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.

Effect of atorvastatin on LDL oxidation and antioxidants in normocholesterolemic type 2 diabetic patients.

BACKGROUND: Oxidative stress in diabetes increases lipid peroxidation, which stimulates the development of atherosclerosis. METHODS: We investigated in a 3-month placebo-controlled study with 19 normocholesterolemic type 2 diabetic patients whether treatment with 10-mg atorvastatin influenced antioxidants and reduced LDL oxidizability, assessed by in vitro production of conjugated dienes after copper-induced LDL oxidation. RESULTS: The lag phase, as a measure of the resistance of LDL to oxidation, did not change (62.8+/-8.2 respectively 59.6+/-9.7 min, p=n.s.), while conjugated dienes decreased (512+/-74 respectively 487+/-50 nmol, p=0.012). Plasma alpha-tocopherol and ubiquinol levels decreased, while their ratios to LDL cholesterol remained stable. CONCLUSIONS: Atorvastatin favourably influences some parameters of LDL oxidation. Whether this effect is clinically relevant remains to be determined.

Prognostic factors for successful insulin therapy in subjects with type 2 diabetes.

OBJECTIVE: To assess which factors influence or predict the efficacy of insulin therapy in subjects with type 2 diabetes, who were poorly controlled despite maximal doses of oral glucose lowering agents. RESEARCH DESIGN AND METHODS: Seventy-five patients with type 2 diabetes participated (mean age (+/- SD), 67 +/- 8 years; body mass index, 25.8 +/- 5.0 kg/m2; median time since diagnosis of diabetes, 8 years (range 1-36); 27 males and 48 females). They were transferred to insulin therapy, in which case either insulin alone, or a combination of insulin and glibenclamide was employed. The importance of baseline parameters (glycaemic control, beta-cell function, measures of insulin resistance) was assessed by comparing good and poor responders (defined as achieved HbA1c < 8.0 or > 9.0%) to insulin therapy, and by multiple logistic regression analysis of these baseline parameters and achieved metabolic control. RESULTS: During insulin therapy, HbA1c levels decreased from 10.9 +/- 1.3 to 8.2 +/- 1.1% (p < 0.001), and fasting blood glucose levels decreased from 14.0 +/- 2.3 to 8.2 +/- 2.1 mmol/l (p < 0.001). Thirty patients reached HbA1c levels < 8.0%, 21 of them even < 7.5%. The mean increase in body weight was 4.5 kg. HbA1c after 6 months was 7.0 +/- 0.6% in the good responders, and 9.8 +/- 0.6% in the poor responders (p < 0.001), despite a comparable insulin dose. Baseline metabolic control was similar in both groups. Also, glucagon-stimulated and calculated insulin secretion, as well as parameters of insulin resistance, such as fasting serum insulin levels, free fatty acids, and serum triglycerides, were not different between both groups, and certainly not higher in the poor responders. Also previous metformin use was not different. However, poor responders were more obese than good responders, and had significantly longer known duration of diabetes. Multiple logistic regression confirmed that only duration of diabetes and body mass index were independent predictors of response to insulin therapy. CONCLUSIONS: We conclude that in elderly patients with type 2 diabetes improvement of glycaemic control can be achieved at the expense of some weight gain. Measurement of residual insulin secretion prior to institution of insulin treatment does not discriminate between good and poor responders to this model of therapy. Especially in obese patients with longer duration of diabetes more attention is needed in order to achieve optimal glycaemic control. Combination of insulin with newer drugs, like thiazolidinediones, may perhaps achieve this.

Lipid peroxidation in type 2 diabetes: relationship with macrovascular disease?

BACKGROUND: Macrovascular disease is the leading cause of death in diabetes. The increased risk of atherosclerosis in diabetes may be partly explained by increased lipid peroxidation. METHODS: We assessed lipid peroxidation in subjects with type 2 diabetes with (n = 23) and without (n = 23) macrovascular complications versus healthy age-matched controls (n = 13). The diabetic groups were matched for glycemic control (mean HbA1c = 9%), and for age had similar known duration of diabetes. RESULTS: Plasma TBARS were comparable between diabetic subjects with and without macrovascular complications (1.89 +/- 0.32 and 1.81 +/- 0.28 mumol/l) and elevated compared to healthy controls (1.64 +/- 0.26 mumol/l, p = 0.025). Ratios of IgG and IgM antibodies to oxidized vs. native LDL were comparable between diabetic subjects and controls, and also between diabetic subjects with or without macrovascular complications. The lag phase, an index of the resistance of LDL to oxidation, was significantly longer in diabetic patients with macrovascular complications (66 +/- 8 min) vs. those without macrovascular complications and controls (resp. 59 +/- 7 and 56 +/- 7 min, p < 0.05). An explanation may be the frequent use of drugs with possible antioxidant potential, e.g. beta-blocking agents, ACE-inhibitors and calcium entry blockers by these patients. Surprisingly, plasma vitamin E levels were higher in diabetic subjects. CONCLUSIONS: We found no evidence of increased lipid peroxidation in diabetic subjects with macrovascular complications, but an increased resistance to oxidation in this group, probably due to an altered antioxidant status. The increased TBARS level in diabetic subjects contrasts with the other indices of lipid peroxidation and may be related to prevalent hyperglycemia and should therefore be interpreted cautiously.

Comparison of different insulin regimens in elderly patients with NIDDM.

OBJECTIVE: To compare the metabolic effects of three different frequently used regimens of insulin administration on blood glucose control and serum lipids, and the costs associated with this treatment, in subjects with NIDDM, who were poorly controlled with oral antihyperglycemic agents. RESEARCH DESIGN AND METHODS: We studied 95 elderly patients with NIDDM (age 68 +/- 9 years, BMI 26.0 +/- 4.6 kg/m2, and median time since diagnosis of diabetes 9 years [range 1-37]; 37 men, 58 women), who were poorly controlled, despite diet and maximal doses of oral antihyperglycemic agents. Three insulin administration regimens were compared during a 6-month period: patients were randomized for treatment with a two-injection scheme (regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was mainly instituted in an outpatient setting. RESULTS: After 6 months of insulin treatment, fasting blood glucose of the total patient population had decreased from an average of 14.1 +/- 2.2 to 8.3 +/- 2.0 mmol/L (P < 0.001), and HbA1c fell from 11.0 +/- 1.3 to 8.3 +/- 1.2% (P < 0.001); 34 patients reached HbA1c levels below 8.0%, 25 of them even below 7.5%. With two insulin injections daily, HbA1c decreased from 11.2 +/- 1.3 to 8.2 +/- 1.2%, while during combined treatment, HbA1c fell from 10.5 +/- 1.2 to 8.1 +/- 1.1% (regimen B) and from 11.1 +/- 1.3 to 8.5 +/- 1.1% (regimen C). Comparable improvement of the other measures of glycemic control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was moderate (mean +/- 4.0 kg) and similar in all patient groups. One-third of patients starting with one insulin injection daily needed a second injection to control glycemia. One episode of severe hypoglycemia was observed. Combined insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone. CONCLUSIONS: Insulin treatment can safely be instituted in elderly patients with NIDDM. However, it is difficult to obtain optimal glycemic control. Insulin has moderate beneficial effects on serum lipoproteins. Although on the basis of glycemic control and weight gain, no preference for any treatment regimen can be discerned, twice-daily insulin administration is the most simple and cost-effective regimen.

Improved blood glucose control by insulin therapy in type 2 diabetic patients has no effect on lipoprotein(a) levels.

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean +/- SD: age 67 +/- 9 years, body mass index 26.1 +/- 4.4 kg m-2, median duration of diabetes 10 (range 1-37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 +/- 2.2 mmol l-1 to 8.4 +/- 1.8 mmol l-1 (p < 0.001), and HbA1c had fallen from 11.1 +/- 1.4% to 8.2 +/- 1.1% (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10%. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8-3050 mg l-1, vs 101, range 8-1747 mg l-1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.

Glucagon-stimulated insulin secretion in patients with type 2 diabetes mellitus: support for the concept of glucose toxicity.

Parameters of blood glucose control and insulin secretion were evaluated in 114 patients with type 2 diabetes mellitus, who were no longer controlled satisfactorily by maximal doses of oral hypoglycaemic agents, and compared with those obtained in 11 healthy control subjects, 32 patients with recently-diagnosed type 2 diabetes, and 16 tablet-treated and 36 insulin-treated patients. Newly-diagnosed patients were slightly younger (60 +/- 13 yr) and had a slightly higher body mass index (29.4 +/- 6.5 kg/m2). Known duration of diabetes was 9 yr (range 1-37) in secondary failure, and 11 yr (range 1-31) in insulin-treated patients. Fasting blood glucose was the highest (13.8 +/- 2.8 mmol/l) in secondary failure and newly-diagnosed patients (12.6 +/- 3.8 mmol/l) compared to tablet-treated (8.7 +/- 3.3 mmol/l) and insulin-treated patients (9.6 +/- 3.2 mmol/l, p less than 0.05). HbA1c levels were comparably elevated. In insulin-treated patients, fasting plasma C-peptide levels were lower relative to the mutually comparable levels in the other 3 diabetic groups. Fasting plasma insulin levels did not differ between the 4 diabetic groups. C-peptide release after glucagon (C-peptide AUC) was comparable in all 4 diabetic groups, although in tablet-treated patients the ratio C-peptide AUC/fasting blood glucose was higher (p less than 0.05). We conclude that the clinical usefulness of determining residual insulin secretion in type 2 diabetic patients is limited, and that the similar reduction of insulin secretion in severely hyperglycaemic newly-diagnosed and secondary failure type 2 diabetic patients supports the concept of "glucose toxicity".

[The effects of insulin combined with glibenclamide on glucose and lipid metabolism in patients with Type II diabetes mellitus]. / De effecten van insuline in combinatie met glibenclamide op glucose- en vetstofwisseling bij patiënten met diabetes mellitus type II.

We compared the effects of twice-daily insulin injections (n = 22) with combined insulin-glibenclamide therapy (n = 25) on glucose and lipid metabolism in 47 type II diabetic patients (age 69 (SD 9) years, BMI 25.5 (4.8) kg/m2, diabetes duration 9 (range 1-34) years) with secondary failure to sulphonylurea. After 6 months, weight gain averaged 4.2 kg (p less than 0.05), fasting blood glucose had decreased from 14.6 to 8.5 mmol/l (p less than 0.001), HbA1c from 10.9% to 8.1% (p less than 0.001). Twenty-one patients reached HbA1c levels less than 8.0%. Patients on insulin alone injected more insulin (42 vs 26 U daily, p less than 0.01). The decrease of fasting blood glucose and HbA1c was comparable in both groups (p less than 0.001). HDL-cholesterol increased (insulin: 1.10 to 1.24 mmol/l, combined therapy: 1.03 to 1.14 mmol/l, both p less than 0.01), while plasma triglycerides and NEFA decreased (p less than 0.01). Only in patients on insulin alone did total cholesterol decrease from 7.1 to 6.3 mmol/l (p less than 0.001), and LDL-cholesterol from 4.7 to 4.1 mmol/l (p less than 0.05). Apolipoproteins AI, AII and B did not show significant changes. Almost all patients reported improved wellbeing; no severe hypoglycaemias were observed.