IGT is a mandatory stage before the onset of almost all type 2 diabetes mellitus, and the increasing number of reports on diabetic retinopathy due to it has become a hot topic of interest in recent years. In this paper, the incidence of diabetic retinopathy in patients with IGT and its pathogenesis are reviewed as follows.
1. Definition and incidence of IGT
According to the current standards of the American Diabetes Association, a 2-hour blood glucose level between 7.8 and 11.1 mmol/l after oral glucose tolerance test (OGTT) is defined as impaired glucose tolerance (IGT), while a 2-hour blood glucose of 11.1 mmol/l is defined as diabetes. In 1997, the American Diabetes Association also set a fasting glucose standard, that is, fasting glucose between 6.1 and 7.0 mmol/l corresponds to IGT (impaired fasting glucose, IFG). As people’s living standards improve and their lifestyles change, the prevalence of IGT and diabetes continues to increase, with the prevalence of diabetes in Australia reaching 7.4% and the prevalence of IGT or IFG reaching 16.4%, more than three times the prevalence in 1981. Screening in the population revealed a prevalence of IGT of 11.2% in people aged 50-59 years and a maximum of 14.2% in people aged 60-75 years, while the prevalence began to decrease in people aged 75 years and older.
The progression of IGT is a dynamic and reversible process. Among the 200 individuals with IGT in Finland over the age of 70, 1/3 of them return to normal blood glucose, while 1/5 progress to diabetes. Almost 1/5 of the diabetic patients at baseline level reversed to IGT.
In the Diabetes Prevention Program study, 3244 patients with IGT were randomized and treated with placebo, metformin, and intensive diet or exercise. 30 percent of the 1082 patients treated with placebo progressed from low glucose tolerance to diabetes, while 25 percent returned to normal postprandial glucose, and most patients’ glucose levels gradually improved, but this progression was slow. In the 3-year follow-up, the mean fasting glucose level in placebo-treated patients was 5.9 to 6.3 mmol/l. Patients experience several years of insulin resistance and postprandial hyperglycemia before developing diabetes.
Retinopathy is very common in diabetic patients. Color vision examination, FM-100Hue test and its contrast sensitivity test were performed on patients with IGT, and it was found that the visual acuity and contrast sensitivity of the patients had decreased to different degrees, suggesting that the visual function of the patients had started to decline during the IGT period. In a sample of Japanese population, the prevalence of retinopathy in type 2 diabetic patients was found to be 18.6%, compared with 1.1% in IGT patients, a result consistent with the findings in whites and lower than in blacks and Hispanics. Simultaneous multiple regression analysis showed that the duration of diabetes and 2-hour postprandial hyperglycemia were independent risk factors for diabetic retinopathy.
The prevalence of retinopathy in the Micronesian population with IGT was three times higher than in normal controls. In the Western Samoan Islands of the South Pacific, the prevalence of retinopathy was 10% in patients with IGT and 17% in patients with newly diagnosed diabetes, compared with 45% in patients with known diabetes. An epidemiological survey of Pima Indians showed an 8.3% prevalence of retinopathy in newly diagnosed diabetic patients compared with 12% in IGT patients. None of the non-diabetic patients developed proliferative diabetic retinopathy. Zhang Xiaomei et al. investigated the incidence of diabetic retinopathy in the population of Liuzhou City and showed that 3 cases of diabetic retinopathy were detected in 385 patients with IGT, and the incidence rate was 0.28%.
IGT is the result of the synergistic effect of insulin resistance and disorders of lipid metabolism. patients with IGT develop elevated hormone-sensitive lipase activity, which enhances the breakdown of adipose tissue; insulin facilitates the transfer of glucose into cells and impairs intracellular metabolism, which reduces triglyceride production. These two factors increase the level of free fatty acids in patients with IGT. The high level of free fatty acids can in turn stimulate insulin secretion, and hyperglycemia in IGT itself can cause an increase in insulin secretion, while the endogenous clearance of insulin is reduced, resulting in hyperinsulinemia and insulin resistance.
Nitric oxide (NO) is the most potent endothelium-derived vasodilatory factor. In the presence of insulin and other stimulating factors, endothelial nitric oxide synthase synthesizes NO, which plays at least two key roles: on the one hand, it inhibits the proliferation of vascular smooth muscle and the adhesion of leukocytes, and diastens the blood vessels; on the other hand, it inhibits factors that cause oxidative damage and plays a role in detoxification of reactive oxygen clusters.
Studies have shown that NO is the main regulator of normal blood flow in the choroid, optic nerve, and retina of human eyes, and can regulate the vasodilatory response of the ocular vasculature to acetylcholine, bradykinin, histamine, and its insulin production, and also plays a role in the choroidal vasodilation produced by hypercapnia. As a result, NO production is reduced and the retinal vasculature is less able to regulate itself. On the other hand, it has been found that NO activates soluble guanylate cyclase, which catalyzes the cyclization of guanosine triphosphate to generate cGMP, which, through activation of protein kinase C, dephosphorylates myosin light chains, thereby diastaging the peripapillary retinal cells, so it is hypothesized that circulating endogenous NO, in addition to diastaging the vasculature, also regulates the tone of the peripapillary retinal cells and affects the blood flow in the retinal capillaries.
The pathogenesis of diabetic retinopathy is still unclear. Recent studies suggest that dysfunction of the retinal vascular endothelium is an important feature of IGT-induced retinopathy. Several aspects, such as hyperglycemia, insulin resistance and hyperinsulinemia, increased release of free fatty acids and adipocytokines, are the main factors influencing the action of NO in IGT.
4.1.1 Decreased NO production: First, damage to retinal vascular endothelial cells directly induced by high glucose or a decrease in acetylcholine receptors induced by high glucose reduces vascular synthesis of NO. Second, insufficient substrate for NO synthesis, lack of nitric oxide synthase cofactor and increased aldose reductase activity may also reduce NO production. Thirdly, a large amount of reactive oxygen clusters are produced during hyperglycemia, resulting in reduced NO overconsumption due to detoxification, which eventually leads to impaired retinal vasodilation and increased retinal ischemia, accelerating the onset of diabetic retinopathy.
4.1.2 Reduced NO activity: NO activity can also be reduced under high glucose, which is mainly caused by increased generation of oxygen radicals and glycosylation end products. Oxygen radicals originate from sugar oxidation in mitochondria, fat oxidation, oxidation of glycosylated proteins in vivo or aldose reduction reactions in the cytoplasm under high glucose status. Oxygen radicals are highly susceptible to reaction with NO, which inactivates them. In the high glucose state, the glycosylation end-products formed by the non-enzymatic glycosylation of proteins in the body accumulate in large quantities, which can react with NO in a rapid chemical reaction to inactivate NO; or compete with NO to bind its carrier, so that the carrier molecules lose the ability to carry NO.
In conclusion, the reduced NO production and activity in hyperglycemic state directly or indirectly cause retinal vascular endothelial cell dysfunction and promote the occurrence of diabetic retinopathy.
Epidemiological surveys show that even before the appearance of hyperglycemia, insulin-resistant patients often exhibit vascular complications. In insulin resistance, retinal vascular endothelial cell dysfunction is associated with an increase in asymmetric dimethylarginine (ADMA) in the blood and a deficiency of NO, a competitive inhibitor of endothelium-derived nitric oxide synthase, and dimethylarginine aminohydrolase ( dimethylarginine dimethylaminohydrolase, DDAH) can increase the metabolism of ADMA. And in insulin resistance, the enhancement of oxidative stress leads to a decrease in the concentration and activity of DDAH and a corresponding increase in ADMA, causing a decrease in NO. It was demonstrated that there was a significant correlation between insulin resistance and plasma ADMA concentration, and pharmacological intervention with rosiglitazone could improve insulin sensitivity while decreasing ADMA levels. The increase in plasma ADMA concentration may aggravate endothelial cell dysfunction in insulin resistant patients. When insulin resistance is present due to hyperglycemia and hyperinsulinemia, it can directly damage the vascular endothelium and reduce basal NO production. On the other hand, endothelial nitric oxide synthase activity is reduced, resulting in decreased NO production. In turn, reduced NO can in turn reduce the sensitivity of the vascular endothelium to insulin, aggravating insulin resistance and forming a vicious circle.
In addition, abnormal pterin metabolism in insulin resistance can also lead to endothelial cell dysfunction due to NO deficiency and inactivation, aggravating the oxidative damage of blood vessels. Experiments have shown that tetrahydrobiopterin (BH4), a natural and essential cofactor of nitric oxide synthase, not only promotes NO production but also plays a key role in controlling the formation of superoxide anion in endothelial cells. In insulin resistance, low BH4 levels reduce NO synthesis and the inactivation of NO due to superoxide anion in the vascular wall is exacerbated. It was further demonstrated that oral supplementation of BH4 could restore endothelial cell function and reduce oxidative tissue damage by activating endothelial nitric oxide synthase.
Therefore, reduced NO production and activity in insulin-resistant states cause retinal vascular endothelial cell dysfunction and promote the development of diabetic retinopathy.
4.3.1 Excessive free fatty acids cause endothelial cell damage During IGT, adipocytes can produce and release excessive free fatty acids. Excess free fatty acids can weaken Ca(2+) signaling, inhibit Ca(2+)-dependent endothelial nitric oxide synthase activity, reduce NO production, decrease acetylcholine-dependent vasodilatory response, and also undergo peroxidation, causing increased production of reactive oxygen clusters, which in turn decreases the vasodilatory response and leads to endothelial cell injury. It has been demonstrated that high concentrations of antioxidants such as VitC can reverse the local effects of free fatty acids on endothelium-dependent vasodilatory effects.
Insulin resistance and hyperlipidemia coexist in most IGT patients. It has been demonstrated that in patients with chronic hypertriglyceridemia, endothelial cell dysfunction is associated with insulin resistance but not with hypertriglyceridemia. Alternatively, lipotoxicity may contribute to chronic inflammatory endothelial damage. In healthy volunteers, lipid administration (50 g/m2) resulted in a sustained elevation of neutrophils and IL-8 in the blood after meals, while postprandial neutrophil aggregation and increased inflammatory cytokines exacerbated endothelial cell dysfunction.
4.3.2 Adipocytokines cause endothelial cell damage Adipocytes secrete adipocytokines, which play an important role in regulating substance metabolism and vasodilatory function. In obesity and IGT, the altered secretion of two main adipocytokines (TNF- and lipocalin) causes endothelial cell damage and early vascular complications.
TNF- can increase vascular permeability through its receptors located in vascular endothelial cells, and on the other hand, it can decrease the biological activity of vasodilators such as NO and increase the activity of vasoconstrictors, leading to endothelial diastolic dysfunction. At the same time, experiments have shown that TNF- can also cause endothelial cell damage by inducing the production of reactive oxygen species clusters. In turn, TNF- can also enhance insulin resistance. It has been shown that the release of TNF- from adipocytes due to acute glucose infusion has a greater effect on patients with hypoglycemia than on normoglycemic controls. Thus, patients with hypoglycemia are more susceptible to TNF-mediated vascular damage.
Lipocalin is an adipocyte-derived peptide with multiple vascular effects. Lipocalin levels are negatively correlated with fasting insulin concentrations and positively correlated with insulin sensitivity. Lipocalin affects not only the glucose metabolism of the body, but also the function of blood vessels: inhibition of vascular smooth muscle proliferation and macrophage-mediated endothelial cell damage. Since lipocalin can inhibit the expression of endothelial cell adhesion molecules and reduce the activity of endothelial cells, it has been speculated that lipocalin may also affect the vasoconstrictor function of endothelial cells, and the reduction of lipocalin levels may be associated with endothelium-dependent vasodilator dysfunction. in IGT, lipocalin levels in blood and lipocalin gene expression in adipose tissue are reduced, which on the one hand increases the expression of endothelial cell adhesion molecules and on the other hand increases the expression of endothelial cell adhesion molecules. On the other hand, due to endothelium-dependent vasodilatory dysfunction, it eventually leads to vascular endothelial cell injury.
The aim of IGT intervention is to increase insulin sensitivity and insulin secretion, and the intervention methods mainly include behavioral and pharmacological interventions. Behavioral interventions mainly start from the following aspects.
1. adjusting lifestyle, quitting smoking and alcohol, improving sleep and its weight loss 2. changing poor dietary habits, high protein and low fat diet, eating more foods with high fiber content 3. strengthening physical exercise and increasing physical activity 4. popularizing diabetes knowledge health education, etc. The results of DPP and a large number of prospective studies from Finland and Daqing, China have shown that behavioral interventions can reduce the incidence of type 2 diabetes in IGT patients by The incidence of type 2 diabetes is reduced by approximately 50%. Various pharmacological interventions have also been shown to be effective in preventing the development of diabetes, although the reduction in the risk of developing diabetes is not significant, ranging from 25% to 35%. The following drugs are commonly used in pharmacological interventions: 1. biguanides: metformin
2. Glucocerebrosides inhibitors: Acarbose
3, thiazolidinediones: rosiglitazone, troglitazone
4. angiotensin-converting enzyme inhibitors and angiotensin receptor II blockers 5. weight loss drugs: orlistat, etc [25].
Early intervention not only improves the quality of survival and slows the conversion of IGT to diabetes, but also prevents the development of diabetic microvascular complications. Therefore, early screening of the IGT population and early interventional care measures are of direct importance to prevent diabetes and also indirectly reduce the occurrence of retinopathy.
In conclusion, IGT is a transitional stage from normal glucose tolerance to type 2 diabetes, and the onset of diabetic retinopathy due to it is mainly due to hyperglycemia, insulin resistance and hyperinsulinemia, excess free fatty acids and abnormal secretion of adipocytokines during IGT, which lead to impaired retinal endothelial cell function and eventually to the development of diabetic retinopathy.
Diabetic retinopathy has become one of the major blinding diseases nowadays. Early detection of diabetic retinopathy and timely administration of necessary treatment has become the basic method to prevent and treat vision loss in patients. Therefore, along with the screening and prevention of low glucose tolerance, close attention should be paid to the occurrence of diabetic retinopathy, which can help early intervention and treatment of diabetic retinopathy and has long-term significance to improve people’s quality of life and reduce the economic burden of the country.