Hemoglobin glycation index as a useful predictor of therapeutic responses to dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes.

INTRODUCTION: A high hemoglobin glycation index (HGI) and glycated hemoglobin (HbA1c) level are associated with greater inflammatory status, and dipeptidyl peptidase-4 (DPP-4) inhibitors can suppress inflammation. We aimed to evaluate the relationship between HGI and the therapeutic effect of DPP-4 inhibitors. METHODS: This retrospective cohort study followed 468 patients with type 2 diabetes receiving DPP-4 inhibitor treatment for 1 year. Estimated HbA1c was calculated using a linear regression equation derived from another 2969 randomly extracted patients with type 2 diabetes based on fasting plasma glucose (FPG) level. The subjects were divided into two groups based on HGI (HGI = observed HbA1c - estimated HbA1c). Mixed model repeated measures were used to compare the treatment efficacy after 1 year in patients with a low (HGI<0, n = 199) and high HGI (HGI≧0, n = 269). RESULTS: There were no significant group differences in mean changes of FPG after 1 year (-12.8 and -13.4 mg/dL in the low and high HGI groups, respectively). However, the patients with a high HGI had a significantly greater reduction in HbA1c from baseline compared to those with a low HGI (-1.9 versus -0.3% [-20.8 versus -3.3 mmol/mol]). Improvements in glycemic control were statistically significantly associated with the tested DPP-4 inhibitors in the high HGI group (-2.4, -1.4, -1.2 and -2.2% [-26.2, -15.3, -13.1 and -24.0 mmol/mol] for vildagliptin, linagliptin, saxagliptin and sitagliptin, respectively) but not in the low HGI group. CONCLUSIONS: The HGI index derived from FPG and HbA1c may be able to identify who will have a better response to DPP-4 inhibitors.

Physical activity and albuminuria were associated with painful diabetic polyneuropathy in type 2 diabetes in an ethnic Chinese population.

BACKGROUND: Diabetic neuropathy is a common complication in patients with type 2 diabetes. However, the prevalence of painful diabetic polyneuropathy (PDPN) have been less studied. We examined the prevalence and risk factors of PDPN in outpatients with type 2 diabetes in an ethnic Chinese population. METHODS: This retrospective study enrolled 2358 outpatients with type 2 diabetes who had completed the Douleur Neuropathique en 4 Questions (DN4) questionnaire from January 2013 to October 2013. Patients with a total score ≥4 were defined as having PDPN. RESULTS: In all, 179 patients were diagnosed as having PDPN with a score of 4.49 on the DN4 questionnaire, compared with 0.66 for patients without PDPN. After adjusting the possible confounding factors, the risk of painful neuropathy was increased in the group without physical activity (Odds ratio 3.38, 95% CI 1.54-9.79), and in the group with macroalbuminuria (Odds ratio 2.31, 95% CI 1.44-3.73). Besides, there was a joint effect of macroalbuminuria and no physical activity habit on PDPN risk. CONCLUSIONS: The prevalence of PDPN was 7.6% among our outpatients with type 2 diabetes. Less physical activity and albuminuria, respectively, increased the risk of PDPN and had a joint effect.

A short-term smoking cessation may increase the risk of developing metabolic syndrome.

Smoking cessation is beneficial for health. However, its potential harmful impact on metabolic syndrome has yet to be clarified. Six smokers who attended the smoking cessation clinic were recruited and given the nicotine replacement therapy for 3 months. The values of body weight, BMI, systolic blood pressure, and fasting glycemia were significantly elevated after smoking cessation. We recommend that clinicians should monitor these cardiovascular risk factors in subjects attempting smoking cessation.

A new formula for estimation of low-density lipoprotein cholesterol in an ethnic Chinese population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease and is usually estimated by the Friedewald formula (FF) calculated from three parameters, namely, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). We aimed to develop a new and simple formula (NF) for LDL-C estimation. METHODS: This cross-sectional study enrolled two study populations (a testing group, n=16,749, and a validation group, n=4940). Linear regression analysis was used in the testing group to investigate the association between measured LDL-C (mLDL-C) and TC concentration, and was verified in the validation group. RESULTS: The NF yielded an estimated LDL-C (eLDL-C) equal to 0.75 × total cholesterol-0.6465 (mmol/L). For the subjects with TC between 2.58 and 7.74 mmol/L, the difference between mLDL-C and eLDL-C using the NF was less than that from the FF (testing group: -0.04 to -0.20 vs. -0.28 to -0.38 mmol/L; validation group: 0.01 to -0.12 vs. -0.23 to -0.30 mmol/L; p<0.001, respectively). The predictability of the NF was not inferior to that of the FF in subjects with different triglyceride and HDL-C concentrations, and was not affected by diabetes diagnosis and statin use. However, the NF performed similar to or worse than the FF at TC concentrations <2.58 mmol/L and >7.74 mmol/L, respectively. CONCLUSIONS: In the Chinese population, the accuracy of eLDL-C measurement with the NF was better than that with the FF, especially in subjects with TC levels between 2.58 and 7.74 mmol/L. The NF is simple and may be used for screening as well as for follow-up of patients on lipid lowering agents.

Higher serum total bilirubin concentration is associated with lower risk of renal insufficiency in an adult population.

BACKGROUND: Chronic inflammation is proposed to play a central role in the pathogenesis of chronic kidney disease (CKD), and serum bilirubin has antioxidant and anti-inflammatory effects. We investigated the association between serum total bilirubin (Tb) concentration and renal function in an adult population. METHODS: We conducted a cross-sectional study and collected anthropometric measurements, fasting blood tests, lifestyle habits and medical history of 3876 subjects attending a health examination. Renal insufficiency was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) calculated by using the CKD-EPI equation. RESULTS: Serum Tb concentrations were higher in subjects without renal insufficiency than in those with renal insufficiency. Multivariable linear regression analysis showed that Tb concentration was positively associated with eGFR after adjusting for important CKD risk factors (P=0.04). Multivariable logistic regression analysis also revealed that higher Tb concentration (each increment of 1.71 µmol/L) (0.1 mg/dL) was associated with a reduced risk of renal insufficiency: odds ratios were 0.94 (P=0.005) for men and 0.90 (P=0.015) for women, respectively. When subjects were divided into quartiles of serum Tb, multivariable-adjusted odds ratios for renal insufficiency comparing the fourth to the first Tb quartile were 0.49 (P=0.001) for men and 0.35 (P=0.003) for women. A stepwise exclusion of subjects, first those with possible liver disease and second, those with CKD stage 4 and 5, showed consistent results. CONCLUSION: Higher serum Tb concentration was associated with lower risk of renal insufficiency, regardless of other conventional CKD risk factors.

Dynamic and dual effects of glycated hemoglobin on estimated glomerular filtration rate in type 2 diabetic outpatients.

BACKGROUND: Diabetic nephropathy is the leading cause of incident end-stage renal disease in Taiwan. Previous studies on the consistent benefits of glycemic control in diabetic nephropathy focused primarily on delaying microalbuminuria. However, this effect on glomerular filtration rate (GFR) remains controversial. This study aims to establish a model that explains the controversial effects of glycated hemoglobin (HbA1C) on GFR. METHODS: This retrospective cohort study followed subjects with type 2 diabetes mellitus, who were enrolled between June 2006 and December 2006, for 4 years. The effects of HbA1C on estimated GFR (eGFR) were examined both cross-sectionally and longitudinally. The dual effects of HbA1C on eGFR, and how renal function interferes with these effects, were investigated. RESULTS: Of the 1,992 subjects enrolled, 1,699 completed the follow-up. HbA1C was positively correlated with eGFR in the cross-sectional study (ß coefficient = 1.44, 95% CI: 0.71-2.17, p = 0.0001). In the longitudinal study, higher baseline HbA1C resulted in a greater decline in eGFR. The annual eGFR decline rates were -1.89, -1.29, and -0.68 ml/min/1.73 m(2)/year for baseline HbA1C >9, 7 to ≤9, and ≤7%, respectively. The eGFR value was simultaneously affected by concurrent (ß coefficient = 0.78, 95% CI: 0.48-1.08, p < 0.0001) and preceding HbA1C (-0.52, -0.82 to -0.23, p < 0.0001). The positive effects of concurrent HbA1C on eGFR reached statistical significance at all stages of chronic kidney disease (CKD); however, the negative effects of preceding HbA1C only applied to CKD stages 3 and 4. CONCLUSIONS: We developed a new model that demonstrates how preceding and concurrent HbA1C simultaneously affect eGFR in opposing ways. The dynamic effects varied among different CKD stages. The deterioration in eGFR at CKD stages 3 and 4 may be postponed by intensive glycemic control. Further prospective studies may be necessary to clarify the specific CKD stage(s) that will benefit from intensive glycemic control.

Tissue metallothionein concentrations in mice and humans with hyperglycemia.

Besides participating in tissue zinc homeostasis and protecting against heavy metal toxicities, metallothionein (MT) is known as an antioxidant. Increased MT activity can ameliorate diabetic hyperglycemia, and subjects with less MT synthesis are more prone to diabetic complications. However, whether tissue MT status is varied in the subjects with diabetes mellitus remains unclear. This study was undertaken to measure tissue MT levels in laboratory mice (serum, liver, and epididymal adipose tissue) and humans (serum) with hyperglycemia. Tissue MT levels were measured by enzyme-linked immunosorbent assay. The results showed that MT status in serum and adipose tissue did not markedly differ between the subjects with and without hyperglycemia. In addition, streptozotocin- and high-fat-diet-induced hyperglycemic mice had higher while ob/ob mice had lower liver MT levels than that of normal control mice. Furthermore, serum MT levels tended to correlate with glycemia values in mice. The results of this study indicate that serum MT value does not differ in subjects with hyperglycemia and cannot be used as an index to evaluate the susceptibility or progress of diabetes mellitus.

The effects of calcium channel blocker benidipine and calmodulin antagonist W7 on GDP-binding capacity of brown adipose tissue in mice.

It has been suggested that increased dietary calcium intake can attenuate obesity. Calcium antagonists, such as benidipine, also have been shown to have an anti-obesity effect. However, the mechanism for calcium-related anti-obesity effect has not yet been established. A defective brown adipose tissue thermogenesis has been shown in obese rodents. This study was designed to examine the direct effects of calcium channel blocker benidipine and calmodulin antagonist W7 administration on the adaptive thermogenesis in brown adipose tissue taken from the genetically obese mice and their lean controls. The GDP binding to brown-fat cell mitochondria was used as a brown adipose tissue thermogenic index. The results show that benidipine treatment had no marked effect on brown-fat cell GDP-binding capacities in both obese and lean mice. However, GDP-binding capacities were significantly reduced in both obese and lean mice after the W7 administration. The results of this study support the previous finding that benidipine did not have direct thermogenic effect on brown adipose tissue and suggest that the change in intracellular calmodulin availability might contribute to the adaptive thermogenesis in brown adipose tissue.

Factors related to clinical hypothyroid severity in thyroid cancer patients after thyroid hormone withdrawal.

BACKGROUND: Thyroid hormone withdrawal (THW) to stimulate thyrotropin (TSH) secretion produces acute thyroid hormone deficiency in patients who have undergone thyroidectomy for differentiated thyroid cancer (DTC), but not all patients developed clinically overt features of hypothyroidism. This prospective study was performed to test the hypothesis that selected factors, including serum thyroid hormone levels and insulin resistance, are associated with the development of overt features of hypothyroidism. METHODS: Thirty-two patients (27 women, aged 51.1 +/- 12.3 years) with DTC who had undergone total or subtotal thyroidectomy were studied while on thyroid hormone suppressive therapy (THST) and 5 weeks after THW. Thyroid function and other tests as well as anthropometric parameters and the Zulewski score for clinical hypothyroidism were assessed. Overt clinical hypothyroidism was defined as having a Zulewski score of > or = 3 after THW. Clinical euthyroidism was defined as having a Zulewski score of <3. RESULTS: Fifteen patients (46.9%) developed overt clinical hypothyroidism after THW. Patients with overt clinical hypothyroidism were older (p = 0.005), had lower baseline serum free thyroxine (p = 0.040) and free triiodothyronine (fT3) (p = 0.006), and higher body mass index (p = 0.038), fasting plasma glucose (p = 0.005), and homeostasis model assessment for insulin resistance (p = 0.043) than those with clinical euthyroidism. The independent factors related to overt clinical hypothyroidism after THW were higher HOMA-IR (odds ratio [OR], 1.098; confidence interval [CI], 1.007-1.198; p = 0.034), lower fT3 (OR, 0.069; CI, 0.006-0.733; p = 0.027), and higher Zulewski score (OR, 3.633; CI, 1.144-11.536; p = 0.029) before THW. CONCLUSIONS: Nearly half of DTC patients suffer from overt clinical hypothyroidism after 5 weeks of THW, as assessed by Zulewski score. Patients with higher HOMA-IR, lower fT3 level, and higher initial Zulewski score are at greatest risk of overt clinical hypothyroidism after THW. Insulin resistance is closely related to post-THW hypothyroidism in patients of DTC.

Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells.

The biological behaviors of thyroid cancer are varied, and the pathological mechanisms remain unclear. Some reports indicated an apparent aggregation of amyloid accompanying medullary thyroid carcinoma (MTC). Amyloid aggregation in neurodegeneration leads to hyperactivation of Cdk5 and subsequent neuronal death. Based on the connection with amyloid, the role of Cdk5 in MTC is worthy of investigation. Initially, the expression of Cdk5 and its activator, p35, in MTC cell lines was identified. Cdk5 inhibition by specific inhibitors or short interfering RNA decreased the proliferation of MTC cell lines, which reveals the importance of Cdk5 in MTC cell growth. Although p35 cleavage has been considered as an important element in neurodegeneration, it seems that p35 cleavage was not a major cause in Cdk5 activity-dependent MTC cell proliferation because neither Cdk5 activity nor cell growth was affected by the inhibition of p35 cleavage. Clearance of amyloid by antibody neutralization indicated that MTC cell proliferation was supported by calcitonin-derived extracellular amyloid and subsequent Her2 and Cdk5 activation. Significantly, the STAT3 pathway was involved in Cdk5-dependent proliferation of MTC cells through Ser-727 phosphorylation. In addition, Cdk5 inhibition reduced nuclear distributions of both the Cdk5-p35 complex and phospho-STAT3 in MTC cells. Finally, Cdk5 inhibition retarded tumor formation in vivo accompanying the reduction of phospho-STAT3. Our findings suggest the first demonstration of a novel and specific role for Cdk5 kinase in supporting the proliferation of the medullary thyroid carcinoma cells and could shed light on a new field for diagnosis and therapy of thyroid cancer.

Relative reduced plasma zinc concentration in middle-aged but not elderly adults in Taiwan.

Zinc is an essential micronutrient and its deficiency relates to many diseases like diabetes mellitus. Although zinc deficiency has become prevalent in many countries, this subject has not yet been studied in Taiwan. The present study was designed to investigate whether healthy elderly Taiwanese have reduced circulating zinc concentrations. Forty-three men and ninety women whose ages were >60 yr were recruited. Moreover, 31 middle-aged (30-40 yr) adults were also included in this study. The results showed that most of the elderly adults had normal plasma zinc values and suggested that they should not have any zinc deficiency. However, we also found that the middle-aged adults had relative hypozincemia, which might deserve further study.

Zinc supplementation attenuates thioacetamide-induced liver injury and hyperglycemia in mice.

Zinc supplementation has been shown to improve not only liver dysfunction but also glucose intolerance in subjects with liver cirrhosis. In this study, we investigated the effects of zinc supplementation on the changes in circulating levels of tumor necrosis factor-alpha and total antioxidant capacity in mice with thioacetamide-induced liver injury. The protective effect of concurrent zinc administration for thioacetamide-induced hepatotoxicity was also examined. The results showed that zinc treatment significantly attenuated thioacetamide-induced liver injury and hyperglycemia. Furthermore, thioacetamide-induced hepatotoxicity was markedly weakened by the simultaneous zinc administration. These effects might be attributed to reduced tumor necrosis factor-alpha production and elevated total antioxidant capacity induced by the mineral. Our data suggest that zinc supplementation might be beneficial for the subjects with a high susceptibility to liver injury.

Simvastatin reduces plasma concentration of high-sensitivity C-reactive protein in type 2 diabetic patients with hyperlipidemia.

High-sensitivity C-reactive protein (hs-CRP) is positively associated with the prevalence of coronary artery disease by epidemiologic data. Prospective studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced the plasma hs-CRP concentration and the risk of recurrent coronary events after myocardial infarction. Type 2 diabetes is associated with high mortality risk of coronary heart disease and this high risk may be involved in the inflammatory factors. We have therefore conducted a prospective study to assess whether simvastatin can rapidly reduce the plasma hs-CRP concentration in type 2 diabetic patients with hyperlipidemia. Seventeen type 2 diabetic patients with hyperlipidemia were enrolled in the study after 6 weeks on a lipid-lowering diet. Fourteen patients completed the study, taking simvastatin 20 mg daily for 8 weeks. Fasting blood samples were collected from each patient before and after 8-week administration of simvastatin. In response to 8-week administration of simvastatin, hs-CRP levels significantly decreased from 0.312+/-0.057 to 0.193+/-0.045 mg/dl (P<.01). Plasma LDL cholesterol also decreased significantly from 130+/-9 to 74+/-3 mg/dl (P=.001). This study shows that plasma hs-CRP concentration can be reduced by 8-week administration of simvastatin in type 2 diabetic patients with hyperlipidemia.