[Insulin resistance and islet beta cell function in type 2 diabetes mellitus and non alcoholic fatty liver disease.].

OBJECTIVE: To investigate insulin resistance and islet beta cell function in type 2 diabetes mellitus (T2DM) and non alcoholic fatty liver disease (NAFLD). METHODS: Two hundred and six study subjects were classified into 4 groups. Hepatic insulin resistance index (HIR), HOMA insulin resistance index (HOMA-IR) and Matsuda index (MSI) were used to assess insulin resistance. HOMA-beta, early and late phase indexes of insulin secretion were used to evaluate islet beta cell function. RESULTS: HIR in the NAFLD group and T2DM with NAFLD group were significantly higher than that in the control group and T2DM group (4.13 +/- 0.64, 4.03 +/- 0.69 vs 3.52 +/- 0.78, 3.53 +/- 0.64, P < 0.05), HOMA-IR in the T2DM with NAFLD group was significantly higher than that in the NAFLD group and T2DM group (3.35 +/- 2.69 vs 2.31 +/- 1.39, 2.40 +/- 1.55, P < 0.05). Early phase insulin secretion index in the NAFLD group was lower than that in the control group significantly (2.13 +/- 0.17 vs 2.61 +/- 0.13, P < 0.05), but there was no significant difference of HOMA-beta and late phase insulin secretion index between the NAFLD group and control group, HOMA-beta, early and late phase indexes of insulin secretion in the T2DM group and T2DM with NAFLD group were significantly lower than those in the control group. CONCLUSIONS: Normal glucose tolerance NAFLD patients may present with insulin resistance, mainly hepatic insulin resistance. Islet beta cell function in the NAFLD patients show damage of early phase insulin secretion. Newly diagnosed T2DM with or without NAFLD patients generally present with insulin resistance, early and later phase insulin secretion dysfunction. Insulin resistance in patients with T2DM and NAFLD is more severe.

Effect of angiotensin II receptor blocker on glucose-induced mRNA expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rat mesangial cells.

BACKGROUND: The decreased degradation of extra-cellular matrix proteins plays an important role in the onset of diabetic nephropathy. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are members of the matrix metalloproteinase family, are associated with this process. Angiotensin II (AII) plays an important role in the development of diabetic nephropathy also. This research aimed to investigate the effect of angiotensin II receptor blocker on glucose-induced mRNA expressions of MMP-9 and TIMP-1 in rat mesangial cells. METHODS: Rat mesangial cells were cultured and divided into 5 groups: normal glucose (group NG), high glucose (group HG), group NG + AII, NG + AII + saralasin (group NG + AII + S, saralasin is the AII receptor blocker) and HG + saralasin (group HG + S). After the cells were incubated for 24 hours, AII concentrations in the supernatant were measured by radioimmunoassay and the expression of MMP-9 and TIMP-1 mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: AII concentrations were higher in group HG ((56.90 +/- 13.54) pg/ml) and group HG + S ((51.30 +/- 5.96) pg/ml) than in group NG ((37.89 +/- 8.62) pg/ml, P < 0.05), whereas there was no significant difference between group HG and group HG + S. The expression of MMP-9 mRNA and MMP-9/TIMP-1 mRNA ratio in group NG + AII (MMP-9, 0.33 +/- 0.04; MMP-9/TIMP-1, 0.40 +/- 0.06) and group HG (MMP-9, 0.36 +/- 0.02; MMP-9/TIMP-1, 0.45 +/- 0.03) were decreased more significantly than those in group NG (MMP-9, 0.72 +/- 0.02; MMP-9/TIMP-1, 1.21 +/- 0.07). These values in group NG + AII + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.18 +/- 0.05) were higher than those in group NG + AII, and the values in group HG + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.16 +/- 0.05) were higher than those in group HG (all were P < 0.05). TIMP-1 mRNA expression was increased more significantly in group NG + AII (0.81 +/- 0.03) and group HG (0.80 +/- 0.03) than in group NG (0.59 +/- 0.02), but it was lower in group NG + AII + S (0.60 +/- 0.01) than in group NG + AII and also lower in group HG + S (0.61 +/- 0.01) than in group HG (all were P < 0.05). CONCLUSIONS: High glucose stimulates AII production. Both high glucose and AII induce a decrease in MMP-9 mRNA expression and MMP-9/TIMP-1 mRNA ratio as well as an increase in TIMP-1 mRNA expression, which can be reversed by saralasin, suggesting that high glucose can aggravate impaired matrix degradation by altering gene expression of MMP-9 and TIMP-1 and that the effect of high glucose may be mediated by AII.

Efficacy of acarbose in Chinese subjects with impaired glucose tolerance.

This multicentre, double-blind, placebo-controlled study investigated the efficacy of acarbose in Chinese individuals with impaired glucose tolerance (determined using a 75 g oral glucose tolerance test). Subjects were randomised to either placebo or acarbose 50 mg t.i.d. for a period of 16 weeks. Primary efficacy variables were the maximum postprandial plasma glucose value (C(max)) and the serum insulin profile. Secondary efficacy parameters included postprandial glucose profile, maximum postprandial insulin concentration (C(max)), changes in lipid profile and blood pressure and HbA(1c) and body weight and conversion to Type 2 diabetes. In the intention-to-treat analysis, acarbose treatment resulted in significantly higher reductions in postprandial glucose and serum insulin concentrations compared to placebo. Triglyceride concentration was the only lipid parameter to be significantly reduced in acarbose subjects. Loss of body weight was also significantly greater for acarbose than placebo subjects. Some 19 individuals converted to Type 2 diabetes (seven acarbose, 12 placebo), but this difference was not significant. Acarbose is efficacious in improving the metabolic state of individuals with impaired glucose tolerance indicating a potential benefit for the delay or prevention of onset of Type 2 diabetes in Chinese subjects.

Effects of resistin on skeletal glucose metabolism.

Resistin is an adipokine highly related to insulin resistance (IR). The purpose of our research was to investigate how resistin influences skeletal glucose metabolism and explore its mechanisms. We constructed the recombinant plasmid pcDNA3.1 expressing resistin and then transfected it into C2C12 myocytes. The expression of resistin in C2C12 myocytes was detected by Western blotting. Glucose uptake was measured by 3H labeled glucose; glucose oxidation and glycogen synthesis was detected with 14C-labeled glucose. GLUT4 mRNA was measured by reverse transcription polymerase chain reaction (RT-PCR). We observed that resistin was expressed in transfected myocytes, and resistin decreased insulin induced glucose uptake rate by 28%-31% and inhibited the expression of GLUT4 mRNA. However, there was no significant difference in basal glucose uptake, and glucose oxidation and glycogen synthesis remained unchanged in all groups. It is concluded that resistin inhibits insulin induced glucose uptake in myocytes by downregulating the expression of GLUT4 and it has no effects on glucose oxidation and glycogen synthesis. Our findings may provide a clue to understand the roles of resistin in the pathogenesis of skeletal IR.

[Effects of losartan on the levels of angiotensin II and its type-1 receptor in diabetic rat kidney].

OBJECTIVE: To investigate the effect of losartan, an angiotensin II type-1 receptor (AT1R) antagonist, on the levels of angiotensin II (Ang II) and AT1R in diabetic rat kidney. METHODS: Male Wistar rats were divided into 3 groups, group A (n=11) served as the control group, group B (n=11) included the diabetic rats (induced by intraperitoneal injection of streptozotocin) without any therapy, and group C (n=9) diabetic rats treated with losartan. After 18 weeks of treatment, the kidneys were taken from all the rats to measure the expression of AT1R mRNA by RT-PCR and detect the Ang II level. Blood was also drawn from the heart to measure Ang II level, and 24-hour urine was collected to measure albumin level (urine albumin excretion, UAE) with rat albumin enzyme immunoassay kit. RESULTS: The blood and renal Ang II levels showed no significant difference between the 3 groups. The expression of renal AT1R mRNA in group B (0.62-/+0.17) was significantly lower than that in group A (1.13-/+0.82, P<0.01) and group C (1.13-/+0.62,P<0.01). UAE in group B (2.18-/+1.98 mg) was significantly higher than that in group A (0.41-/+0.47 mg/d, P<0.01) and C (0.65 -/+0.89 mg/d, P<0.01). CONCLUSION: Losartan can increase the expression of AT1R mRNA in diabetic rat kidneys without altering the blood and renal Ang II levels.

[Relationship between serum interleukin-10 and insulin resistance in metabolic syndrome].

OBJECTIVE: To investigate the relationship between serum interleukin-10 (IL-10) level and insulin resistance (IR) in patients with metabolic syndrome (MS). METHODS: Eighteen MS subjects and 18 age-matched normal subjects were enrolled. IR was evaluated by hyperinsulinemic-euglycemic clamp technique and serum IL-10 level measured by ELISA. Pearson's correlation analysis was used to investigate the relationship between serum IL-10 level and IR. RESULTS: Serum IL-10 levels were significantly higher in patients with MS than in the controls [1.3 (0.8/3.1) pg/ml vs 2.4 (1.1/4.5) pg/ml, P<0.05], and glucose metabolic rate (M value) derived from hyperinsulinemic-euglycemic clamp technique was lower in MS subjects than in controls [(5.76+/-1.81) mg/kg.min vs (8.39+/-1.25) mg/kg.min], P<0.05]. Serum IL-10 levels showed a positive correlation with M value (P<0.05). CONCLUSION: Patients with MS have greater IR and lower serum IL-10 levels than normal subjects, and lowered IL-10 levels might be involved in the pathogenesis of IR in MS.

Effect of losartan on the mRNA expressions of MT3-MMP and TIMP-2 in diabetic kidneys.

BACKGROUND AND OBJECTIVES: The renin-angiotensin system plays a critical role in circulatory homoeostasis. Evidence has emerged that suggests a pathologic role for angiotensin II in patients with kidney disease. Losartan is an antagonist of angiotensin II and blocks the angiotensin II type-1 receptor. Thus it may reduce proteinuria and delay the progression of renal disease in diabetic nephropathy. We investigated the effects of losartan on the mRNA expressions of membrane-type3 matrix metalloproteinases (MT3-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP-2) in diabetic kidneys in order to evaluate degradation and remodeling of the extracellular matrix. METHODS: Male Wistar rats were divided into 3 groups. Group A was the control group containing healthy rats (n = 11), group B comprised diabetic rats without any therapy (n = 11), and group C consisted of diabetic rats treated with losartan (n = 9). 24-hr urine samples were collected in order to measure urinary albumin excretion (UAE). After a period of 18 weeks, the kidneys were extracted from all rats in order to measure the mRNA expressions of MT3-MMP, TIMP-2 and transforming growth factor-beta1 (TGF-beta1) by RT-PCR. We also examined the glomerular basement membrane thickening and the mesangial matrix (MM) density (MM area/mesangial area). RESULTS: The expression of renal MT3-MMP mRNA in group B (1.37 +/- 0.96) was significantly higher than that in group A (0.75 +/- 0.34, p < 0.05), but also significantly higher than in group C (0.75 +/- 0.30, p < 0.05). Similarly, the mRNA expression of renal TIMP-2 in group B (0.73 +/- 0.37) was significantly increased compared to that in group A (0.32 +/- 0.19, p < 0.05), but also higher than in group C (0.34 +/- 0.17, p < 0.05). In addition, subjects in group B showed abundant TGF-beta1 mRNA expression and UAE compared to groups A and C, as well as significantly higher glomerular basement membrane thickening and MM density (all p < 0.05). CONCLUSIONS: We conclude that MT3-MMP and TIMP-2 production in the renal cortex of diabetic kidneys is increased. Losartan can prevent the development of diabetic nephropathy by decreasing MT3-MMP and TIMP2 production in diabetic kidneys.

The relationship of lmp2 and DR3 genes with susceptibility to type I diabetes mellitus in south China Han population.

AIM:To study the relationship of lmp2 and DR3 genes with type I diabetes mellitus.METHODS:lmp2 genotypes and DR3 were identified in 68 patients with type I diabetes mellitus (I -DM) and 71 healthy controls. Then,I -DM patients and controls were respectively allocated into DR3-positive and DR3-negative groups. The frequencies of lmp2 and DR3 gene in random subjects, and lmp2 genotypes in DR3 matched subjects were compared between I -DM patients and controls. At the same time, I DM patients were divided into 3 groups based on the onset age of diabetics:group A < = 14 years, group B 15-30 years and group C > = 31 years.RESULTS:The frequency of DR3 in I-DM patients was significantly higher than that in controls (47% vs 21%, P < 0.005), and it was significantly higher in group A than that in group B+C (70% vs 36%, X(2) = 7.07, P < 0.01). There was a significant difference among groups with different onset age of diabetics (X(2) = 8.19, rp = 0.33, P <0.05). In random subjects, the frequency of lmp2-R/R in I -DM patients was lower (43% vs 61%, P <0.05)and lmp2-R/H higher (53% vs 28%, P<0.05) than that in controls, and there was no significant difference among groups with different onset age of diabetics.In DR3-positive subjects, the frequency of lmp2-R/R in I-DM patients was lower (47% vs 87%, P<0.05) and lmp2-R/H higher (47% vs 13%, P <0.05) than that in controls. In DR3-negative subjects,the frequency of lmp2-R/H in I -DM patients was higher than that in controls (58% vs 32%, P <0.01), but the frequency of lmp2-R/R and lmp2-H/H was not significantly different between these two groups.CONCLUSION:DR3 gene may be one of the susceptible genes of I-DM,and significantly related to the onset age of diabetics, and the persons with DR3 may have an younger onset age of diabetes.The lmp2-R/R may be the protective genotype of I-DM, and lmp2-R/H the susceptible genotype. These were not affected by DR3 gene. lmp2 genotypes were not related with the onset age of diabetics.