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Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial.

Little is known about the metabolic or cardiovascular effects of selective ER modulators (SERMs), such as raloxifene hydrochloride (RLX), in postmenopausal women with type 2 diabetes mellitus (DM). Therefore, the effect of RLX vs. placebo (PL) on glycemic control, insulin sensitivity, as well as effects on a number of hormone, lipid, coagulation, and safety factors were determined in 30 postmenopausal women with type 2 DM in a randomized, double blind, cross-over trial. All participants had a SHBG serum concentration below 60 nmol/liter at baseline and had stable diabetes controlled by either oral hypoglycemic agents or diet for 1 month. In the first treatment period, participants received 12 wk of either PL or RLX, followed by an 8-wk washout before the second treatment period. In the second treatment period, participants were crossed over to the other treatment. Compared with PL, RLX did not significantly affect fasting blood glucose, hemoglobin A(1c), lipids, fasting insulin, or insulin sensitivity (as measured by the euglycemic clamp technique). Compared with PL, RLX reduced fibrinogen levels by 0.77 g/liter (P < 0.001), IGF-I by 2.4 nmol/liter (P < 0.001), and free T by 0.73 pmol/liter (P = 0.038) and increased SHBG by 5.5 nmol/liter (P = 0.001) and IGF-binding protein-3 by 0.57 ng/ml (P = 0.007). Our results demonstrate that RLX does not significantly affect glycemic control and has favorable or neutral effects on selected surrogate markers of cardiovascular risk in postmenopausal women with type 2 diabetes mellitus while decreasing hyperandrogenicity in these patients.

Aged↗

Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial.

OBJECTIVE: Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. RESEARCH DESIGN AND METHODS: People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet(morn+bed)) or at a 12-h interval (IDet(12h)). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart. RESULTS: With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet(12h) vs. NPH, -1.5 mmol/l [95% CI -2.51 to -0.48], P = 0.004; IDet(morn+bed) vs. NPH, -2.3 mmol/l (-3.32 to -1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet(morn+bed) group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference -0.18% [-0.34 to -0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet(12h) vs. NPH, -0.8 kg [-1.44 to -0.24], P = 0.006; IDet(morn+bed) vs. NPH, -0.6 kg [-1.23 to -0.03], P = 0.040). CONCLUSIONS: Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs.

Adult↗

Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin.

Fifty-seven type 2 diabetic patients with metabolic syndrome and on insulin were assessed by a paired analysis before and 6 months after addition of metformin as combination therapy to evaluate the impact of the association on glycemic control, blood pressure, and lipid profile. This was a historical cohort study in which the files of type 2 diabetic patients with metabolic syndrome on insulin were reviewed. The body mass index (BMI), waist circumference, lipid profile, A1C level, fasting blood glucose level, daily dose of NPH insulin, systolic blood pressure, and diastolic blood pressure were assessed in each patient before the start of metformin and 6 months after the initiation of combination therapy. Glycemic control significantly improved (P < 0.001) after the addition of metformin (1404.4 +/- 565.5 mg/day), with 14% of the 57 patients reaching A1C levels up to 7%, and 53% reaching values up to 8%. There was a statistically significant reduction (P < 0.05) of total cholesterol (229.0 +/- 29.5 to 214.2 +/- 25.0 mg/dL), BMI (30.7 +/- 5.4 to 29.0 +/- 4.0 kg/m2), waist circumference (124.6 +/- 11.7 to 117.3 +/- 9.3 cm), and daily necessity of insulin. The reduction of total cholesterol occurred independently of the reductions of A1C (9.65 +/- 1.03 to 8.18 +/- 1.01%) and BMI and the reduction of BMI and WC did not interfere with the improvement of A1C. In conclusion, our study showed the efficacy of the administration of metformin and insulin simultaneously without negative effects. No changes were detected in HDL-cholesterol or blood pressure.

Blood Glucose↗

A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes.

OBJECTIVE: This open-label, active-controlled study investigated the cardiac safety and antihyperglycemic effect of rosiglitazone (RSG) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Of the 203 patients randomly assigned to RSG (4 mg b.i.d.) or glyburide (GLB) (titrated to achieve optimal glycemic control for the first 8 weeks only to limit the risk of hypoglycemia; mean 10.5 mg/day), 118 had an echocardiogram performed at week 52. Left ventricular (LV) mass index, ejection fraction, and left ventricular end-diastolic volume were assessed by M-mode echocardiography at baseline and weeks 12, 28, and 52; 24-h ambulatory blood pressure was assessed at baseline and at weeks 28 and 52. Glycemic control was assessed by measuring fasting plasma glucose (FPG) and HbA(1c). RESULTS: Neither treatment produced an increase in LV mass index that exceeded 1 SD. Ejection fraction did not change in either group. Both groups had clinically insignificant increases in LV end-diastolic volume. RSG, but not GLB, caused a statistically significant reduction in ambulatory diastolic blood pressure. Both treatments reduced HbA(1c) and FPG. CONCLUSIONS: A total of 52 weeks of therapy with RSG (4 mg b.i.d.) did not adversely affect cardiac structure or function in patients with type 2 diabetes and produced significant and sustained reductions in hyperglycemia. Decreases in ambulatory diastolic blood pressure with RSG were superior to those with GLB.

Adult↗

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

Blood Glucose↗

Glycemic control and lens transparency in patients with type 1 diabetes mellitus.

PURPOSE: To assess quantitatively the cumulative effect of hyperglycemia on lens transparency in patients with juvenile type 1 diabetes mellitus. METHODS: Subjects were 30 patients (30 eyes) with type 1 diabetes mellitus who had well-documented records on the duration of diabetes mellitus and condition of glycemic control from the onset. They were 35 years of age or younger (mean, 26.0 years), had a history of type 1 diabetes mellitus at least 5 years (mean, 8.4 years), had corrected visual acuity of 20/20 or better, and showed no clinically apparent cataract on slit-lamp examination. Twenty-one eyes of 21 subjects served as age-matched normal controls. They were 35 years of age or younger (mean, 25.7 years), had no diabetes mellitus, had corrected visual acuity of 20/20 or better, and showed no signs of cataract on slit-lamp examination. The degree of lens opacity was quantified using the anterior eye segment analysis system based on the Scheimpflug principle. An index was created to represent the cumulative effect of long-term glycemic control (hyperglycemic accumulation) by multiplying the average hemoglobin A(1c) value and the number of months from the onset. RESULTS: The patients with diabetes mellitus exhibited significantly greater degree of lens opacity than the normal controls (P =.017, Mann-Whitney U-test). Among the patients with diabetes mellitus, the lens opacity was greater in eyes with retinopathy than those without retinopathy (P =.011). Multiple regression analysis revealed that only the index of hyperglycemic accumulation significantly correlated with the degree of lens opacity (P =.042). CONCLUSION: Accumulated effect of hyperglycemia is related to the lens transparency in patients with diabetes.

Adult↗

[Risk of infections and glycemic control in type 2 diabetes mellitus].

BACKGROUND AND OBJECTIVE: Although association between Diabetes Mellitus (DM) type 2 and prevalence of infections is a frequently considered issue in current literature there is few evidence of it. The objective of this study has been to analyse the infection risk in DM type 2 patients according to their glycemic control level (Hb Aic%). PATIENTS AND METHOD: In this cohort-study of 740 patients, we evaluated the incidence rates of infectious episodes in DM2-type diabetic patients during a period of 5 years, from May, 1997 to May, 2002. RESULTS: The average period of follow-up was 4.26 years. We found no significant correlation (p=0.33) between higher levels of HbAic% and presentation of infections. Data clearly show a direct correlation between risk of infection and number of associated chronic diseases (p=0.035), age (p=0.007) and diabetes duration (0.012). We also found an unexplained association between more aggressive treatment and higher glycemic levels (Hb Aic%) (p=0.0001) and also higher infection risk (0.038). CONCLUSIONS: Although there is no association between risk of infection and glycemic control (Hb Aic%) among analysed patients, this study shows a clear correlation between risk of infection and number of complications or number of associated chronic diseases.

Adult↗

Does bromocriptine improve glycemic control of obese type-2 diabetics?

BACKGROUND: Various oral hypoglycemic agents have already been administered to type-2 diabetic patients to normalize their plasma glucose concentrations but they have not had complete and sustained success. In recent years, bromocriptine has been tried with controversial results. In present study, the effect of bromocriptine on glycemic control was evaluated in obese type-2 diabetic patients. METHODS: In a double-blind placebo-controlled clinical trial, 40 obese patients with type-2 diabetes (aged 32-70 years) were randomly allocated to the two treatment groups. The first group received bromocriptine (2.5 mg daily) for a total of 3 months. The second group received placebo. They had been uncontrolled on fixed doses of glibenclamide or its combination with metformin in the 3 months before enrolling in the study. The fasting plasma glucose (FPG) level and glycosylated hemoglobin (HbA1) were measured and body mass index (BMI) was calculated before and 1, 2 and 3 months after treatment. RESULTS: The FPG level decreased in the bromocriptine-treated group from 10.59 +/- 0.42 to 9.06 +/- 0.41 mmol/l (mean +/- SEM; p < 0.01), whereas in the placebo group it was not changed, 10.69 +/- 0.52 and 10.6 +/- 0.57 mmol/l, respectively. The HbA1 concentration was reduced in the bromocriptine-treated group from 9.9 +/- 0.3 to 9.5 +/-0.2% (p = 0.06), whereas it increased in the placebo-treated group from 10.2 +/- 0.3 to 11.3 +/- 0.6% (p < 0.05). The differences in HbA1 (1.8%, p < 0.01) and FPG (1.55 mmol/l, p < 0.05) levels between the bromocriptine and placebo groups at 3 months were significant. No changes in body weight or BMI occurred during the study in either placebo- or bromocriptine-treated group. CONCLUSION: The data further support the contention that bromocriptine improves glycemic control in obese type-2 diabetic patients, although the mechanism of action remains to be determined.

Adult↗

Glycemic control and cardiovascular disease in type 2 diabetes: a review.

Cardiovascular disease is the major cause of morbidity and mortality in people with Type 2 diabetes, and risk of atherosclerotic disease is markedly increased in people with diabetes compared to people with normal glucose tolerance. The excess risk can not be completely explained by increased prevalence of other cardiovascular disease risk factors such as hypertension and hyperlipidaemia in people with diabetes. This review examines the role of hyperglycemia and glycemic control in cardiovascular disease in people with Type 2 diabetes. The results of prospective observational studies and randomized controlled trials are summarized. We conclude that control of hypertension and hyperlipidemia are important to reduce risk of cardiovascular disease in people with diabetes and may be more easily achieved than tight glycemic control.

Cardiovascular Diseases↗

Glycemic control in English- vs Spanish-speaking Hispanic patients with type 2 diabetes mellitus.

BACKGROUND: Hispanic individuals compose the fastest growing minority group in the United States, yet little is known about how language impacts their health care. The primary objective of this study was to determine whether the inability to speak English adversely affected glycemic control in Hispanic patients with type 2 diabetes mellitus. METHODS: This retrospective cohort study selected 183 Hispanic patients with type 2 diabetes mellitus aged 35 to 70 years from a public health care system; patients were Spanish-speaking (SS) only, and control patients were English-speaking (ES) or bilingual. Clinical information was collected via telephone survey, and data on health care use, diagnosis, and glycosylated hemoglobin A(1c) (HbA(1c)) values were obtained from administrative and laboratory information systems. RESULTS: Values of HbA(1c) for SS (mean, 9.1%; range, 5.0%-15.3%) and ES (mean, 9.0%; range, 4.9%-16.2%) patients with diabetes mellitus and the total number of hospitalizations related and unrelated to diabetes mellitus did not differ (P =.86). Spanish-speaking patients had a diagnosis of diabetes mellitus for fewer years than ES patients (8.2 and 11.2 years, respectively; P =. 01). Spanish-speaking patients were less likely to understand their prescriptions; 22% of SS patients reported no comprehension vs 3% of ES patients (P =.001). There was a trend toward decreased prevalence of insulin use among SS patients compared with ES patients (30% vs 42%, respectively; P =.07). CONCLUSIONS: Glycemic control in Hispanic patients was not related to their ability to speak English. This finding may be explained by a high degree of language concordance between patients and providers.

Adult↗

Glycemic control and nutrition in the intensive care unit.

PURPOSE OF REVIEW: Hospital clinicians frequently encounter hyperglycemia due to diabetes or the stress of critical illness in patients who are receiving nutrition support. RECENT FINDINGS: A growing body of evidence suggests that hyperglycemia in the hospital is associated with adverse outcomes (e.g. disability after acute cardiovascular events, infection and death) and that improvement in outcomes can be achieved with improved glycemic control or insulin. Therefore, familiarity with the implications of hyperglycemia and with its treatment are essential for clinicians practicing in hospital settings. SUMMARY: Questions persist regarding the optimal glucose goal range in differing patient groups. In addition, while the technology to deliver glycemic control in intensive care unit settings is widely available, data are limited about effective and safe insulin infusions. Research should focus on the risks and benefits of providing nutrition support in this group of patients, optimal glucose goal ranges, and on methods of achieving desired glucose goal ranges.

Blood Glucose↗

Post-diagnosis family adaptation influences glycemic control in women with type 2 diabetes mellitus.

Family adaptation to type 2 diabetes management after nutrition education was studied as part of a 2.5-year ethnography. Data analysis included descriptive data (observations, transcribed audio recordings, written field notes) and quantitative data (self-monitored morning fasting blood glucose, food records) from the families of 5 New York suburban women. The following inferences emerged from data analysis. Among the women with improved glycemic control, the home and family routines had changed. Diabetes management was observed as certain tasks: food tasks, patient care tasks, management tasks, and medical advice tasks. The social context of the women's daily lives influenced their glycemic control; specifically, family members other than the women with diabetes took on new "hospital roles and routines." Nutrition education should be directed toward assessing existing family social support and helping women organize and supplement this support to ensure the successful completion of the tasks of diabetes self-management.

Adaptation, Psychological↗

Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes.

OBJECTIVE: It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS: A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS: Accrual goals were met, mean follow-up time was 27 months (range 18-35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS: Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

Aged↗

Changes in activities of enzymes related to energy metabolism in peripheral leukocytes of diabetic dogs with glycemic control by intensive insulin treatment.

Changes in plasma glucose, immunoreactive insulin (IRI), and free fatty acids (FFA) concentrations and activities of enzymes related to energy metabolism in peripheral leukocytes were measured in type 1 diabetic dogs induced by streptozotocin administration before and after intensive insulin treatments. Before the insulin treatment, the plasma glucose concentrations were over 16.7 mmol/L and the activities of enzymes remarkably decreased in leukocytes of the diabetic dogs. In particular, malate dehydrogenase (MDH) activities decreased significantly. After glycemic control was achieved by insulin treatment, the plasma glucose concentrations were maintained between 6.8 and 7.7 mmol/L and the activities of enzymes restored to those in the control dogs. The changes in ML ratio (cytosolic MDH/lactate dehydrogenase specific activity ratio) reflected faithfully to metabolic conditions of animals and were considered to be a useful parameter to evaluate glycemic control and the effect of injected insulin in the diabetic dogs.

Animals↗

CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes.

BACKGROUND: The role of non-specific inflammation in beta-cell loss in type 1 diabetes is unclear. In the present study, inflammatory markers were determined in patients with newly diagnosed disease and related to beta-cell function, glycemic control and autoimmunity. METHODS: Ninety-seven adult patients with type 1 diabetes mellitus (80% islet antibody positives, ab(+)) were examined at diagnosis and 3, 6, 9 and 12 months after the start of insulin treatment. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, islet autoantibodies, insulin requirement and HbA(1c) were assessed. RESULTS: The concentrations of CRP were high-normal at diagnosis and did not change during the study period. A positive correlation between CRP at diagnosis and BMI was observed in ab(+) as well as in ab(-) cases. Detectable concentrations of IL-6 were found in 32% (157/485) of the samples and did not change during the study. Ab(-) patients had higher values of CRP at diagnosis and throughout the study compared to the ab(+). Among the ab(+) patients, CRP concentrations during the study were positively correlated to C-peptide at 12 months and an increase in HbA(1c) levels between 6 and 12 months. No associations between the presence or levels of islet autoantibodies and CRP were noted. CONCLUSIONS: In type 1 diabetes, the islet destructive process and the development of beta-cell remission are not associated with changes in CRP or IL-6. Instead, elevated CRP concentrations are prevalent and seem to reflect insulin resistance, as positive associations to BMI, C-peptide and deterioration of glycemic control were observed.

Adolescent↗

Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension.

BACKGROUND: n-3 Fatty acids lower blood pressure, improve lipids, and benefit other cardiovascular disease risk factors. Effects on glycemia in patients with type 2 diabetes are uncertain. OBJECTIVE: We determined whether purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on glycemic control, including insulin sensitivity and stimulated insulin secretion; 24-h ambulatory blood pressure; and serum lipids in type 2 diabetic patients with treated hypertension. DESIGN: In a double-blind, placebo-controlled trial of parallel design, 59 subjects were randomly assigned to consume 4 g EPA, DHA, or olive oil/d for 6 wk while continuing to consume their usual diet. RESULTS: Thirty-nine men and 12 postmenopausal women with a mean (+/- SE) age of 61.2 +/- 1.2 y completed the study. In comparison with the change from baseline in fasting glucose in the olive oil group, fasting glucose in the EPA and DHA groups increased 1.40 +/- 0.29 mmol/L (P = 0.002) and 0.98 +/- 0.29 mmol/L (P = 0.002), respectively. Neither EPA nor DHA had significant effects on glycated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure. Serum triacylglycerols in the EPA and DHA groups decreased 19% (P = 0.022) and 15% (P = 0.022), respectively. There were no significant changes in serum total, LDL, or HDL cholesterol, although HDL(2) cholesterol in the EPA and DHA groups increased 16% (P = 0.026) and 12% (P = 0.05), respectively. HDL(3) cholesterol decreased 11% (P = 0.026) with EPA supplementation. CONCLUSIONS: EPA and DHA had similar benefits on lipids but adverse effects on short-term glycemic control in hypertensive diabetic patients. The overall implications for cardiovascular disease require long-term evaluation.

Aged↗

Rat tissue collagen modified by advanced glycation: correlation with duration of diabetes and glycemic control.

Collagenous proteins are especially prone to nonenzymatic glycation, because they contain several dibasic amino acid residues with free amino groups, have a very slow turnover rate, and are exposed to ambient levels of glucose. The aim of this study was to determine the time-dependent course of advanced glycation process in diabetic rats in relation to glycemic control and duration of diabetes, compared to age-matched controls. Immunochemical assay with antibodies to advanced glycation end products (AGE) was first developed to qualitatively detect and quantify the AGE formed in rat tendon and aortic collagen. Individual collagen samples were extracted by extensive pepsin and collagenase digestion. The amount of AGE was measured by competitive ELISA and results were expressed as AGE U/mg collagen. Diabetic rats showed a significant increase in AGE content in aortic collagen at 20 weeks (n = 6, 206.6 +/- 16.7 U/mg collagen) compared with that measured at 4 and 12 weeks (n = 6, 110 +/- 12.8 U/mg collagen, and n = 13, 184.9 +/- 12.3 U/mg collagen at 4 and 12 weeks, respectively; p < 0.001 between 20 weeks and 4 weeks; p < 0.01 between 20 weeks and 12 weeks). The amount of AGE in tendon collagen of diabetic rats increased from 1.9 +/- 0.38 U/mg at 4 weeks to 11.2 +/- 6.1 U/mg collagen at 20 weeks, p < 0.001. Considerable disparity was observed in the intensity of glycation between aortic and tendon collagen. AGE-content per mg of aortic collagen was several-fold to that found in tendon collagen (p < 0.001). To investigate the effect of glycemic control on the advanced glycation process, total aortic AGE-collagen content was compared between untreated diabetic rats (D; n = 13, 184.9 +/- 12.3 U/mg) and diabetic rats treated for 12 weeks with insulin (DI; n = 6, 133.9 +/- 10.7 U/mg), or phlorizin (DP; n = 6, 132.4 +/- 8.9 U/mg), or by a combination of insulin/phlorizin (DIP; n = 6, 124.3 +/- 6.5 U/mg). In spite of therapy used, all groups of diabetic animals had a significantly higher aortic AGE-collagen content than those in the nondiabetic control group (C: n = 8, 104.6 +/- 14.9 U/mg) of the same age (D, DI, DP, DIP vs. C, p < 0.001). Comparison between the mean levels of glycated hemoglobin (D: 5.62 +/- 0.38 % vs. C: 1.7 +/- 0.05%) and mean AGE levels in the studied group of animals yielded a very good exponential correlation (r = 0.89, p < 0.001). Glycation-derived late-stage collagen modification was detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and by immunoblotting confirmed to contain (an) AGE-structure(s). Our study provides strong immunochemical evidence of AGE formation in vivo during hyperglycemia, and of their temporal association with structural alterations of extracellular matrix proteins. The advanced glycation process is retarded and reduced in intensity, but not completely abolished, by glycemia regulation with, or independently of, insulin.

Alloxan↗

Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study.

BACKGROUND: Patients with type 2 diabetes mellitus are at high risk of cardiovascular disease. Carotid intima-media thickness (IMT) is a strong predictor of myocardial infarction and stroke. METHODS AND RESULTS: We compared the effects of pioglitazone-based therapy (45 mg/d) and glimepiride-based treatment (2.7+/-1.6 mg/d) for 12 and 24 weeks on metabolic control (HbA1c), insulin resistance (homeostasis model assessment), and carotid IMT (B-mode ultrasonography) in a randomized controlled study in 173 orally treated patients with type 2 diabetes (66 women, 107 men; mean+/-SD age, 62.6+/-7.9 years; body mass index, 31.8+/-4.6 kg/m2; HbA1c, 7.5+/-0.9%). Treatment was generally well tolerated in both groups. Despite similar improvements in metabolic control (HbA1c) after 24 weeks (-0.8+/-0.9% [pioglitazone] versus -0.6+/-0.8% [glimepiride]; P=NS), carotid IMT was reduced only in the pioglitazone group after 12 weeks (-0.033+/-0.052 versus -0.002+/-0.047 mm [glimepiride]; P<0.01 between groups) and 24 weeks (-0.054+/-0.059 versus -0.011+/-0.058 mm [glimepiride]; P<0.005 between groups). Insulin resistance was also improved only in the pioglitazone group (homeostasis model assessment, -2.2+/-3.4 versus -0.3+/-3.3; P<0.0001 between groups). Reduction of IMT correlated with improvement in insulin resistance (r=0.29, P<0.0005) and was independent of improvement in glycemic control (r=0.03, P=0.68). CONCLUSIONS: We found a substantial regression of carotid IMT, independent of improved glycemic control, after 12 and 24 weeks of pioglitazone treatment. This finding may have important prognostic implications for patients with type 2 diabetes mellitus.

Aged↗