Sitagliptin Compared with Thiazolidinediones as a Third-Line Oral Antihyperglycemic Agent in Type 2 Diabetes Mellitus

ObjectiveTo compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus.MethodsIn an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A_1c levels less than 7.5% at 4 months continued through 1 year of follow-up.Results:One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptinand thiazolidinedione-treated patients had identical hemoglobin A_1c levels (mean ± SD) (9.4 ± 1.8% and 9.4 ± 1.9%, respectively) and similar known diabetes duration (6.7 ± 5.0 years and 7.6 ± 5.8 years, respectively). Hemoglobin A_1c was reduced in both groups at 4 months (P < .001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 ± 1.7% vs -1.3 ± 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A_1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A_1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A_1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated.ConclusionsAmong ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, thirdline add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months. (Endocr Pract. 2011;17:691-698)     

Renal handling of zinc in insulin-dependent diabetes mellitus patients

Hyperzincuria is a common feature in diabetic patients, which is still not understood. Based on the above consideration, the aim of the present study was to investigate the renal handling of zinc in insulin-dependent diabetes mellitus (IDDM) patients. The glomerular filtration rate, urinary zinc excretion, zinc clearance, zinc clearance/creatinine clearance ratio, zinc tubular reabsorption, glycosuria, plasma glucose, C-peptide, glucagon, and cortisol were investigated in 10 normal individuals (Group C1 and Group C2, respectively) and 10 IDDM patients (Group E1: hyperglycemic and glycosuric and Group E2: normoglycemic and aglycosuric) during placebo or venous zinc tolerance test. The results showed that urinary zinc excretion and renal zinc clearance were increased after zinc injection in normal individuals (Group C2) and IDDM patients (Groups E1 and E2) when compared with normal individuals-placebo (Group C1). However, these renal parameters were statistically more significant in the hyperglycemic and glycosuric diabetics (Group E1). Because patients in Group E1 had the lowest plasma C-peptide levels and showed a strong negative correlation between CZn⁺⁺/Ccr ratio and this hormone, we suggest that in this setting insulin inhibits urinary zinc excretion.     

Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes

In Diabetes Mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator of nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18–36 years) and eighteen individuals without diabetes (17–35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (μg/l) and CEC (μg/l) were significantly higher in DM (55.73 ± 29.43, 521.47 ± 239.13, respectively) compared to controls (24.25 ± 10.26, 262.85 ± 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.     

Ethnic disparity in hemoglobin A1c levels among normoglycemic offspring of parents with type 2 diabetes mellitus

ObjectiveTo investigate the racial/ethnic disparities in hemoglobin A_1c levels among nondiabetic persons with similar parental history of type 2 diabetes mellitus.MethodsWe studied a community-based sample of adult offspring of parents with type 2 diabetes mellitus. Measurements included anthropometry, hematology assessments, serial fasting plasma glucose, oral glucose tolerance testing, plasma insulin, hemoglobin A_1c, insulin sensitivity, and b-cell function, using a homeostasis model assessment.ResultsThe study included 302 participants (135 white, 167 black). Compared with white participants, black participants had lower fasting plasma glucose levels (91.9 ± 0.51 mg/dL vs 93.6 ± 0.50 mg/dL, P = .015), lower area under the curve of plasma glucose during oral glucose tolerance testing (P = <.001), higher body mass index (31.1 ± 0.61 kg/m² vs 28.5 ± 0.57 kg/m², P = <.001), and similar insulin sensitivity and b-cell function. Hemoglobin A_1c was higher in black participants than in white participants (5.68 ± 0.033% vs 5.45 ± 0.028%, P <.001). The absolute black-white difference in hemoglobin A_1c level of approximately 0.22% persisted after adjusting for age, hemoglobin, hematocrit, body mass index, waist circumference, fasting plasma glucose, glucose area under the curve, and other covariates.ConclusionsAmong healthy offspring of parents with type 2 diabetes mellitus in this study, African American participants had higher hemoglobin A_1c levels than white participants after adjusting for age, adiposity, blood glucose, and known variables. Thus, plasma glucose level is more valid than hemoglobin A_1c for diagnosing prediabetes or diabetes in black persons. (Endocr Pract. 2012; 18:356-362)     

Effect of C111T polymorphism in exon 9 of the catalase gene on blood catalase activity in different types of diabetes mellitus

Hydrogen peroxide plays a major role in the pathomechanism of diabetes mellitus and its main regulator is enzyme catalase.

The blood catalase and the C111T polymorphism in exon 9 was examined in type 1, type 2 and gestational diabetes mellitus.

Compared to the control group (104.7 ± 18.5 MU/l) significantly decreased (p < 0.001) blood catalase activities were detected in type 2 (71.2 ± 14.6 MU/l), gestational (68.5 ± 12.2 MU/l) diabetes mellitus and without change in type 1 (102.5 ± 26.9 MU/l). The blood catalase decreased (p = 0.043) with age for type 2 diabetics and did not change (p>0.063) for type 1, gestational diabetic patients and controls. Blood catalase showed a weak association with hemoglobin A1c for type 1 diabetic patients (r = 0.181, increasing).

The mutant T allele was increased in type 1 and gestational diabetes mellitus, and CT+TT genotypes showed decreased blood catalase activity for type 1 and increased activities for type 2 diabetic patients.

The C111T polymorphism may implicate a very weak effect on blood catalase activity in different types of diabetes mellitus.     

Effects of diabetes type and treatment on zinc status in diabetes mellitus

Zinc status was assessed in 53 diabetic patients: 18 insulin-dependent diabetic patients (IDDM), 22 noninsulin-dependent diabetic patients (NIDDM) treated with oral antidiabetic agents, and 13 insulin-treated, noninsulin-dependent diabetic patients (IRDM). Plasma zinc concentrations were in the usual range for healthy subjects in these three groups (15.3±0.9 μmol/L). Urinary zinc excretions were elevated in the IDDM group (18.3±4.1 μmol/24 h;p<0.01 vs normal) and in the NIDDM group (17.5±3.5 μmol/24 h;p<0.01 vs normal), but normal in the IRDM group (11.3±2.4 μmol/24 h). In 14 NIDDM patients treated with transient continuous sc insulin injections, urinary zinc decreased from 16.5±2.2 μmol/24 h before insulin treatment to 11.5±0.3 μmol/24 h after insulin treatment without any modification in plasma zinc concentrations.     

Exenatide Therapy in Obese Patients With Type 2 Diabetes Mellitus Treated with Insulin

ObjectiveTo evaluate the effect of exenatide on clinical parameters in obese patients with type 2 diabetes mellitus whose hyperglycemia is not adequately controlled despite treatment with oral hypoglycemic agents and insulin.MethodsIn this retrospective analysis, clinical progress of 52 obese patients with type 2 diabetes treated with exenatide, 5 mcg twice daily, in an outpatient setting was reviewed. Treatment initiation was between September and December 2005. Mean follow-up period was 26 weeks. Thirty-eight patients took exenatide regularly (Group A); 14 patients discontinued exenatide because of insurance, personal, or economic reasons (Group B). Measurements at baseline and at follow-up included body weight; blood pressure; and levels of hemoglobin A_1c (HbA_1c), high-sensitivity C-reactive protein (CRP), and plasma lipids. Insulin dosage requirements were assessed.ResultsMean body weight (± standard error of the mean) decreased by 6.46 ± 0.8 kg (P < .001) in Group A and increased by 2.4 ± 0.6 kg in Group B (P < .001). In Group A, mean HbA_1c decreased by 0.6 ± 0.21% (P = .007), and the insulin dosage requirement decreased for rapid-acting and mixed insulins (P < .02). In Group A, means of the following parameters decreased: serum total cholesterol by 8.5 ± 3.3% (P = .03), triglycerides by 26 ± 7.6% (P = .01), systolic blood pressure by 9.2 ± 3.3 mm Hg (P = .02), and high-sensitivity CRP by 34 ± 14.3% (P = .05). These indices did not change in Group B.ConclusionExenatide effectively treats obese patients with type 2 diabetes on insulin, leading to weight loss and reduction in levels of HbA_lc, systolic blood pressure, triglycerides, and high-sensitivity CRP. (Endocr Pract 2007;13:444-450)     

Urinary Excretion of Zinc and Metabolic Control of Patients with Diabetes Type 2

The objective of this study was to assess urinary excretion of zinc and evaluation parameters of metabolic control in type 2 diabetic patients. Thirty-one type 2 diabetic patients, of both genders, with 5.8 ± 5.6 years average time of the disease, age range 20–60 years, were selected. Evaluation of the nutritional status was performed using anthropometric measurements. To evaluate food consumption, the 3-day alimentary log method was used, and its analysis was performed using a software. Determination of urinary zinc was by atomic absorption spectrophotometry. From the obtained results, it was concluded that 51.6% of the patients were overweight. The mean of found waist circumference was 100.4 and 92.2 cm for men and women, respectively. Blood glucose and glycated hemoglobin values were higher than reference values, and plasma albumin concentration was adequate. The median of found urinary zinc excretion was 474.9 μg/24 h, within normal standards (300–600 μg/day). Regarding diet composition, calorie and protein concentration were above recommendation, while mean zinc concentration was adequate. This data allow the conclusion that the evaluated patients presented adequate urinary zinc excretion in comparison with reference values.     

Serum netrin and VCAM-1 as biomarker for Egyptian patients with type IΙ diabetes mellitus

ObjectiveThis study aimed to evaluate the serum level of netrin and soluble vascular cell adhesion molecule 1 (VCAM-I) in patients with type IΙ diabetes mellitus (T2DM) and evaluate the association of their levels with the development of a diabetic complication.Patients and methodsThis study was carried out on type II diabetic patients with and without complications and healthy individuals served as controls. All subjects were submitted to the estimation of serum lipid profile, serum creatinine, urinary albumin/creatinine ratio (ACR), fasting blood glucose (FBG), glycated hemoglobin (HbA1c), visceral adiposity index (VAI), atherogenic index of plasma (AIP), lipid accumulation product (LAP) and detection of serum level of netrin1 and VCAM1.ResultsDiabetic patients with complications had significantly higher serum levels of creatinine, ACR, cholesterol, Triglyceride, low-density lipoprotein, netrin1, and VCAM1 than diabetic patients without complications. Likewise, the level of VAI and LAP as markers of excessive body fat were significantly higher in diabetic patients with complications than diabetic patients without complications. The netrin1 and VCAM1 were a significant discriminator of T2DM renal complications with a sensitivity of 96%, 90%, and specificity of 82.7%, 91.3% respectively.ConclusionIt can be concluded that serum netrin1 and VCAM1 correlated significantly with markers of excessive body fat, a renal complication in the patient with type 2 diabetes mellitus.     

Urinary zinc excretion is normalized in primary arterial hypertension after perindopril treatment

Increased or unchanged urinary zinc excretion has been reported in hypertension. In the present article, this observation was confirmed in a group of 10 untreated hypertensive patients of both sexes that had no diabetes or obesity. The 24-h zinc excretion was significantly different between the patients: 7.46±3.01 μmol and healthy controls: 5.19±2.19 μmol (p<0.025). After a 1-mo treatment with 4 mg perindopril per day, a decrease of urinary zinc was observed until it reached levels not significantly different from those of the healthy controls (5.98±2.13 μmol). The decrease was significantly different from that of the pretreatment values (p<0.05).     

Iron-induced oxidative stress in haemodialysis patients: a pilot study on the impact of diabetes

Background: Administration of intravenous iron preparations in haemodialysis patients may lead to the appearance of non-transferrin bound iron which can catalyse oxidative damage. We investigated this hypothesis by monitoring the oxidative stress of haemodialysis patients and the impact of iron and diabetes mellitus herein. Materials and methods: Baseline values of serum iron and related proteins, transferrin glycation, non-transferrin bound iron, antioxidant capacity and lipid peroxidation (malondialdehyde) of 11 haemodialysis patients (six non-diabetic and five type 2 diabetes) were compared to those of non-haemodialysis control subjects (non-diabetic and type 2 diabetes). Changes in these parameters were monitored during haemodialysis before and after iron administration. Results: Baseline values of malondialdehyde correlated with ferritin concentration (r = 0.664, P = 0.036) and were elevated to the same extent in non-diabetic and diabetic haemodialysis patients (median of 1.09 compared to 0.60 μmol/l in control persons, P < 0.02). After iron infusion, transferrin saturation increased more markedly in non-diabetic subjects from 28% to 185% vs. from 33% to 101% in diabetic patients (P = 0.008). This increase was accompanied by the appearance of non-transferrin bound iron (5.91 ± 1.33 μmol/l), a loss in plasma iron-binding antioxidant capacity and a further increase in malondialdehyde which was more pronounced in diabetic patients (from 0.93 ± 0.30 μmol/l to 2.21 ± 0.69 μmol/l vs. from 1.21 ± 0.42 μmol/l to 1.86 ± 0.56 μmol/l in the non-diabetic subjects, P = 0.046). Conclusions: In haemodialysis patients, higher lipid peroxidation is determined by higher body iron stores. The increase induced by iron infusion is accompanied by a loss in iron-binding antioxidant capacity and is more pronounced in diabetes mellitus.     

Comparison of 2 Intensification Regimens with Rapid-Acting Insulin Aspart in Type 2 Diabetes Mellitus Inadequately Controlled by Once-Daily Insulin Detemir and Oral Antidiabetes Drugs: The Step-Wise Randomized Study

ObjectiveTo compare the efficacy and safety of 2 intensification strategies for stepwise addition of prandial insulin aspart in patients with type 2 diabetes mellitus treated with insulin detemir.MethodsThis randomized, controlled, parallel-group, open-label, 48-week trial compared the stepwise addition of insulin aspart to either the largest meal (titration based on premeal glucose values [SimpleSTEP]) or to the meal with the largest prandial glucose increment (titration based on postmeal glucose values [ExtraSTEP]) in patients with type 2 diabetes inadequately controlled on basal insulin and oral antidiabetes drugs. After 12 weeks of basal insulin detemir dosage optimization, participants with a hemoglobin A₁ level of 7% or greater entered three 12-week treatment periods with stepwise addition of a first insulin aspart bolus, then a second, and then a third, if hemoglobin A_1c remained at 7% or greater after 12 and 24 weeks of treatment, respectively. Endpoints included hemoglobin A_1c (primary endpoint), fasting plasma glucose, self-measured plasma glucose, adverse events, and hypoglycemia.ResultsTwo hundred ninety-six patients were randomly assigned to treatment with insulin aspart in the SimpleSTEP (n = 150) and ExtraSTEP (n = 146) groups. Hemoglobin A_1c decreased by approximately 1.2% in both groups, to 7.5 ± 1.1% (SimpleSTEP) and 7.7 ± 1.2% (ExtraSTEP) at end of trial (estimated treatment difference, SimpleSTEP ExtraSTEP: -0.06% [95% confidence interval, -0.29 to 0.17]). Self-measured plasma glucose levels decreased with both regimens. At trial end, approximately 75% of patients in each group were using 3 prandial injections. The frequency of adverse events and hypoglycemia was low and similar between groups.ConclusionThe SimpleSTEP and ExtraSTEP strategies for stepwise addition of insulin aspart to 1 or more meals were equally effective at intensifying therapy in patients with type 2 diabetes not achieving glycemic control on basal insulin and oral antidiabetic drugs. (Endocr Pract. 2011;17:727-736)     

Assisting effects of lithium on hypoglycemic treatment in patients with diabetes

In this article, we report the assisting effect of lithium on hypoglycemic treatment in patients with diabetes. Thirty-eight diabetic patients, 15 male and 23 female, aged 20–70 yr, 33 noninsulin-dependent diabetesmellitus (NIDDM) patients, and 5 insulin-dependent diabetesmellitus (IDDM) patients, were recruited in this study. Fasting and 1-h postprandial blood glucose (BG) profiles were undertaken from three groups of patients with diabetes before and after short-term of treatment of lithium carbonate. Group I was treated with diet only, Group II with oral hypoglycemic agents (OHA), and Group III with insulin. The fasting blood glucose (FBG) level and 1-h postprandial blood glucose (1-h PBG) level before and after treatment of lithium were: Group I: FBG: 7.67 ± 0.48 vs 7.13 ± 0.82; 1-h PBG 15.13 ± 0.88 vs 10.33 ± 0.96; Group II: FBG: 8.84 ± 0.67 vs 6.04 ± 0.57; 1-h PBG: 12.33 ± 0.72 vs 9.95 ± 0.82; Group III: FBG: 10.87 ± 0.83 vs 6.83 ± 0.79; 1-h PBG: 12.45 ± 0.93 vs 9.17 ± 1.00 mmol/L, respectively. The FBG and PBG of all three groups decreased significantly after lithium treatment, except the FBG in Group I. These data suggest that combined with other therapy, lithium could improve glucose metabolism in most patients with diabetes. Our results suggest that lithium has an assisting hypoglycemic effect on antidiabetic treatment.     

Microalbuminuria in non-insulin-dependent diabetes: its prevalence in Indian compared with Europid patients

Non-insulin-dependent diabetes mellitus is strikingly common in British Indians, but their susceptibility to diabetic complications is unknown. The ratio of albumin to creatinine concentrations was measured in samples of the first urine voided in the morning in 154 Indian and 82 Europid patients with non-insulin-dependent diabetes and in a control group of 129 non-diabetic Indians. The ratio was significantly higher in the Indian patients than in the Europid patients and the Indian controls. There were no significant correlations between the logarithm of the albumin: creatinine ratio and age, known duration of diabetes, haemoglobin A₁ concentration, or body mass index within either diabetic group. Hypertension and raised albumin:creatinine ratio were significantly associated, and significant correlations were seen between the logarithm of the albumin:creatinine ratio and systolic and diastolic blood pressures in the Indian but not the Europid diabetics.Because of the high prevalence of diabetes at a relatively early age in Indians, nephropathy may emerge as an important clinical problem.     

A Retrospective Study Comparing Neutral Protamine Hagedorn Insulin With Glargine As Basal Therapy In Prednisone-Associated Diabetes Mellitus In Hospitalized Patients

ObjectiveTo compare glycemic outcomes in hospitalized patients with or without type 2 diabetes mellitus receiving neutral protamine Hagedorn insulin (NPH) vs glargine as basal insulin for management of glucocorticoid-associated hyperglycemia.MethodsWe conducted a retrospective review of electronic medical records in prednisone-treated adult patients with hyperglycemia in a university hospital. Consecutive patients were selected in both the NPH and glargine cohorts using inclusion and exclusion criteria. Baseline characteristics were assessed in each cohort. Glycemic outcomes were analyzed by comparing fasting blood glucose, mean daily blood glucose concentration, median daily blood glucose concentration, and the number of hypoglycemic episodes on a prespecified index day.ResultsOne hundred twenty patients were included: 60 patients in the NPH cohort and 60 patients in the glargine cohort. The weight-based insulin requirement was lower in the NPH cohort than in the glargine cohort (0.27 ± 0.2 units/kg vs 0.34 ± 0.2 units/kg [P = .04] for basal insulin and 0.26 ± 0.2 units/kg vs 0.36 ± 0.2 units/kg [P = .03] for bolus insulin). NPH and glargine cohorts were similar regarding age, sex, race, body mass index, hemoglobin A_1c, serum creatinine, and prednisone dosage. Glycemic outcomes in the NPH cohort compared with outcomes in the glargine cohort were similar regarding mean fasting blood glucose concentration (134 ± 49 mg/dL vs 139 ± 54 mg/dL [P = .63]), mean daily blood glucose (167 ± 46 mg/dL vs 165 ± 52 mg/dL [P = .79]), median blood glucose (160 ± 49 mg/dL vs 159 ± 57 mg/dL [P = .90]), and number of hypoglycemic episodes per day (0.12 ± 0.3 vs 0.10 ± 0.3 [P = .77]).ConclusionsNPH and glargine appear to be equally effective as basal insulin in the management of hyperglycemia in hospitalized patients receiving prednisone. However, the total daily insulin doses used were lower in the NPH cohort. (Endocr Pract. 2012;18:712-719)     

High-Resolution Imaging of Parafoveal Cones in Different Stages of Diabetic Retinopathy Using Adaptive Optics Fundus Camera

PurposeTo assess cone density as a marker of early signs of retinopathy in patients with type II diabetes mellitus.MethodsAn adaptive optics (AO) retinal camera (rtx1^™; Imagine Eyes, Orsay, France) was used to acquire images of parafoveal cones from patients with type II diabetes mellitus with or without retinopathy and from healthy controls with no known systemic or ocular disease. Cone mosaic was captured at 0° and 2°eccentricities along the horizontal and vertical meridians. The density of the parafoveal cones was calculated within 100×100-μm squares located at 500-μm from the foveal center along the orthogonal meridians. Manual corrections of the automated counting were then performed by 2 masked graders. Cone density measurements were evaluated with ANOVA that consisted of one between-subjects factor, stage of retinopathy and the within-subject factors. The ANOVA model included a complex covariance structure to account for correlations between the levels of the within-subject factors.ResultsTen healthy participants (20 eyes) and 25 patients (29 eyes) with type II diabetes mellitus were recruited in the study. The mean (± standard deviation [SD]) age of the healthy participants (Control group), patients with diabetes without retinopathy (No DR group), and patients with diabetic retinopathy (DR group) was 55 ± 8, 53 ± 8, and 52 ± 9 years, respectively. The cone density was significantly lower in the moderate nonproliferative diabetic retinopathy (NPDR) and severe NPDR/proliferative DR groups compared to the Control, No DR, and mild NPDR groups (P < 0.05). No correlation was found between cone density and the level of hemoglobin A_1c (HbA_1c) or the duration of diabetes.ConclusionsThe extent of photoreceptor loss on AO imaging may correlate positively with severity of DR in patients with type II diabetes mellitus. Photoreceptor loss may be more pronounced among patients with advanced stages of DR due to higher risk of macular edema and its sequelae.     

Effect of glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in diabetes mellitus

Liquorice extract has been claimed to induce inhibition of the activity of 11β-hydroxysteroid dehydrogenase which converts cortisol to cortisone. This enzyme is thought to protect the mineralocorticoid receptor from being occupied by endogeneous glucocorticoids in the kidney. Based on these hypotheses, we investigated the effect of low-dose glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in eight subjects with NIDDM. The mean serum potassium concentration decreased from 5.3 ± 0.3 (SD) mEq/1 to 4.9 ± 0.2 mEq/1 when 15 g of calcium polystyrene sulfonate, a potassium-binding resin, was given per day, and it decreased significantly to 4.4 ± 0.4 mEq/1 with 150 mg/day of glycyrrhizine therapy. Changes in fasting plasma glucose and hemoglobin A_1C were not significant. These data support the assumption that liquorice extract can be used safely in the therapy for treating hyperkalemia due to selective hypoaldosteronism in diabetes mellitus subjects.     

Correlation of low molecular weight advanced glycation end products and nitric oxide metabolites with chronic complications in type 1 diabetic patients

Advanced glycation end products (AGEs) are involved in the occurrence of vascular complications in diabetes. The present study was undertaken to investigate the level of low-molecular weight products of AGEs (LMW-AGEs) in relation to microvascular complications in type 1 diabetes, and the possible relationship with nitric oxide (NO) as a marker of endothelial function. Patients with normal renal function (NRF) were classified into two groups: (1) without, and (2) with diabetic neuropathy; and patients with renal impairment also into two groups: (3) diabetic renal disease, and (4) end-stage renal disease. The fluorescence of LMW-AGEs and measurement of NO metabolites was assessed in 277 serum samples. In addition, multiple regression analysis was performed. In group 1, LMW-AGEs level (9.3±1.1 AF%) was higher than in the control group (2.4±0.3 AF%). A trend in the increase of LMW-AGEs with neuropathy (29.7±5.5 AF%, group 2), and further with renal impairment (47.0±8.0, group 3 and 137.8±25.5 AF%, group 4), was observed. In multivariate regression analysis LMW-AGEs were associated with NO metabolites in group 2. In NRF patients, diabetic neuropathy was significantly correlated with LMW-AGEs and NO metabolites, independently of serum creatinine and duration of diabetes. This relationship suggests that the NO and LMW-AGEs’ actions (possibly synergistic) in endothelial activation possess a role in the initiation and development of diabetic microvascular complications.     

A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)₂, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)₂ as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)₂ and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)₂, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)₂-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)₂ and Zn(ma)₂ were then compared, and both complexes were found to normalize hyperglycemia in KK-A^y mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)₂ improved glucose tolerance in KK-A^y mice much more than did Zn(ma)₂, indicating that Zn(alx)₂ possesses greater in vivo anti-diabetic activity than Zn(ma)₂. In addition, Zn(alx)₂ improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-A^y mice. On the basis of these observations, we conclude that the Zn(alx)₂ complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0590-8