There is an ongoing controversy: Chinese people seem to have worse islet function. Insulin resistance is more pronounced in Europeans and Americans, so is islet function less impaired in Europeans and Americans? A report from the ADA in 2006 suggests that this is not the case. There is a 10-20 year compensatory phase (increasing number of islet beta cells) in obese people, during which type 2 diabetes does not occur if the compensations are successful. 2005 article in science pointed out that apoptosis and proliferation and replication of islet beta cells are more significant in type 2 diabetics than in normal people, which means that if we can inhibit beta cell apoptosis, we can hope to take advantage of their proliferation and This means that if we can inhibit β-cell apoptosis, we can hope to take advantage of their active proliferation and replication to achieve reversal of type 2 diabetes. Therefore, the main contradiction is not that β-cells are difficult to proliferate and replicate, but that β-cell apoptosis increases significantly (apoptosis increases between the ages of 20 and 30 and reaches a peak around the age of 50), which leads to type 2 diabetes. There are many reasons for the occurrence of apoptosis in β-cells, and the reason for not achieving the reversal of their function at present is that there are four major difficulties: (1) progressive deterioration of fasting glucose and postprandial glucose, leading to progressive deterioration of HbA1c; (2) increased apoptosis of β-cells, leading to progressive deterioration of β-cell function; (3) current treatment at the cost of hypoglycemia, and if hypoglycemia can be avoided, it is also a protection of β-cell function; (4 ) some drugs cause weight gain in patients. mechanisms of β-cell apoptosis include: genetic susceptibility, high glucose toxic effects, high lipotoxic effects, synergistic effects of glucose and lipotoxicity, insulin-specific inflammatory responses, and drug effects on β-cells. Inhibition of the above apoptotic mechanisms is an important way to reverse β-cell function. Third, the main therapeutic measures to protect β-cell function currently we have the means to reverse β-cell function: (1) GLP-1: the presence of GLP-1 is important for β-cell regeneration. in 2004 it has been found that the use of GLP-1 enhanced β-cell regeneration while apoptosis was inhibited and promoted the differentiation of pancreatic duct stem cells to β-cells. the GLP-1 analogue is known as the differentiation of β-cells factor (which leads to increased neogenesis), growth factor (which leads to enhanced replication) and survival factor (which leads to prolonged survival and reduced apoptosis). In this regard, we have relatively strong evidence from animal experiments: in rats with intrauterine growth retardation, diabetes occurs in 90% of adults, while if treated with the GLP-1 analogue exendin-4 for 6 days right after birth, the hypoglycemic effect is maintained for 8 months, no diabetes occurs and the number of beta cells is normal. The investigators thus concluded that the above results are a reflection of the metabolic memory effect. for type 1 diabetes, in NOD mice treated with anti-lymphocyte serum combined with exendin-4 for 8 days, 88% of type 1 diabetes was cured after 75 days. It was confirmed that GLP-1 analogues can inhibit β-cell apoptosis induced by cytokines and fatty acids. In a clinical study, the efficacy of exendin-4 was compared with that of glargine insulin in the treatment of type 2 diabetes using the glucose clamp technique. The results showed that the intensity of HbA1c reduction was almost the same between the two, but patients in the glargine insulin group had a significant increase in body weight, while those in the exendin-4 group lost 3.56 kg; regarding the effect on first-phase insulin secretion, the C-peptide secretion level was significantly higher in the exendin-4 group than in the glargine insulin group. It can be seen that the main difference between these two drugs lies in their protection of islet secretion function and β-cell function. (2) DPP-4 inhibitors: Clinical trials have shown that intervention with DPP-4 inhibitors in patients with type 2 diabetes resulted in a decrease in blood glucose, an increase in first-phase insulin secretion, an increase in C-peptide levels consistent with first-phase insulin secretion, and a decrease in glucagon levels. (3) TZD: It has both direct and indirect protective effects on β-cells. Insulin degranulation is strong in diabetic gerbils, and rosiglitazone can inhibit its degranulation effect. Clinically, TRIPOD and DREAM studies showed that TZD can reduce the risk of IGT by 55% and 62%, respectively, and its efficacy in preventing diabetes is much better than that of lifestyle change treatment. The annual incidence should have rebounded to 18% after discontinuation of the drug, but the actual incidence was only 3% after the use of troglitazone. This shows that TZD has a longer-term clinical effect. TZD provides smoother glycemic control than sulfonylureas, meaning that it is more conducive to improving beta-cell function. The results of the ACT NOW trial were presented at the ADA annual meeting this year. A total of 602 patients with IGT or IFG were enrolled in the trial and randomized to pioglitazone or placebo with 2.6 years of follow-up observation. Annual prevalence of diabetes: 1.5% vs. 6.8%. More promisingly, the glucose handling index (DI, insulin sensitivity x insulin secretion index) was very significantly increased, implying that diabetes reversal is expected. There was no significant difference between the two groups in terms of heart failure, fractures, and cardiovascular disease deaths. The use of pioglitazone was efficient in preventing the occurrence of type 2 diabetes for every 3.5 patients with IGT or IFG treated for 1 year. (4) Intensive insulin therapy: A report by our scholars published in Diabetes care showed that 72% of patients with type 2 diabetes achieved reversal of β-cell function 3 months after intensive insulin therapy, and 47% of patients still maintained normal blood glucose at 1 year and 42.3% at 2 years. Researchers believe that this is the result of inhibiting the toxic effects of hyperglycemia on beta cells. (5) Weight loss: A report in Diabetes in 2003 stated that weight loss surgery could normalize first-phase insulin secretion in type 2 diabetic patients at 6 months postoperatively, achieving reversal of β-cell function without medication. In a study published in JAMA this year, 60 extremely obese diabetic patients were enrolled, with one group receiving gastric banding and one group treated with conventional diabetes control. The results showed that patients in the surgical group lost significant weight, while there was no significant change in the conventional group; 73% of patients in the surgical group were cured of diabetes (defined as fasting glucose <7 mmol/L and HbA1c <6.2%) and no longer required further treatment, while only 13% of patients in the conventional group were cured. deFranzo noted that if a quadruple therapy (lifestyle intervention + metformin + TZD + GLP-1 analogue) - a multifactorial intervention - is likely to be much more effective than the ADA-recommended lifestyle intervention + metformin. He believes that HbA1c should be controlled to less than 6% in patients with primary diagnosis of type 2 DM to achieve reversal of beta-cell function.