| Background and objectiveThe incidence and morbidity of diabetes mellitus (DM) were increased in these years with the development of world economy and elevation of people's life. DM becomes an important social problem to threaten people's health. It invokes attention of governments, departments of health and medical workers all over the world. The morbidity of type 1 diabetes mellitus (T1DM) is far lower than that of type 2 diabetes mellitus (T2DM). The morbidity of T2DM in the earth was reased sharply in these years, which is the main reason for quick enhancement of the total of diabetic patients.The morbidity of DM in our country was increased prominently. The epidemiological findings of 30 ten thousands persons in 14 provinces showed that the morbidity of DM was 0.67% in 1980. The findings of 21 ten thousands persons in 19 provinces indicated that the morbidity of DM was 2.5% and the morbidity of impaired glucose regulation (IGR) was 3.2% in 1994. The amount of diabetic patients in 1994 grew 3 times than that in 1980. The epidemiological results in 2002 revealed that the morbidity of DM was 2.6% in the population over 18 years old. The morbidity of DM mounted up 4 times in the past 20 years. IDF estimates that diabetic patients in China still grow swiftly. The amount of diabetic patients was 3980 ten thousands in 2007. And it will be 5930 ten thousands in 2025.Coronary heart disease (CHD) is the major macrovascular complication of DM. 72.3 percent of diabetic patients were companied with CHD. 50 percent of type 2 diabetic patients were coupled with CHD at the beginning of diagnosis. DM accelerates the development of CHD. NCEP-ATPⅢput forward definitely in 2001 that DM was as dangerous as CHD. The findings of ten hospitals in Beijing, Tianjin, Shanghai and Chongqing in 2001 pointed out that 93 percent of diabetic patients incorporated various cardiovascular diseases. And 80 percent of diabetic patients died from cardiovascular diseases. So the aim to prevent and cure DM is to prevent and suspend the occurrence of CHD, which decreases consequently the mortality of CHD among diabetic patients.Non-alcoholic fatty liver disease (NAFLD) is characterized with diffuse bulbous fatty changes of hepatic cells except for alcoholic and other definite causes damaging liver. It includes simple fatty liver disease, fatty hepatitis and cirrhosis. NAFLD becomes one of common chronic hepatic diseases in China with the modification of diets. NAFLD is related closely to metabolic syndrome (MS). AACE put NAFLD as one of diagnostic criteria of MS in 2003. NAFLD is not only companied with insulin resistant syndrome, but also is an early mark of insulin resistance (IR). Insulin resistant syndrome and its related diseases would be postponed if NAFLD was prevented.IR means that target organs'sensitivity to insulin declines, which is a condition that normal amount of insulin can not produce normal biological effects. It is related to more than 10 metabolic diseases, which include central obesity, abnormal glycometabolism, T2DM, disturbing lipid metabolism, hypertension, microalbuminuria, CHD, NAFLD, and so on. The summation of these diseases are called insulin resistant syndrome because IR is the common basis of them. Researchers realize gradually that IR is not only the important pathogenesis but also the pathological foundation of diabetic complications. More and more researches show that although intensive glucose control can reduce the occurrences of ophthalmopathy, neuropathy and nephropathy, it can not stop the occurrence and development of macrovascular complications. So there are other factors acting on diabetic patients except for high blood glucose. Insulin resistant patients are usually obese. Adipose cells in obese persons secret many new hormones, such as adiponectin, resistin, leptin, and so on. All of these hormones influence the body sensitivity to insulin. IR results in hyperinsulinemia in the body. Meanwhile hyperinsulinemia causes obesity.Adiponectin is a new specific protein of adipose cells. It is a study hot due to its protection for diabetic tissues. It is negatively correlated to obesity. Its level is decreased in insulin resistant patients and type 2 diabetic patients. Visceral obesity is an independent predictor of low adiponectin level. The characteristics of MS are negatively correlated to adiponectin. The decline of adiponectin level comes before the progress of T2DM. Blood glucose goes down and insulin sensitivity (IS) goes up after the patient is given adiponectin. Hypoadiponectinemia plays a role in IR, because low expression of adiponectin is relative to IR in animal models. Adiponectin speeds fatty acid oxidation, accelerates glucose transportation and heightens IS. So adiponectin can improve IS. Plasma adiponectin is obviously depressed in macrocardiological diseases. Adiponectin is loosely related to cardiovascular diseases. It has functions of protecting endothelial cells, anti-inflammation and anti-AS. It may be a kind of insulin sensitizer. It may be a new drug to cure IR.Metformin has all-round efficacy and good safety. Firstly, it improves IR, increases utilization of glucose and inhibits production of hepatic glycogen. It doesn't aggravate burden ofβcells in islet. It can not cause hyperinsulinemia. Secondly, it has perfect effect on reducing blood glucose. Thirdly, it reduces body weight. Fourthly, it has cardiovascular protection. It is the only one hypoglycemic drug with the proof to decrease cardiovascular complications of type 2 diabetic patients until now. It can depress risks of myocardial infarction and stroke. Fifthly, it has low price and good cost performance. The mechanism of AS is closely related to IR in type 2 diabetic patients. NAFLD is an early mark of IR. Adiponectin can counteract IR. Metformin can ameliorate IR. The research investigates whether metformin may increase expression of adiponectin, whether improvement of IR may prevent AS in type 2 diabetic patients, and the relationship between adiponectin and IR in type 2 diabetic patients accompanying with NAFLD. The deep study was made to see whether adiponectin would be a new thought for curing insulin resistant diseases.Methods:1. Effects of metformin on adiponectin in diabetic rats. Diabetic rats were induced by feeding fat rich food and injecting streptozotocin (25mg·kg-1).Then diabetic rats were fed with metformin. According to the dose of metformin, these rats were divided into three groups: metformin with low dose group (Met-L, 100mg.kg-1.d-1), metformin with high dose (Met-H, 156mg.kg-1.d-1), and diabetic rats without metformin (DM). Healthy SD rats were as normal control (NC). Rats were killed after 4 weeks and were taken blood in aorta abdominalis. Fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), fasting insulin (FINS), TNF-αand adiponectin were measured. IR index (HOMA-IR) was calculated. The expressions of TNF-αand adiponectin genes in perinephral adipose tissues were tested by RT-PCR. The scores for AP-lesion of aorta were evaluated according to the pathological degrees with oil red Ostaining, The pathologic changes was examined by hematoxylin and eosin (HE) staining.2. Effects of metformin on adiponectin and AS in patients with T2DM. One hundred and forty patients with T2DM aged from 35 to 70 years old, with the course less than 1 year and without subclinical AS. All patients received 100-week intervention based on anti-platelet therapy integrated with intensive controls of blood glucose, blood lipid, blood pressure and body weight. According to the category of oral antidiabetic drug (OHA), the patients were divided into two groups: patients with metformin and patients without metformin. All patients did not use thiazolidinediones (TZDs) and insulin. Body mass index (BMI), waist-to-hip ratio (WHR), blood pressure (BP), FBG, post 2-hour blood glucose (P2hBG), glycated hemoglobin A1C (HbA1C), TG, TC, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), FINS and common carotid intima-media thickness (CC-IMT) were measured. Dynamic changes in all metabolic indicators were observed after 100-week intensive intervention. CC-IMT was an indicator for AS.3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. There were three groups: T2DM patients with NAFLD, T2DM patients without fatty liver disease, and normal control. Body height, body weight, waist circumstance, hip circumstance, BP, FBG, blood lipid, FINS and adiponectin were measured. BMI, WHR and HOMA-IR were calculated.Results:1. Effects of metformin on adiponectin in diabetic rats. The body weights in DM group, Met-L group and Met-H group were significantly higher than that in NC group (P<0.01 or P<0.05). The body weights in Met-L group and Met-H group were significantly lower than that in DM group (P<0.05). FBG, TC and TG in DM group were higher than those in NC group (P<0.01 or P<0.05). While there was no significant change of FINS between DM group and NC group (P>0.05). Blood glucose and lipid were decreased significantly in Met-L group and Met-H group (P<0.05). And the changes were depended on the dose of metformin. While there was still no significant change of FINS (P>0.05). HOMA-IRs in DM group, Met-L group and Met-H group were higher than that in NC group (P<0.05). HOMA-IR in Met-L group and Met-H group were lower than that in DM group (P<0.05). The more the dose, the more the decline.TNF-αin DM group was significantly higher than that in NC group (P<0.05). TNF-αin Met-L group and Met-H group were dropped compared with that in DM group (P<0.05). And TNF-αin Met-H group was lower than that in Met-L group (P<0.05). Adiponectin in DM group was significantly lower than that in NC group (P<0.05). Adiponectin in Met-H group was augmented compared with that in DM group (P<0.05), whose concentration was tended similar to that in NC group. Adiponectin in Met-H group was also fortified, while the change didn't get statistical significance (P>0.05).The expression of adiponectin mRNA in adipose tissue was decreased (P<0.05). The expression of TNF-αmRNA in adipose tissue was increased (P<0.05). Metformin can renovate partly abnormal expression of adiponectin and TNF-α. The more the dose, the stronger the action.HOMA-IR was negatively related to adiponectin (r=-0.498, P<0.05). HOMA-IR was positively related to TNF-α(r = 0.35, P<0.05).All rats had no atheromatous plaques.2. Effects of metformin on adiponectin and AS in patients with T2DM.There was no significant difference of all metabolic indicators between both groups before intensive intervention (P> 0.05). Diastolic blood pressure (DBP), FBG, P2hBG, HbA1C, TG, TC and LDL-C were significantly decreased in both groups after intensive intervention for 100 weeks (P<0.05). There was no significance of WHR and systolic blood pressure (SBP) in both groups after intensive intervention (P> 0.05). BMI, HOMA-IR and CC-IMT in metformin group were declined after intensive intervention (P<0.05). While HDL-C were raised (P<0.05). BMI, HOMA-IR, HDL-C and CC-IMT were varied tendency after intensive control. But the changes were not significant between pre- and post-intensive control (P> 0.05). Adiponectins in both groups were heightened after intensive control (P<0.05). HOMA-IR and CC-IMT in metformin group were lower than that in non-metformin group after intensive control (P<0.05). Adiponectin in metformin group was higher than that in non-metformin group (P<0.05).Correlative analysis showed that CC-IMT was positively related to BMI (r = 0.489, P<0.05), TC (r = 0.429, P<0.05), LDL-C (r = 0.426, P<0.05), HOMA-IR (r = 0.428, P < 0.05). CC-IMT was negatively related to adiponectin (r = -0.485, P<0.05).3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. BMI, WHR, SBP, DBP, FBG, FINS, TG, TC and HOMA-IR in both groups of T2DM with NAFLD and T2DM without fatty liver disease were higher than those in NC group (P<0.05). BMI, WHR, FINS, TG and HOMA-IR in the group of T2DM with NAFLD were higher than those in the group of T2DM without fatty liver disease (P<0.05). There was no significant difference of SBP, DBP, FBG and TC between both groups of T2DM with NAFLD and T2DM without fatty liver disease (P>0.05).Serum adiponectins in both groups of T2DM with NAFLD and T2DM without fatty liver disease were lower than that in NC group (P<0.05). Serum adiponectin in the group of T2DM with NAFLD was lower than that in the group of T2DM without fatty liver disease (P<0.05).Logistic regression multiple factor analysis showed that BMI, WHR, TG and adiponectin were correlated to IR in type 2 diabetic patients with NAFLD. Adiponectin was more closely related to IR than others in type 2 diabetic patients with NAFLD.Conclusions:1. Metformin can ameliorate IR. Meanwhile it can increase expression of adiponectin in serum and fatty tissue. One of mechanisms of metformin improving IR may be by way of enhancing expression of adiponectin.2. Metformin can decrease CC-IMT of type 2 diabetic patients. So it can prevent type 2 diabetic patients from AS. The concentration of serum adiponectin is negatively correlated to CC-IMT. Adiponectin plays an evident role in anti-IR and anti-AS.3. The level of serum adiponectin was dropped in type 2 diabetic patients with NAFLD. Adiponectin is closely related to IR. Adiponectin may have important affect on the occurrence and development of NAFLD in type 2 diabetic patients.
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