Journal of Diabetes and Its Complications

2010-09-01

Pioglitazone, but not metformin, reduces liver fat in Type-2 diabetes mellitus independent of weight changes

2009-07-06

Abstract: Background: Pioglitazone (Pio) treatment induces weight gain in Type 2 diabetes mellitus (T2DM), which could worsen hepatic lipid accumulation, and alter adiponectin and high-sensitivity C-reactive protein (hs-CRP).Objective: To compare changes in hepatic lipid, serum adiponectin and hs-CRP in diabetics treated with Pio (with and without weight gain) against metformin (Met) treatment, which produces weight loss.Design: Fifty-one men and women with T2DM, naive to thiazolidinediones, entered a 16-week, open-label, parallel arm study, where participants were randomized to one of three groups: (1) Pio plus the American Diabetes Association diet (Pio+ADA); (2) Pio plus a portion control weight loss diet (Pio+PC), or (3) metformin plus ADA diet (Met+ADA).Methods: Hepatic lipid was assessed with abdominal computed tomography (CT) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end.Results: Forty-eight subjects completed the study. The Pio+ADA group gained (mean±S.E.M.) 2.15±1.09 kg, while Pio+PC and Met+ADA group lost −2.59±1.25 and −3.21±0.7 kg, respectively. Pio-treated groups (Pio+ADA and Pio+PC) significantly decreased hepatic fat as indicated by increased liver density on CT scan [10.1±2.4: 11.4±1.0 Hounsfield units (HU)], compared with Met+ADA group (−2.4±3.1 HU). The Pio groups demonstrated significantly increased serum adiponectin, (8.6±1.5; 7.4±1.6 μg/ml) independent of weight change, compared to Met+ADA (−0.14±0.6 μgm/ml) group which lost weight. Serum hs-CRP decreased in groups showing weight loss (Pio+PC, −3.1±1.7 mg/l; Met+ADA, −1.5±1.2 mg/l) compared to Pio+ADA (1.8±3.0 mg/l) group that gained weight.Conclusions: Pio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change, while decreasing hs-CRP with weight loss.

Lifetime prevalence of comorbid mood disorders in a representative sample of Canadians with type 1 diabetes

Esme Fuller-Thomson, Jami-Leigh Milinovich, Joseph R. Merighi — 2009-06-01

Abstract: Aims: To compare the lifetime prevalence of mood disorders among those with and without type 1 diabetes.Methods: Data from a nationally representative sample were obtained. Individuals were classified as having type 1 diabetes if a health professional diagnosed them with diabetes before age 30 and they began insulin within 1 month of their diagnosis (N=314).Results: The prevalence of mood disorders in persons with type 1 diabetes was 7.9% (95% CI 3.1–12.7) compared to 5.6% (95% CI 5.4–5.8) for those without type 1 diabetes (age- and sex-adjusted OR=1.56, 95% CI 1.04–2.34).Conclusions: Future research would benefit from the use of community-based representative samples.

Investigation of glycemia recovery with oral administration of glycerol, pyruvate, and l-lactate during long-term, insulin-induced hypoglycemia

2009-09-14

Abstract: Aim: The acute effect of oral administration of isolated or combined glycerol, pyruvate, and l-lactate on glycemia recovery (GR) during long-term, insulin-induced hypoglycemia (IIH) was compared.Methods: Glycemia of 24 h-fasted rats that received intraperitoneal injection (1.0 U/kg) of regular insulin (IIH group) or saline (COG group) and, 15, 150, or 165 min later, oral saline (control IIH), glycerol (100 mg/kg), pyruvate (100 mg/kg), l-lactate (100 mg/kg), or combined glycerol+pyruvate+l-lactate (each 33.3 or 100 mg/kg) was compared. In addition, for comparative purposes, a group that received glucose (100 mg/kg) was included. Glycemia was measured 180 min after insulin or saline injection. To investigate the participation of the hepatic availability of gluconeogenic substrates to GR, livers from IIH and COG rats that received physiological or supraphysiological concentrations of isolated or combined glycerol, pyruvate, and l-lactate were compared. Liver experiments were done 180 min after insulin or saline injection.Results: Oral glycerol, pyruvate, and l-lactate (isolated or combined) or glucose promoted GR. Moreover, the best GR was obtained with combined glycerol+pyruvate+l-lactate (100 mg/kg). In agreement, livers that received supraphysiological concentrations of glycerol, pyruvate, and l-lactate (isolated or combined) showed higher glucose release than livers that received physiological concentrations of these substances (isolated or combined).Conclusion: The best GR obtained with combined administration of glycerol, pyruvate, and l-lactate (100 mg/kg) during long-term IIH was a consequence of the higher liver availability of these substances associated with a maintained liver ability to produce glucose from gluconeogenic substrates.

Transforming growth factor beta 1 as a biomarker of diabetic peripheral neuropathy: cross-sectional study

Juan Ybarra, Josep M. Pou, June Hart Romeo, Javier Merce, Jeroni Jurado — 2009-10-05

Abstract: Background: Simple and efficient screening methods are lacking for diabetic peripheral neuropathy (DPN), the most common and most difficult to treat of the long-term diabetic complications. Increased levels of transforming growth factor beta 1 (TGFβ1) in type 2 diabetic patients (T2DM) plays an immunomodulatory role in diabetic nephropathy and, possibly, in atherosclerotic evolution. Since preliminary interrelationships between experimental DPN and TGFβ1 have been observed, we sought to assess whether TGFβ1 could be a biomarker molecule for human DPN.Materials and Methods: Cross-sectional cohort study focused on the assessment of the interrelationships between TGFβ1 levels, cardiovascular disease (CVD), diabetic nephropathy (DNF), and neuropathy (DPN) in a group of T2DM patients (N=180; male 117, female 63) randomly selected from the North Catalonia Diabetes Study. DPN was diagnosed using clinical and neurophysiology evaluation. Incipient DNF was assessed by microalbuminuria (MAU). Total TGFβ1 (without acidification) was measured by immunoassay by ELISA (Promega).Results: DPN correlated with age, time of diabetes duration, MAU, CVD, and TGFβ1 (P<.0001). Log-transformed TGFβ1 (logTGβ1) was significantly higher in patients with DPN than in those without (P<.0005). LogTGFβ1 (OR=7.5; P=.006), age (OR=1.1; P<.0005), and logMAU (OR=2.0; P=.016) appear as significant estimators of the occurrence of DPN in our series. The integrated ROC curve evaluation with these three parameters expressed an important sensitivity (78.1%), specificity (76.0%), positive predictive value (79.2%), and negative predictive value (70.3%) in relation to DPN presence.Discussion: TGFβ1 stands as an important biomarker molecule for DFN and DPN screening in our series. Further prospective studies are warranted.

Association of a functional polymorphism (C59038T) in GTP cyclohydrolase 1 gene and Type 2 diabetic macrovascular disease in the Chinese population

Yun-fei Liao, Tian-shu Zeng, Lu-Lu Chen, Yu-ming Li, Fan Yu, Li-jun Hu, Ling Yue — 2009-06-10

Abstract: Nitric oxide (NO) unavailability plays an important role in the progression of macrovascular diseases in Type 2 diabetes (T2DM). C59038T polymorphism in GTP cyclohydrolase 1 (GCH1) gene is a functional mutation involved in NO metabolism and cardiovascular risk in a multiethnic population. To clarify the relationship between C59038T polymorphism and macrovascular disease in T2DM, an association study was performed among 611 unrelated T2DM patients. C59038T polymorphism was detected by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products after digestion displayed three genotypes, including CC, CT, and TT. The prevalence of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease was significantly higher in T2DM patients with TT genotype than those with CC or CT genotype (P<.001). Compared with CC or CC+CT genotype, T2DM patients with TT genotype had a significantly increased risk of macrovascular disease (P<.001, P=.001), with odds ratio for 4.717 [95% confidnce interval: 3.056–7.370] and 4.082 (2.716–5.868), respectively. Subjects with TT genotype showed lower levels of plasma NOx (nitrite and nitrate), flow-mediated artery dilatation and activities of superoxide dismutase but higher levels of plasma malonaldehyde and intima-media thickness of carotid artery than those with CC or CT genotype (P<.05). This study demonstrated that in Chinese T2DM population, C59038T polymorphism was associated with an increased risk of macrovascular disease, which was likely due to its effects on NO metabolism, oxidative stress, and subsequently vascular dysfunction.

Prevalence of impaired fasting glucose and analysis of risk factors in Han adolescents

2009-07-06

Abstract: Objective: To evaluate the prevalence of impaired fasting glucose (IFG) and its relationship with cardiovascular risk factors in Han adolescents aged 13 to 18 years.Methods: Step 1: A cross-sectional study was conducted on 3937 Han adolescents. IFG was defined as a fasting glucose of 5.6 to 7.0 mmol/l. Measurements included anthropometric measurements, fasting plasma glucose (FPG), and serum lipids. Step 2: We identified 60 adolescents with IFG from the IFG group using a random number table, and 60 adolescents with normal fasting glucose (NFG) were matched for age and gender with the random IFG sample. Serum true insulin (TI) was further measured.Results: (1) The prevalence of IFG was 3.5% and was similar in boys and girls (3.9% vs. 3.1%, P=.177). The prevalence of IFG in adolescents with a family history of type 2 diabetes (FHD) was higher than in adolescents without FHD (6.3% vs. 2.5%, P=.000). (2) In logistic regression, the clustering of cardiovascular risk factors among adolescents with IFG was 1.889 (95% CI: 1.125–3.171, P=.016) times compared with adolescents with NFG adjusted by age and gender. (3) Multiple linear regression analysis using FPG as the dependent variable showed that waist circumference (β=0.003, P=.000) was a significant independent predictor. (4) In Step 2, the IFG group showed significantly higher levels of lnTI and lnHOMA-IR than the NFG group (P<.01). FPG was a significant independent predictor for lnTI (β=0.478, P=.000) and lnHOMA-IR (β=0.671, P=.000).Conclusion: We found a high prevalence of IFG in Han adolescents. Genetic susceptibility and abdominal obesity were the main factors causing adolescent IFG. Adolescents with IFG increased the clustering of cardiovascular risk factors.

Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy

2009-06-24

Abstract: The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme (PON1) activity in type 2 diabetic Egyptian patients with or without nephropathy. The present study was carried out on the following groups: control group, which consisted of 30 healthy persons; Group I, which consisted of 20 type 2 diabetic patients without nephropathy; and Group II, which consisted of 20 type 2 diabetic patients with nephropathy. All the patients selected were under an antidiabetic regimen of insulin, and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies. Twenty-two patients (15 without nephropathy and seven with nephropathy) received atorvastatin in individually adjusted oral dosage (range 10–20 mg) once per day for 12 weeks. All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity, malondialdehyde (MDA), glutathione reductase activity, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, and creatinine. Urine samples were collected for determination of proteinuria. The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group, with significant difference in their levels between Group II and Group I. MDA, total cholesterol, and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group. Urea, creatinine, and proteinuria levels showed significant increase in Group II when compared to the control group and Group I, with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity, and serum levels of MDA and glutathione reductase activity were significantly decreased and increased, respectively. Also, total cholesterol, triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels. There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level. Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period. PON1 activity showed a significant negative correlation with glucose and LDL, and a significant positive correlation with HDL in all the studied groups. It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia, but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy. More specifically, restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy. Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications.

Metformin reverses the deleterious effects of high glucose on osteoblast function

Donghu Zhen, Yirong Chen, Xulei Tang — 2009-07-23

Abstract: An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In the present study, we examined the effects of different concentrations of glucose (5.5, 11, 22, and 44 mmol/L) with or without metformin (10–640 μmol/L) on rat primary osteoblasts cultured in an osteogenic medium. With 11 mmol/L glucose, cellular proliferation, alkaline phosphatase (ALP) activity, the number of nodules formed, and calcium deposition in mineralized nodules were increased significantly; intracellular reactive oxygen species (ROS) and apoptosis were slightly reduced, although these reductions were not statistically significant. At higher concentrations of glucose (22 and 44 mmol/L), cellular proliferation, ALP activity, the number of nodules formed, and calcium deposition were greatly reduced; ROS and apoptosis were significantly increased in a dose-dependent manner. Metformin markedly increased cellular proliferation, ALP activity, calcium deposition, and the number of nodules formed and inhibited ROS and apoptosis in all glucose groups. Moreover, we assessed the gene expression levels of Runx2, IGF-1, and IGF-1R. Eleven micromole per liter glucose stimulated Runx2 and IGF-1 expression; 44 mmol/L glucose inhibited Runx2, IGF-1, and IGF-1R expression. Metformin stimulated the expression of Runx2 and IGF-1 in three glucose groups, but it did not affect IGF-1R. In conclusion, our findings suggest that the dual effects of glucose on cell proliferation and development are dose dependent. Metformin not only significantly decreased intracellular ROS and apoptosis, but also had a direct osteogenic effect on osteoblasts at all glucose concentrations, which could be partially mediated via promotion of Runx2 and IGF-1 expression.

Substantially increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis of epidemiologic evidence in Japan

Hiroshi Noto, Keiichiro Osame, Takehiko Sasazuki, Mitsuhiko Noda — 2010-07-26

Abstract: Aims: Several meta-analyses have shown that diabetes mellitus affects the risk of certain site-specific cancers. However, a meta-analysis on the overall risk of cancer has not yet been performed.Methods: We performed a search of MEDLINE and the Cochrane Library for pertinent articles (including their references) that had been published as of June 10, 2010. English-language, original observational cohort studies and case-control studies conducted in Japan were included for a qualitative review and a meta-analysis.Results: A total of 22,485 cancer cases were reported in four cohort studies and one case-control study (with a total of 250,479 subjects). With these five reports, a meta-analysis of the all-cancer risk in both men and women showed an increased risk in subjects with diabetes, compared with nondiabetic subjects (OR 1.70, 95% CI 1.38–2.10). The increase in the risk ratio adjusted for possible confounders was significant in men and borderline in women (adjusted RR 1.25, 95% CI 1.06–1.46 in men; adjusted RR 1.23, 95% CI 0.97–1.56 in women). An analysis of site-specific cancers revealed increased risks for incident hepatocellular cancer (OR 3.64, 95% CI 2.61–5.07) and endometrial cancer (OR 3.43, 95% CI 1.53–7.72).Conclusions: As is the case in Western countries, Asian people with diabetes have a higher risk of incident cancer than those without diabetes. Cancer prevention and early detection should be important components of diabetes management in light of the exponentially increasing prevalence of diabetes, which has substantial implications in public health and clinical practices.

Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review

Kate E. Schemmel, Rosalyn S. Padiyara, Jennifer J. D'Souza — 2009-09-14

Abstract: Purpose: The purpose of this article was to examine how aldose reductase (AR) inhibitors are used in the prevention and treatment of peripheral neuropathy in diabetes, specifically focusing on efficacy.Methods: Medline searches were used to identify clinical trials investigating AR inhibitors and their proposed mechanism of action, efficacy, and adverse effects. Additionally, the references of the articles returned by the Medline search were examined for pertinent publications.Results: Three AR inhibitors were selected for review. Modest improvements in the preservation and restoration of nerve conduction velocities were reported in the studies. Additionally, patients reported improvements in the subjective symptoms associated with diabetic peripheral neuropathy. Adverse effects for the studied agents were minimal or not reported.Conclusions: Given the mechanism by which diabetic peripheral neuropathy can result, targeting the polyol pathway as a method of treatment appears promising, yet the efficacy of newer AR inhibitors is still to be proven. Currently, these agents are not marketed in the United States. As newer studies emerge, diabetes educators will learn more about their efficacy and safety in preventing and treating diabetic peripheral neuropathy.