plasma insulin.

　　The following methods cannot be used to evaluate the individual's insulin resistance status, but can be used for population studies.

　　1. FINS/FPG, INSlh/PGlh, and the area under the insulin curve, etc.

　　2. The steady-state model method: Homa's insulin resistance index (Homa-IR) = FINS×FPG/22.5.

　　3. 1/(Fins×FPG), compared with the classic clamp method, it has a good correlation and can reflect the sensitivity of individuals to insulin-mediated glucose metabolism, which is a more practical and effective indicator in population studies.

　　Secondly, through the experiment of detecting the body's sensitivity to insulin by adding external load

　　1. Clamp technique (including hyperglycemic clamp technique, normal glucose-high insulin clamp technique), the normal glucose-high insulin clamp technique is currently the gold standard for detecting insulin sensitivity and can be used to judge the insulin resistance status of individuals.

　　2. The minimum model method: it is cumbersome and time-consuming, and its application and promotion are limited, but it can be used to judge the insulin resistance status of individuals.

　　3. Clinically, six parameters can be used to simply estimate the presence of insulin resistance in diabetic patients: hypertension, waist-to-hip ratio, triglyceride and HDL cholesterol levels, family history of type 2 diabetes, and blood glucose control.

      The following are the recommendations and taboos for the diet of patients with insulin resistance and metabolic syndrome:

　　1. When dieting for insulin resistance and metabolic syndrome, pay attention to: consume an adequate amount of vegetables and fruits. Eating an adequate amount of vegetables (400-500g per day, preferably more than 5 types) and fruits is beneficial for the prevention and treatment of cardiovascular diseases such as hypertension, but the vegetables and fruits chosen should not cause an increase in blood sugar. More low-glycemic index vegetables and fruits should be chosen. Vegetables such as celery, winter melon, zucchini, bitter melon, spinach, rapeseed, and mushrooms, and fruits such as grapefruit, cherry, apple, starfruit, orange, and snow lotus can be chosen.

　　2. Control the intake of sodium. Daily intake of less than 1.7g of sodium can significantly reduce the risk of hypertension, which is approximately equivalent to the amount of 5g of salt. Reduce the consumption of high-sodium foods, including pickled vegetables. Products such as pickled vegetables, preserved vegetables, salted fish, salted duck eggs, and other preserved foods. Choosing low-sodium salt that partially replaces potassium salt can help in the prevention and control of hypertension. It is worth mentioning that for patients with combined kidney dysfunction, medication should be taken under the guidance of a doctor.

　　3. Pay attention to dietary balance. Avoid spicy and stimulating foods.

　　TZD mainly includes rosiglitazone and pioglitazone, which have been widely used in clinical practice. Rosiglitazone or pioglitazone is one of the most significant classes of drugs currently available to improve insulin resistance, and it also has a good protective effect on beta cells. It not only can improve glucose metabolism effectively but also has beneficial effects on many risk factors of cardiovascular diseases such as hypertension, dyslipidemia, elevated fibrinogen, and inflammatory factors.

　　1. TZD and Insulin Resistance

　　Currently, there is sufficient evidence from both laboratory and clinical studies to confirm that thiazolidinedione drugs are potent insulin sensitizers. Compared with placebo, TZDs such as rosiglitazone can reduce insulin resistance in type 2 diabetes by 33% (as evaluated by the HOMA-IR index), increase muscle glucose uptake by 38% (as evaluated by the hyperinsulinemic-euglycemic clamp test), and increase systemic glucose uptake by 44%. In combination therapy, metformin and sulfonylurea drugs combined with rosiglitazone can reduce insulin resistance by 21% and 32%, respectively, and their duration can last for at least 24 months or longer.

　　2. TZD and Abnormal Glucose Metabolism

　　TED drugs improve insulin resistance through direct or indirect mechanisms while protecting B cells, and have a good effect on improving glucose metabolism. Preliminary studies with small samples show that TZDs such as troglitazone, rosiglitazone, and pioglitazone can significantly reduce the risk of IGT and the risk of progressing to diabetes by 56% to 88.9%. A large-scale, multicenter, prospective evaluation of the prevention of diabetes by rosiglitazone is currently underway. At present, a large number of medium to short-term clinical studies have confirmed that TEDs such as rosiglitazone can significantly improve blood glucose control in patients with type 2 diabetes when used as monotherapy or in combination with sulfonylurea drugs or biguanide drugs or insulin. The UKPDS report indicates that currently, traditional antidiabetic drugs (such as sulfonylurea drugs, biguanide drugs, or insulin, etc.) cannot prevent the deterioration of diabetes and the long-term stable control of blood glucose as the course of diabetes extends. Most patients see an increase in HbA1c gradually after 2 to 3 years as the course of the disease extends. The prospective, multicenter ADOPT (a diabetes outcome progression trial) is currently underway to compare and evaluate the long-term single drug rosiglitazone, metformin, and glibenclamide (yijiangtang) for the control of blood glucose in patients with type 2 diabetes and the endpoint trial.

　　3. TZD and Hypertension

　　The incidence of hypertension in patients with type 2 diabetes is 55% to 60%, and those with proteinuria (microalbuminuria or macroalbuminuria) can reach 80% to 90%. Hypertension not only accelerates the occurrence of macrovascular complications in diabetes but also promotes the occurrence and development of microvascular complications. Some scholars prospectively compared the rosiglitazone treatment group and the glibenclamide (yijiangtang) treatment group in patients with type 2 diabetes, and after 52 weeks, the diastolic and systolic blood pressures in the rosiglitazone group (8mg/d) were significantly reduced (compared with baseline), while there was no significant change in diastolic blood pressure in the glibenclamide (yijiangtang) treatment group, and systolic blood pressure increased; a study of 24 patients with non-diabetic primary hypertension (all with insulin resistance) showed that the application of rosiglitazone (8mg/d) can significantly increase the insulin sensitivity of non-diabetic hypertensive patients, reduce systolic and diastolic blood pressures, and can also make other cardiovascular risk factors transform to the benign side. For this reason, some scholars believe that in the future, insulin sensitizers may occupy a certain position in the treatment of patients with primary hypertension accompanied by insulin resistance (about 50% may have insulin resistance).

　　4. TZD and Lipid Metabolism Disorders

　　Some large-scale, multi-center clinical trials have shown that rosiglitazone (2-8mg/d) can increase HDL-C by 10%-14%, even up to 20%, and reduce LDL levels by 9%-19% (especially small and dense LDL, which is the main component causing atherosclerosis). Most studies report that rosiglitazone has no significant effect on fasting triglycerides.

　　5. TZD and Plasma PAI-1 Levels

　　Within the blood vessels, plasminogen is converted into plasmin under the action of plasminogen activators, which degrades the fibrin-platelet aggregates within the blood vessels. PAI-1 is the main physiological inhibitor of tissue-type plasminogen activator in the body, maintaining a relative balance between the coagulation and fibrinolysis systems. The risk of atherosclerosis is significantly increased in individuals with elevated PAI-1 levels. Diabetic patients, especially those with vascular lesions, have significantly elevated blood PAI-1 levels. Some studies report that compared with placebo or biguanide drugs, rosiglitazone alone or in combination with other hypoglycemic drugs can significantly reduce plasma PAI-1 levels in patients with type 2 diabetes.

　　6. TZD and Anti-inflammatory Action

　　Recent studies have shown that inflammatory responses also play an important role in the occurrence and development of vascular lesions, especially in large vascular lesions. When vascular lesions occur, systemic markers of inflammation such as C-reactive protein (-RP) and interleukin-6 (IL-6) levels increase. Some prospective clinical studies report that CRP can not only be used as a systemic marker for predicting cardiovascular diseases but also directly or indirectly participates in vascular injury, and is one of the risk factors for cardiovascular diseases. The level of IL-6 is related to the consequences of vascular lesions, and IL-6 is an important regulatory factor of CRP, and it can also induce insulin resistance and dyslipidemia. Haffner et al. showed that compared with placebo, rosiglitazone can significantly reduce the levels of inflammatory response markers such as CRP and IL-6 by improving insulin resistance. Matrix metalloproteinase-9 (MMP-9) can degrade the matrix, making it easier for monocytes to infiltrate the vascular wall, making the fibrous cap of atherosclerotic plaques more unstable or more susceptible to damage, or making plaques more prone to rupture, increasing the risk of cardiovascular events. Literature reports show that the serum MMP-9 levels of patients with type 2 diabetes and coronary heart disease are significantly increased, while rosiglitazone can significantly reduce the serum MMP-9 levels in the treatment of type 2 diabetes, suggesting that the drug may have a certain stabilizing effect on the fibrous cap of atherosclerotic plaques, but there is no conclusive evidence to prove that the drug can prevent the rupture of atherosclerotic plaques, and further observation is needed.

　　7. ZD and Microalbuminuria and Metabolic Syndrome

　　They often coexist. Increased urinary albumin excretion in diabetic patients not only reflects diabetic kidney damage but also reflects widespread vascular lesions, and is closely related to the increased risk of cardiovascular lesions and mortality. Effective control of microalbuminuria can significantly reduce the incidence and mortality of cardiovascular diseases. Bakris et al. reported that during a 52-week study period, compared with sulfonylurea drugs, rosiglitazone, under similar blood glucose control, significantly reduced microalbuminuria, with a reduction in urinary microalbumin excretion of 54% compared to the baseline. The mechanism of reducing urinary albumin excretion is unclear, and may be related to its improvement of insulin resistance, reduction of blood pressure, or improvement of lipid profile, or may act directly through PPARs.

　　8. TZD and Polycystic Ovary Syndrome

　　Insulin resistance is one of the important pathophysiological bases of polycystic ovary syndrome. Some small sample clinical studies have reported that TZDs such as rosiglitazone or pioglitazone can induce a decrease in hyperandrogenism in women with polycystic ovary syndrome of reproductive age, restore ovulation, restore menstruation, and can lead to pregnancy.

　　Ideal Blood Glucose Control: Hyperglycemia caused by insulin resistance leads to increased blood glucose levels. Long-term hyperglycemia further aggravates the insulin resistance state of tissues such as muscles, fats, and liver tissues through its 'glucotoxicity'. Therefore, in clinical practice, maintaining good control of blood glucose levels in type 2 diabetic patients through reasonable hypoglycemic treatment is helpful to reduce insulin resistance. In recent years, many clinical studies have reported that for type 2 diabetic patients with significantly elevated blood glucose levels or secondary failure of oral antidiabetic drugs after new diagnosis, insulin reinforcement therapy can stabilize blood glucose control in the short term, significantly improve insulin resistance, and thus help with their future blood glucose control.