Time course of specific AGEs during optimised glycaemic control in type 2 diabetes.

BACKGROUND: Several advanced glycation endproducts (AGEs) are formed in the hyperglycaemic state. Although serum AGEs correlate with average glycaemic control in patients with type 2 diabetes and predict the development of complications, it is not known how serum AGEs change during optimisation of diabetes therapy. METHODS: We evaluated the change in serum levels of total AGE and the AGEs CML (Nepsilon-carboxymethyllysine) and MGHI (methylglyoxal-derived hydroimidazolone), as well as markers of endothelial function in 28 subjects with type 2 diabetes, who were poorly controlled on oral agents,before and after the institution of insulin therapy. RESULTS: Mean subject age (+/- SEM) was 58 +/- 2 years,body mass index 27.7 +/- 0.8 kg/m2, and known duration of diabetes was 8.1 +/- 0.9 years. With insulin treatment fasting blood glucose levels dropped from 12.1 +/- 0.9 mmol/l to 6.9 +/- 0.3 and 8.1 +/- 0.4 mmol/l after three and six months, respectively (both p<0.001), while HbA1c decreased from 10.0 +/- 0.3 to 7.8 +/- 0.2% (p<0.001). Endothelial function improved as indicated by a small but significant decrease in soluble intercellular cell adhesion molecule (sICAM-1) (152 +/- 10 to 143 +/- 8 ng/ml, p<0.02)and sE-selectin (111 +/- 16 to 102 +/-12 ng/ml, p<0.02)levels. In contrast, we observed only a tendency towards a decrease in CML levels (110 +/-22 to 86 +/- 13 microg/mg protein, p=ns), but a small increase of MGHI (from 0.23 +/- 0.02 to 0.29 +/- 0.04 U/mg protein, p<0.02). At baseline, 16 patients were on metformin, which is known to reduce methylglyoxal levels and reduce generation of reactive oxygen species. They had similar levels of CML and MGHI to the 12 non-metformin users, although their HbA1c was lower (9.4 +/- 0.3 vs 10.7 +/- 0.6 %). During insulin, patients receiving concomitant metformin therapy showed a similar course of CML and MGHI to those not taking metformin. CONCLUSION: Although insulin therapy improved HbA1c and markers of endothelial function, the levels of serum AGEs did not follow the same time course. This suggests that these specific AGEs are influenced by other factors in addition to overall glycaemia, such as oxidative stress.

Serum levels of advanced glycation end products are increased in patients with type 2 diabetes and coronary heart disease.

OBJECTIVE: To investigate whether serum levels of advanced glycation end products (AGEs) and the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) are increased in patients with type 2 diabetes compared with nondiabetic control subjects and whether levels of AGEs and/or CML differ in patients with type 2 diabetes with or without coronary heart disease (CHD). RESEARCH DESIGN AND METHODS: Serum levels of AGEs and CML were measured with an immunoassay in 32 men and 21 women aged 59.3+/-6.2 years (means +/- SD) with type 2 diabetes for 7.3 + 3.1 years and in 17 men and 17 women aged 56.2+/-4.2 years without diabetes. Of the patients with diabetes, 18 had CHD. RESULTS: The serum levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects (median [5th-95th percentile]: AGEs 7.4 [4.4-10.9] vs. 4.2 [1.6-6.4] U/ml, P < 0.0001; CML 15.6 [5.6-29.9] vs. 8.6 [4.4-25.9] U/ml, P < 0.0001). The median level of AGEs but not CML was significantly increased in patients with type 2 diabetes and CHD compared with patients without CHD (8.1 [6.4-10.9] vs. 7.1 [3.5-9.8] U/ml, P = 0.03). There were significant positive correlations between serum levels of AGEs and CML in both patients and control subjects. CONCLUSIONS: Levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects, and levels of AGEs but not CML were significantly higher in patients with type 2 diabetes and CHD than in patients without diabetes. These results may indicate a role for non-CML AGEs in the development of macrovascular disease in patients with type 2 diabetes.

Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes.

A time-delayed fluorescence immunoassay was developed for the determination of serum levels of methylglyoxal (MG)-derived hydroimidazolone using a monoclonal antiserum raised against Nalpha-acetyl-Ndelta-(5-hydro-5-methyl)-4-imidazolone, Europium-labeled anti-mouse IgG antiserum as indicator, and MG modified bovine serum albumin (BSA) as standard. Serum levels of hydroimidazolone were measured in 45 patients with type 2 diabetes aged 59.4 +/- 6.1 (mean +/- SD) years and with duration of diabetes of 7.3 +/- 3.1 years, and in 19 nondiabetic controls aged 56.3 +/- 4.3 years. The serum levels of hydroimidazolone were significantly higher in patients compared to controls: median, 3.0 (5-95 percentile, 1.6 to 5.4) U/mg protein versus 1.9 (1.2 to 2.8) U/mg protein (P =.0005). Significant positive correlations were observed between the serum levels of hydroimidazolone and serum levels of advanced glycation end products (AGEs), measured with a polyclonal anti-AGE antibody: r = 0.59 for patients (P <.0001), and r = 0.65 for controls (P =.002). Similarly, significant correlations were also found between serum levels of hydroimidazolone and N(epsilon)-(carboxymethyl)-lysine (CML): r = 0.36 in patients and r = 0.55 for controls (both P =.02). Serum hydroimidazolone levels did not correlate with fasting plasma glucose or hemoglobin A(1c) (HbA(1c)) levels. The observed differences between patients with diabetes and nondiabetic controls seem to be comparable to differences measured for other AGE compounds.

Eating fish may reduce infarct size and the occurrence of Q wave infarcts.

OBJECTIVE: The present investigation was carried out to see whether intake of fish could influence infarct size as assessed by peak enzyme levels (CKmax and LDmax) as well as the occurrence of Q wave infarcts. DESIGN: The investigation was a prospectively planned cohort study. SETTING: The investigation was carried out at Ullevål University Hospital, Department of Cardiology and Department of Pharmacotherapeutics, University of Oslo, Oslo, and in four other Hospitals in Oslo and Lillehammer. SUBJECTS: Seven hundred and forty-five patients (median age 70 y, 64% males) admitted with proven acute myocardial infarction. RESULTS: Crude effects showed that the regression lines between the number of fish meals/week (FM/week) and CKmax in all patients and in the restricted cohorts of patients receiving/not receiving thrombolytic treatment were: y = 2086-157.x(2P = 0.004); y = 2807-156.x (2P = 0.110) and y = 1260-54.x (2P = 0.230); the corresponding results regarding LDmax were: y = 1329-76.x (2P = 0.009); y = 1556-73.x (2P = 0.120) and y = 1047-39 x (2P = 0.230). Odds ratio (OR) for developing Q wave infarcts in patients consuming > 1.0 FM/week was 0.52, 95% confidence interval (CI) 0.34-0.79; 2P = 0.001. For the adjusted effects, the coefficients of FM/week for log (peak enzyme levels) in all three groups of patients (all patients, and the restricted cohorts of patients receiving/not receiving thrombolytic treatment) were negative with 2P values of 0.014, 0.033 and 0.165 (CKmax), and 0.006, 0.033 and 0.158 (LDmax). OR for developing Q wave infarcts in patients consuming > 1.0 FM/week was 0.59, 95% CI 0.38-0.92; 2P = 0.022. CONCLUSIONS: The results indicate that consuming fish may reduce infarct size as assessed by CKmax and LDmax as well as the occurrence of Q wave infarcts.

Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study.

AIMS/HYPOTHESIS: AGEs, modification products formed by glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes. We investigated whether increased serum levels of AGEs predict total, cardiovascular (CVD) or CHD mortality in a population-based study. SUBJECTS AND METHODS: Serum levels of AGEs were determined by immunoassay in a random sample of 874 Finnish diabetic study participants (488 men, 386 women), aged 45-64 years. These participants were followed for 18 years for total, CVD and CHD mortality. RESULTS: Multivariate Cox regression models revealed that serum levels of AGEs were significantly associated with total (p = 0.002) and CVD mortality (p = 0.021) in women, but not in men. Serum levels of AGEs in the highest sex-specific quartile predicted all-cause (hazards ratio [HR] 1.51; 95% confidence intervals [CI], 1.14-1.99; p = 0.004), CVD (HR 1.56; 95% CI 1.12-2.19; p = 0.009), and CHD (HR 1.68; 95% CI 1.11-2.52; p = 0.013) mortality in women, even after adjustment for confounding factors, including high-sensitivity C-reactive protein. CONCLUSIONS/INTERPRETATION: Increased serum levels of AGEs predict total and CVD mortality in women with type 2 diabetes.

Infarct size as estimated from peak creatine kinase and lactate dehydrogenase is probably reduced in patients using calcium antagonists at the onset of symptoms.

In animal models, calcium antagonists (Ca-A) administered before ischemia and reperfusion reduced myocardial necrosis, attenuated postischemic contractile dysfunction, and reduced tissue calcium. In 753 patients with acute myocardial infarction (AMI), we examined if use of Ca-A at the onset of symptoms (n = 127 patients) reduced infarct size as estimated from peak creatine kinase (CKmax) and lactate dehydrogenase (LDmax) activities. The study had an observational exposed/nonexposed design, and both crude and adjusted effects were investigated. Crude effects: In the restricted cohort of patients not receiving thrombolytic treatment (thr- pts; n = 411 patients), CKmax and LDmax were lower in Ca-A+ patients than in Ca-A- patients, being 643 versus 887 U/l (2 p = 0.004) and 708 versus 867 U/l (2 p = 0.005), respectively. When using log (CKmax) and log (LKmax) as outcomes, the same results were found (2 p = 0.002). More of the restricted cohort of the pts used Ca-A in the lower quartiles of CKmax and LDmax (p for linear trend = 0.005 and 0.004 for CKmax and LDmax, respectively). Adjusted effects: Thrombolysis was an effect modifier of the association between Ca-A and peak enzyme levels. In thr-pts, the coefficients of Ca-A were negative and borderline significant for log (CKmax; 2 p = 0.088) and negative and highly significant for log (LDmax; 2 p = 0.010) when adjusting for confounders. The present observational study indicates that the use of a Ca-A at the onset of AMI reduces infarct size, as estimated from CKmax and LDmax activities.

Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1-year multicentre study.

AIMS: To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes. METHODS: Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily. RESULTS: Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively). CONCLUSIONS: Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

[Hypoglycemic treatment of type 2 diabetes]. / Blodsukkersenkende behandling ved type 2-diabetes.

BACKGROUND: Hyperglycaemia in type 2 diabetes results from reduced beta-cell function and insulin resistance. The treatment of type 2 diabetes must be targeted against both conditions to reduce symptoms of hyperglycaemia and the risk of diabetic late complications. MATERIAL AND METHODS: In this review we cover the recent scientific documentation from long term studies on treatment effects. We also discuss the different treatments available. RESULTS: Recent clinical trials have shown that lowering blood glucose levels over time significantly reduces development of microvascular complications in type 2 diabetes. There are several treatment options available which make adequate blood glucose control possible in patients with type 2 diabetes. INTERPRETATION: A reduction in the development of microvascular complications in type 2 diabetes is an achievable goal.

Use of fish oils appears to reduce infarct size as estimated from peak creatine kinase and lactate dehydrogenase activities.

In 753 patients with acute myocardial infarction, use of fish oils (FO, n = 242) before onset of infarction seemed to reduce infarct size as estimated from peak creatine kinase (CKmax) and lactate dehydrogenase (LDmax) activities. The study had an observational exposed/nonexposed design, and both crude and adjusted effects were looked for. CRUDE EFFECTS: In the restricted cohort of patients not receiving thrombolytic treatment (n = 411), FO reduced CKmax from 879 to 759 U/l (2 p = 0.030) and LDmax from 870 to 768 U/l (2 p = 0.011), respectively. More of these patients in the lowest enzyme quartiles used FO, p for linear trend was for CKmax 0.008 and for LDmax 0.06, respectively. ADJUSTED EFFECTS: In patients not receiving thrombolytic treatment, FO reduced CKmax (2 p = 0.007) and LDmax (2 p = 0.005), but in patients receiving such treatment, CKmax and LDmax values increased, 2 p being 0.036 and 0.097, respectively. In patients not receiving thrombolysis, FO increased the incidence of small infarcts (the 25% quartile), odds ratio for CKmax was 1.82 (2 p = 0.018) and for LDmax 1.66 (2 p = 0.048), respectively. The results indicate that FO may reduce infarct size and the incidence of large infarcts. In addition, FO seems to enhance the effect of thrombolysis.

Heterogeneity of non-insulin-dependent diabetes expressed as variability in insulin sensitivity, beta-cell function and cardiovascular risk profile.

AIMS: The present study investigated the variability in insulin sensitivity and beta-cell function and their relationship to anti-glutamic acid decarboxylase (GAD) positivity and the metabolic syndrome in a group of patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: Fifty-four subjects aged 59.5 +/- 6.1 (mean +/- SD) years with NIDDM for 7.9 +/- 3.9 years referred to hospital due to poor glycaemic control, were investigated. Insulin sensitivity was determined by the euglycaemic hyperinsulinaemic glucose clamp technique as the glucose disposal rate relative to the insulin level obtained (GDRI), and also estimated with the homeostasis model assessment (HOMA-S). beta-cell function was measured by assaying the fasting and glucagon-stimulated C-peptide levels and with the HOMA-B. RESULTS: The insulin sensitivity varied 18-fold between subjects when estimated with the clamp and six-fold when estimated with HOMA-S, and was lower the more criteria for the metabolic syndrome present (P = 0.0001 by anova). The beta-cell function varied four-fold when measured as stimulated C-peptide, and eight-fold when estimated with the HOMA-B. The levels of fasting C-peptide and HOMA-B values tended to be lower in anti-GAD+ (n = 11) than in anti-GAD-subjects (P = 0.06 and P = 0.08, respectively). From previously published coronary risk charts, we estimated the 10-year risk of a coronary heart disease (CHD) event to be > 20% in 17 of 39 patients free from cardiovascular disease at the time of study, 16 of whom qualified for a diagnosis of the metabolic syndrome. CONCLUSIONS: The wide variations in insulin sensitivity and beta-cell function found among subjects with NIDDM support the notion that the disorder is highly heterogeneous. Reduced insulin sensitivity was clearly related to the metabolic syndrome and an increased risk for CHD.