People with diabetes know this. Diabetes itself is not terrible, but once complications arise the problem is serious. Diabetic complications are divided into two categories: acute complications and chronic complications. Due to the invention and application of insulin and antibiotics, and the popularity of glucose monitoring, the mortality rate of acute complications of diabetes (ketoacidosis, hyperglycemic hyperosmolar syndrome, lactic acidosis, hypoglycemic coma, and various serious infections) has decreased significantly. The main cause of death and disability in diabetic patients is now chronic complications of diabetes mellitus. According to statistics, chronic complications account for 76% of the causes of death in diabetic patients. Therefore, early prevention of chronic complications of diabetes is of great importance to improve the condition and prognosis of diabetes and reduce the death and disability rate of diabetes. Clinical practice and the results of some large clinical treatment studies such as DCCT (USA) and UKPDS (UK) show that strict glycemic control can reduce the occurrence of diabetic chronic complications, but cannot completely avoid them. The reason for this is that diabetes is a complex syndrome and the causative factor in the development of the disease is not only hyperglycemia. Therefore, to prevent or delay the occurrence of diabetic complications, an integrated and intensive treatment program targeting multiple causative factors is required.
I. Common chronic complications of diabetes mellitus
Chronic complications of diabetes mainly refer to the specific damage and lesions to large blood vessels, microvessels and nerves after 5-10 years of diabetes, which endanger human health and even lead to disability and death. The common chronic complications of diabetes are mainly the following.
1, cardiovascular lesions The basic pathological changes are atherosclerosis and microangiopathy. Vascular lesions are very widespread and can involve both large and small vessels, arteries, capillaries and veins. The incidence of atherosclerosis is much higher than that of normal people, and it occurs earlier, progresses faster and is more severe. The incidence of atherosclerosis is much higher than that of normal people, and it occurs earlier, progresses faster and is more serious. On this basis, it is often complicated by many organ lesions, including heart, brain, kidney, fundus and lower limb vessels, etc. 1/3 of patients with acute myocardial infarction are related to diabetic vascular lesions, and 1/4 of patients with stroke are related to diabetes, so diabetes is extremely harmful to cardiovascular lesions.
Diabetic nephropathy is mainly caused by microangiopathy, and the pathological change is glomerulosclerosis, which can be divided into three types: nodular, diffuse and exudative. Diabetic nephropathy occurs in 25-44% of diabetic patients and can be clinically divided into five phases: glomerular hyperfiltration phase, silent phase, microproteinuria phase, massive proteinuria phase and uremic phase. The first three stages can be reversed if they are detected and treated in time. About half of the patients with diabetes combined with diabetic nephropathy die from renal failure.
3, neuropathy Diabetic neuropathy is the appearance of symptoms, signs or / and abnormal objective indicators (such as nerve conduction velocity slowing, etc.) of peripheral nerve involvement in patients with diabetes. If there are no signs and symptoms then it is subclinical neuropathy. Diffuse neuropathy, such as distal symmetric polyneuropathy and vegetative neuropathy, is more common and often develops in a chronic progressive fashion. When neuropathy occurs, the patient has early hyperalgesia, which may present as symmetric lower extremity pain, burning pain, and sometimes severe pain. When the vegetative nerves are involved, patients develop postural hypotension, intractable diarrhea or constipation, recurrent vomiting after meals in those with gastroparesis, urinary retention and incontinence, and impotence. Neuropathy brings great pain to diabetic patients, and patients may even have suicidal thoughts that are difficult to survive.
4, diabetic eye complications Diabetic retinopathy is the primary cause of blindness. Diabetic patients often complain of blurred vision, in addition to diabetic retinopathy, most diabetic patients have varying degrees of crystal changes, namely diabetic cataract. Cataracts affecting vision account for 47%, of which 16.5% have severe visual impairment or even blindness. Diabetic cataract is a snowflake-like clouding under the crystal capsule, and it occurs early and progresses quickly.
5, diabetic foot lesions diabetic foot is mainly the result of vascular and or neuropathy. Clinically, the diabetic foot is divided into five stages, manifesting as local sensory abnormalities, blistering, skin darkening, ulceration, until most of the foot necrosis. The vast majority of amputees due to necrosis of the lower limb are related to diabetic foot lesions.
Second, the comprehensive prevention and control measures of chronic complications of diabetes mellitus
The occurrence and severity of chronic complications of diabetes mellitus are closely related to the degree of elevated blood glucose and the duration of the disease, but there are some patients who still have chronic complications even if their blood glucose is well controlled. Can these chronic complications be prevented or not, and what preventive measures can be taken to reduce or delay their occurrence? According to the research results in recent decades, the main measures that can be taken to prevent and treat chronic complications of diabetes include the following 10 aspects.
1. Monitoring of risk factors and early warning indicators for complications The key to preventing and treating diabetes complications lies in the control of risk factors for complications, as well as the early detection and timely treatment of complications. Therefore, the risk factors and early warning indicators of complications that lead to diabetes complications must be tested regularly in order to get rid of these causative factors immediately, detect them early and strive to reverse the complications. These monitoring indicators include: (1) physical examination and physical examination indicators blood pressure, weight and abdominal circumference, dorsalis pedis artery pulsation and ankle artery/brachial artery systolic pressure ratio, pain, temperature and palpation at the extremity ends, fundus examination, electrocardiography and large vessel ultrasound, electromyography, etc.; (2) hematological indicators blood glucose, glycosylated hemoglobin, lipids, uric acid, cysteine, C-reactive protein, prothrombin time and activity of Fibrinogen, platelet aggregation function; (3) urine indicators urine microalbumin or microtransferrin excretion rate.
(2) Correction of poor lifestyle Regular lifestyle, avoiding excessive mental stress, weight control, exercise, low-salt and low-fat diet, smoking cessation and limited alcohol consumption can prevent hypertension and reduce cardiovascular diseases. Studies have confirmed that a lower calorie and fat, higher fiber diet such as wild bitter jojoba, which contains 2.6 times more crude fiber than rice, can slow down the absorption of blood sugar and reduce the stimulation of insulin secretion, plus regular and regular exercise can help control weight, enhance insulin sensitivity and reduce hyperinsulinemia in type 2 diabetic patients.
3. Eliminate insulin resistance Insulin resistance, which means that muscle, liver and adipose tissue cells are insensitive to insulin action, is considered to be the common “soil” for the development of type 2 diabetes, hypertension, hyperlipidemia, obesity and atherosclerosis. Insulin resistance causes disturbance of blood glucose and lipid metabolism, which leads to compensatory increase of plasma insulin level, thus promoting thrombosis, lipid deposition in arterial wall and proliferation of arterial smooth muscle, water and sodium retention and increase of blood pressure, and accelerating the process of atherosclerosis. The main clinical drugs used to increase insulin sensitivity are: (1) insulin sensitizers It is a new class of drugs that increase insulin sensitivity most strongly. Clinical application shows that these drugs can not only lower blood sugar, but also effectively prevent and treat cardiovascular and renal complications by correcting lipid profile and fibrinolysis abnormalities, restoring vascular endothelial function and anti-inflammatory effects. Domestic clinical use includes rosiglitazone tablets and pioglitazone tablets. (2) Biguanide drugs, including metformin hydrochloride and hypoglycemia. It can reduce insulin resistance, lower plasma insulin levels and LDL cholesterol, thus preventing diabetic macroangiopathy. Therefore, for patients with type 2 diabetes, as long as the liver and kidney function is normal and the weight is at or above the standard weight, metformin drugs can be preferred, and only when metformin hydrochloride is taken to the effective therapeutic dose (1500mg/d), blood sugar is still not controlled in a good state, other hypoglycemic drugs are added. (3) Chromium supplementation Trivalent chromium forms a cationic complex with nicotinic acid and various amino acids, called glucose tolerance factor (GTF). GTF does not stimulate insulin secretion and is involved in membrane insulin transport and enhancing the initiation response of insulin and insulin receptors, alleviating insulin resistance and lowering insulin levels, while lowering blood glucose. (4) a-glucosidase inhibitors The ones currently entering clinical application are acarbose and voglibose, which competitively inhibit α-amylase and sucrase at the epithelial brush border of the small intestine, slowing down the rate of intestinal hydrolysis of polysaccharides to produce glucose, gradually flattening the postprandial blood glucose peak and reducing fluctuations, causing plasma insulin levels to drop and improving Insulin resistance. Animal experiments suggest that long-term application of acarbose can reduce the incidence and severity of atherosclerosis and glomerulosclerosis.
The UKPDS trial confirmed that blood pressure control is more beneficial than blood glucose control in reducing the incidence of diabetic complications and complication-related mortality. 2007 European hypertension guidelines recommend that renin-angiotensin blockers should be the first choice for blood pressure lowering treatment in diabetic patients, and that blood pressure control should be achieved at a target of 130/80 mmHg. The goal is 130/80 mmHg, and if diabetic nephropathy is present blood pressure should be controlled to less than 125/75 mmHg. However, in diabetic patients with cerebrovascular accidents, blood pressure levels can be adjusted upward appropriately according to the patient’s cerebral blood supply status. The choice of other blood pressure lowering drugs should be based on the patient’s systolic and diastolic blood pressure levels, heart rate, heart, liver and kidney function, and the patient’s economic status.
5.Adjustment of lipid profile Abnormal lipid profile in diabetes is one of the important risk factors for diabetic macroangiopathy. The abnormal lipid profile is characterized by high triglyceride, high cholesterol, high low-density lipoprotein and low high-density lipoprotein. Lipid correction is to lower the high harmful lipids, i.e., triglycerides, high cholesterol, and LDL, to the desired level, and to raise the low beneficial lipids, i.e., HDL, to an appropriate level. Large-scale clinical studies such as 4S and cardioprotection trials have proven that long-term application of lipid-regulating therapy significantly reduces cardiovascular and cerebrovascular accidents. Thus, lipid-modifying therapy is an important tool in the prevention and treatment of macrovascular complications of diabetes. The U.S. Adult Cholesterol Education Program states that although high TG and/or low HDL-C is common in patients with diabetes, clinical findings support the use of LDL-C as the primary target for treatment. The American Diabetes Association 2008 guidelines suggest that all patients with diabetes, regardless of pretreatment lipid levels, should be treated with statins in addition to lifestyle changes; the primary goal for patients with diabetes alone is LDL-C < 100 mg/dL; patients with diabetes combined with cardiovascular disease may be treated with high-dose statins to achieve LDL-C < 70 mg/dl.
6. Blocking protein non-enzymatic glycation Protein non-enzymatic glycation refers to the reaction process in which the aldehyde group of glucose combines with the ε-amino group of lysine or hydroxylysine in protein molecules to form glycosylated proteins, eventually forming glycosylated end products (AGE). Blood glucose level, protein half-life and lysine and hydroxylysine content in proteins are the main factors affecting glycosylation. Protein glycosylation causes changes in the structure, physicochemical properties and function of the protein. Each chronic complication of diabetes is closely related to protein glycosylation. Therefore, taking various measures to control the glycosylation process and reduce AGE formation can effectively prevent chronic complications of diabetes mellitus. The main measures currently used are: (1) Glycemic control Strict glycemic control is still an extremely important and effective basic treatment to prevent glycosylation and combat chronic complications. Because the level of glycosylation is related to the contact time between protein and high concentration of glucose, early control of high blood glucose can reduce glycosylation. Generally speaking, the occurrence of vascular complications is significantly reduced in those with fasting blood glucose below 7.0 mmol children and within 10.0 mmol children 2 hours after glucose load. (2) Aminoguanidine (aminoguanidine) is more active than the ε-amino group of lysine or hydroxylysine in protein and can prevent AGE production. Animal experiments have demonstrated that aminoguanidine can prevent the accumulation of AGE in the vessel wall, prevent the thickening of basement membrane, inhibit AGE-induced atherosclerosis; prevent diabetes-induced hypertension; reduce the leakage of glomerular capillaries and inhibit thylakoid proliferation, thus reducing proteinuria. phase 1 clinical trials have shown that aminoguanidine has a preventive effect on cardiovascular lesions, nephropathy and neuropathy in diabetic patients, and is It is considered to be a promising drug for the prevention of chronic complications of diabetes and is currently undergoing phase III clinical studies in the United States. (3) Vitamin C competes with glucose to bind proteins, thereby reducing glycosylated protein levels. Oral administration of 1 gram of vitamin C daily for three months resulted in a 33% reduction in glycosylated albumin and an 18% reduction in glycosylated hemoglobin. However, there is no evidence-based medical evidence as to the safety of long-term application of large amounts of vitamin C and whether it can reduce diabetic complications. (4) Aspirin Human crystallin accounts for about 30% of the wet weight of crystals. Crystallin is almost completely unmetabolized after it is formed once. Therefore, once the crystallin is glycated, it accumulates in an irreversible reaction and becomes the main cause of diabetic cataract. Aspirin can cause free amino acetylation of crystallin and reduce the level of non-enzymatic glycation, thus preventing the formation of cataract. (5). Rutin also inhibits glycation, reduces AGE formation, effectively prevents vascular collagen glycation, and reduces microvascular fragility and permeability.
7. Scavenging over-produced free radicals Free radicals are groups of atoms or molecules or atoms with unpaired electrons. In diabetic patients, large fluctuations in blood glucose are accompanied by the production of a large number of free radicals, while the activity of the free radical scavenging system in the body is significantly reduced, such as superoxide dismutase (SOD), catalase, peroxidase, glutathione peroxidase and other activities are reduced. Increased lipid oxidation, in turn, stimulates the auto-oxidation of sugar, which results in increased vascular permeability, thickened basement membranes and damage to tissues and organs. In addition, the incidence of cholelithiasis in diabetic patients is 2-3 times higher than in non-diabetic patients, which may be related to excessive free radical production. The application of natural antioxidants to capture the highly active and instantaneous free radicals to prevent chronic complications of diabetes has been effective. (1) Vitamin E (VE) is one of the best natural fat-soluble antioxidants, which is highly susceptible to oxidation itself and thus protects surrounding substances from oxidation.VE can scavenge free radicals from the vascular wall and prevent LDL from being oxidized, thus acting as a vascular protector. (2) Vitamin C (VC) can react directly with free radicals, and can also reduce oxidized VE to reduced VE, so that VE can continue to play its antioxidant role. Application of VC helps prevent hyperlipidemia atherosclerosis. VC and VE synthesis, can prevent the formation of gallstones. (3).SOD SOD containing zinc and copper ions is an important part of the free radical scavenging system in the body. Diabetic patients have insufficient SOD due to excessive free radical production. Taking SOD can prevent and slow down the process of atherosclerosis. Salvia injection can also restore endogenous SOD activity better, and the efficacy is similar to SOD. (4). Coenzyme Q10 (ubiquinone) is a naturally occurring fat-soluble antioxidant. Tissue levels of ubiquinone are low in diabetic patients. Ubiquinone plays a key role in energy metabolism; it also prevents low-density lipoprotein (LDL) oxidation, protects and restores the structural integrity of biofilms, and prevents vascular complications. (5). Appropriate selenium supplementation Through the study of the relationship between blood selenium and chronic complications of diabetes in different regional populations, it was found that the mortality rate of cardiovascular complications of diabetes in populations in selenium-rich regions was significantly lower than that in populations in low selenium regions. Selenium is an essential component of glutathione peroxidase, on which the body relies to scavenge lipid peroxides and free radicals.
8.Inhibit the excessive activation of polyol pathway The aldose reductase (AR) and sorbitol dehydrogenase (SDH) together constitute the polyol pathway, also known as the sorbitol enzyme pathway. In the hyperglycemic state of diabetes, AR activity increases, and the amount of glucose metabolized through the polyol pathway can be up to four times of normal, resulting in the synthesis of large amounts of sorbitol and fructose by cells. Because sorbitol is a very polar compound, it cannot enter and exit the cell freely, the accumulation of intracellular sorbitol, which produces hypertonicity and a large amount of extracellular fluid infiltration, caused cell edema and rupture; the accumulation of sorbitol damages the cell membrane and makes a large amount of inositol loss, on the other hand, the stereo-configuration of glucose and inositol is similar, and in hyperglycemia, glucose competes with inositol and inhibits the uptake of inositol by nerves. Inositol is an important component of neurophospholipid metabolism. Decreased inositol content in nerves interferes with neurophospholipid metabolism, decreases Na-K an ATPase activity, and causes slowing of nerve conduction velocity, axonal transport, etc. This shows the importance of inhibiting AR activity. The main aldose reductase inhibitors currently used are the following: (1) Epalrestat Tablets is the only aldose reductase inhibitor currently available in China. Animal experiments have shown that Epalrestat Tablets correct various biochemical abnormalities in nerve tissue and lens, and also restore the blood flow rate and nerve conduction function of tissue nerve tissue. A double-blind randomized parallel controlled multicenter clinical study of diabetic neuropathy demonstrated that oral administration of epalrestat tablets 50mg 3/day x 12 weeks significantly improved the subjective signs and symptoms of patients with diabetic peripheral neuropathy and caused a significant acceleration in the conduction velocity of both the median nerve and common peroneal nerve, with an efficacy similar to that of methylcobalamin. (2). Silymarin Silymarin has a strong aldose reductase inhibitory effect. Clinical application of silymarin tablets, 6 tablets per day, after 4 weeks of treatment, there was no significant change in blood glucose in diabetic patients, but erythrocyte sorbitol decreased significantly, and clinical symptoms and nerve conduction velocity improved significantly.
9. Correction of hypercoagulable state in vivo The prothrombin time of diabetic patients was shortened, platelet aggregation function and fibrinogen were significantly higher than those of normal controls, and endogenous fibrinolytic activity was weakened. These changes were not correlated with the patient’s blood glucose level and were present at the end of the clinical period when the microangiopathy was present. Increased platelet membrane phospholipase activation in diabetic patients leads to an increase in thromboxane A2 (TxA2), which directly causes endothelial damage. Therefore, correcting the abnormal platelet function and protecting the vascular endothelium are necessary to effectively prevent diabetic vascular complications. Clinically used anti-diabetic patients in vivo hypercoagulable state of drugs are: (1) aspirin Diabetic patients take aspirin 150 a 300mg daily for five years, can significantly reduce the incidence of myocardial infarction and retinopathy in diabetic patients, completely prevent transient ischemic attack (TIA). (2) Warfarin can hinder the utilization of vitamin K and anticoagulation. A trial showed that diabetic patients with Warfarin 24-63 months later, the mortality rate due to myocardial infarction, cerebral thrombosis and other complications was significantly reduced. The recurrence rate of myocardial infarction was reduced by 43%. (3). Fibrinolytic plasminogen activator (t-PA) In diabetic patients, t-PA levels are reduced but inhibitor (PAI) levels are increased, indicating impaired fibrinolysis. Genetically recombinant t-PA is currently available for application. Combined application of heparin anticoagulation during thrombolysis or within 1 month of myocardial infarction, followed by oral warfarin and low-dose aspirin, may reduce ischemia, reinfarction after tethering, and mortality from cardiovascular complications. (4) Fibrin-lowering enzymes such as earthworm kinase and viper antithrombin can improve blood rheology index, mildly inhibit platelet aggregation, significantly decrease fibrinogen, and increase plasma t-PA content, with obvious antithrombotic and thrombolytic effects, without obvious toxic side effects and bleeding complications. It has therapeutic and ameliorative effects on early diabetic nephropathy, neuropathy and macroangiopathy. 5 Clopidogrel is a new type of antiplatelet drug, with a dosage of 50-75mg/d, which can effectively inhibit platelet aggregation in diabetic patients. In the process of applying the above drugs to prevent chronic complications of diabetes, the changes of coagulation and fibrinolytic system should be closely monitored to prevent serious hemorrhage.
10. Antagonize the overexpression of growth factors Clinically, it has been observed that growth hormone (GH) levels are closely related to chronic complications of diabetes mellitus. For example, after pituitary stroke in diabetic patients, GH levels decrease and diabetic retinopathy improves; pituitary removal method has been used to treat diabetic retinopathy; diabetic with GH deficiency alone has rare retinopathy and atherosclerosis is also less common; those with retinopathy Increased GH secretion promotes excessive production of insulin-like growth factor-l (IGF-1), which in turn leads to the synthesis and thickening of glycated proteins in the basement membrane of micro-arteries, an important risk factor for early renal hypertrophy and proliferative retinopathy in diabetic patients. Therefore, lowering GH secretion levels and reducing IGF-I production can help prevent and reduce vasculopathy. The application of GH antagonist agents to prevent diabetic complications has yet to be clinically proven, and angiotensin-converting enzyme inhibitors, calcium antagonists, and hexoketococine may indirectly inhibit the expression of growth factors in tissues. Other anti-growth factor methods to be explored are: (1) cholinergic receptor inhibitors It has been confirmed that acetylcholine in the arcuate nucleus of the hypothalamus can promote the secretion of growth hormone-releasing hormone and inhibit the secretion of growth inhibitory hormone, thus increasing the level of GH, and the application of cholinergic inhibitors can eliminate the above effects and reduce the level of GH. At present, the trial are: pipepiridiazepine, atropine, scopolamine. (2) Growth inhibitor analogues Renal hypertrophy and hyperfiltration in the early stage of diabetic nephropathy are associated with increased levels of GH and IGF-I. Experiments have shown that the use of synthetic growth inhibitor analogues such as Sandostatin can reduce plasma GH and IGF-I levels, reduce kidney volume and normalize glomerular hyperfiltration rate in the early stage of diabetic nephropathy. (3) 5-Hydroxytryptamine blocker Cyproheptadine has moderate anti-5-hydroxytryptamine and anticholinergic effects, which can reduce blood GH and cortisol levels and counteract the diabetic dawn phenomenon.
The above discusses ten aspects of the prevention and treatment of chronic complications of diabetes, some measures have been confirmed by clinical evidence-based medicine; the efficacy of some approaches has yet to be confirmed by further research. The focus of each individual diabetic patient varies, but “monitoring of risk factors and early warning indicators for complications, correction of poor lifestyle, elimination of insulin resistance, and blocking non-enzymatic glycation of proteins” are essential measures for all patients with type 2 diabetes. Therefore, diabetic patients should be informed about the main factors of chronic complications and take appropriate measures to prevent them at the same time as the diagnosis of diabetes. Only in this way can the death and disability rates of diabetes be reduced and the life expectancy of diabetic patients be brought up to the level of normal people.