Chee Fang Sum

MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

Background Dysregulation of microRNA (miRNA) expression in various tissues and body fluids has been demonstrated to be associated with several diseases, including Type 2 Diabetes mellitus (T2D). Here, we compare miRNA expression profiles in different tissues (pancreas, liver, adipose and skeletal muscle) as well as in blood samples from T2D rat model and highlight the potential of circulating miRNAs as biomarkers of T2D. In parallel, we have examined the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients. Methodology/Principal Findings Employing miRNA microarray and stem-loop real-time RT-PCR, we identify four novel miRNAs, miR-144, miR-146a, miR-150 and miR-182 in addition to four previously reported diabetes-related miRNAs, miR-192, miR-29a, miR-30d and miR-320a, as potential signature miRNAs that distinguished IFG and T2D. Of these microRNAs, miR-144 that promotes erythropoiesis has been found to be highly up-regulated. Increased circulating level of miR-144 has been found to correlate with down-regulation of its predicted target, insulin receptor substrate 1 (IRS1) at both mRNA and protein levels. We could also experimentally demonstrate that IRS1 is indeed the target of miR-144. Conclusion We demonstrate that peripheral blood microRNAs can be developed as unique biomarkers that are reflective and predictive of metabolic health and disorder. We have also identified signature miRNAs which could possibly explain the pathogenesis of T2D and the significance of miR-144 in insulin signaling.

Circulating miRNA profiles in patients with metabolic syndrome.

CONTEXT Coordinated interplay of dysregulated microRNAs in isolated metabolic disorder is implicated in the pathogenesis of metabolic syndrome. OBJECTIVE The objective of the study was to characterize microRNA expression in the blood and exosomes of individuals with metabolic syndrome and compare them with those manifesting one of the metabolic vascular risk factors (type 2 diabetes, hypercholesterolemia, or hypertension). RESEARCH DESIGN/SETTING/PARTICIPANTS: A total of 265 participants were recruited in a health screening and characterized into distinct groups as follows: 1) healthy controls (n = 46); 2) metabolic syndrome (n = 50); 3) type 2 diabetes (n = 50); 4) hypercholesterolemia (n = 89); and 5) hypertension (n = 30). Total RNA was subjected to microRNA profiling, and a panel of significantly dysregulated microRNAs was validated using quantitative PCR. MAIN OUTCOME MEASURES Analysis of profiling data characterized unique pools of miRNAs that could categorize the different risk factors of metabolic syndrome. RESULTS We have identified miR-197, miR-23a, and miR-509-5p as potential contributors of dyslipidemia in metabolic syndrome (correlation with body mass index; P = 0.029, 0.021, and 0.042, respectively) and miR-130a and miR-195 as contributors of hypertension (correlation with blood pressure; P = 0.019 and 0.045, respectively). A plausible association of miR-27a and miR-320a with metabolic syndrome and type 2 diabetes patients has also been found because these miRNAs remained dysregulated in both cases (correlation with fasting glucose; P = 0.010 and 0.016, respectively). CONCLUSIONS Significant dysregulation of seven candidate microRNAs has been found to be associated with risks involved in the manifestation of metabolic syndrome.

Metabolic Signature Shift in Type 2 Diabetes Mellitus Revealed by Mass Spectrometry-based Metabolomics

OBJECTIVE Metabolic profiling of small molecules offers a snapshot of physiological processes. To identify metabolic signatures associated with type 2 diabetes and impaired fasting glucose (IFG) beyond differences in glucose, we used mass spectrometry-based metabolic profiling. RESEARCH DESIGN AND METHODS Individuals attending an institutional health screen were enrolled. IFG (n = 24) was defined as fasting glucose (FG) of 6.1 to 6.9 mmol/L and 2-hour post glucose load <11.1 mmol/L or glycosylated hemoglobin <6.5%, type 2 diabetes (n = 27), FG ≥7.0 mmol/L, or 2-hour post glucose load ≥11.1 mmol/L, or glycosylated hemoglobin ≥6.5%, and healthy controls (n = 60), FG <6.1 mmol/L. Fasting serum metabolomes were profiled and compared using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. RESULTS Compared to healthy controls, those with IFG and type 2 diabetes had significantly raised fructose, α-hydroxybutyrate, alanine, proline, phenylalanine, glutamine, branched-chain amino acids (leucine, isoleucine, and valine), low carbon number lipids (myristic, palmitic, and stearic acid), and significantly reduced pyroglutamic acid, glycerophospohlipids, and sphingomyelins, even after adjusting for age, gender, and body mass index. CONCLUSIONS Using 2 highly sensitive metabolomic techniques, we report distinct serum profile change of a wide range of metabolites from healthy persons to type 2 diabetes mellitus. Apart from glucose, IFG and diabetes mellitus are characterized by abnormalities in amino acid, fatty acids, glycerophospholipids, and sphingomyelin metabolism. These early broad-spectrum metabolic changes emphasize the complex abnormalities present in a disease defined mainly by elevated blood glucose levels.

Relationship between circulating irisin, renal function and body composition in type 2 diabetes ☆ ☆☆

AIMS Chronic kidney disease (CKD) secondary to type 2 diabetes mellitus (T2DM) is associated with multifaceted energy dysmetabolism. We aim to study the relationship between renal function, body composition and irisin, the recently identified myokine which is involved in energy regulation, in T2DM. METHODS Circulating irisin and body composition were measured in 365 T2DM subjects across a wide range of renal function. RESULTS Circulating irisin was significantly decreased in T2DM with renal insufficiency (77.4 ± 13.7 ng/ml in T2DM with eGFR ≥ 60 ml/min/1.73 m(2) versus 72.5 ± 14.9 ng/ml in those with eGFR<60 ml/min/1.73 m(2), p = 0.001) and the reduction in irisin was most pronounced in stage 5 CKD patients. In T2DM with preserved renal function, irisin was correlated with age (r = -0.242, p = 0.001) and pulse pressure (r = -0.188, p = 0.002). Among those with renal insufficiency, irisin was correlated with BMI (r = 0.171, p = 0.022), fat mass (r = 0.191, p = 0.013), percentage of fat mass (r = 0.210, p = 0.007) and eGFR (r = 0.171, p = 0.020). Multivariate linear regression models revealed that variations in circulating irisin were mainly attributable to eGFR and age in T2DM with and without renal impairment, respectively. CONCLUSION Our observations suggest that the level of circulating irisin may be associated with renal function in T2DM. The role of reduced irisin in energy dysmetabolism in diabetic patients with renal insufficiency deserves further investigation.

High normal albuminuria is independently associated with aortic stiffness in patients with Type 2 diabetes

High normal albuminuria is associated with higher cardiovascular risk in patients with diabetes. Increased aortic stiffness is an established risk factor of vascular events. However, the relationship between albuminuria within the normal range (0–30 mg/g) and aortic stiffness in patients with Type 2 diabetes is unknown.

Adipocytokine zinc α2 glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy.

Diabet. Med. 29, 945–949 (2012)

Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients

Introduction: The aging-suppression gene α-klotho is potentially reno-protective. Animal studies suggest that angiotensin II may be a negative regulator of α-klotho expression. Therefore, we hypothesize that renin–angiotensin system antagonism may increase α-klotho secretion in type 2 diabetes (T2DM). Subjects and methods: In this post-hoc analysis of a randomized crossover study, 33 T2DM subjects with albuminuria received either 50 mg of losartan or 20 mg of quinapril (both 50% maximal dose) daily for 4 weeks with 4-week wash-out period in between. Results: Our data showed that losartan, but not quinapril, significantly increased circulating α-klotho level by an average of 23% (from 542 pg/ml to 668 pg/ml, p=0.001). Linear regression revealed that, besides different mode of treatment, increment in plasma α-klotho was associated with decrement in urine albumin/creatinine ratio (β=-0.263, p=0.029). Conclusions: The angiotensin receptor blocker losartan increases circulating α-klotho in T2DM with albuminuria. The clinical significance of this rise in α-klotho associated with losartan intervention deserves further investigation.

Ethnic disparities in risk of cardiovascular disease, end-stage renal disease and all-cause mortality: a prospective study among Asian people with Type 2 diabetes.

To study prospectively the ethnic‐specific risks of cardiovascular disease, end‐stage renal disease and all‐cause mortality in patients with Type 2 diabetes mellitus among native Asian subpopulations.

COMPUTER-BASED IDENTIFICATION OF PLANTAR PRESSURE IN TYPE 2 DIABETES SUBJECTS WITH AND WITHOUT NEUROPATHY

Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels), especially after eating. People with diabetes have problems converting food to energy. The most common form of diabetes is type 2 diabetes. Foot disease is a common complication of diabetes that can have tragic consequences. Abnormal plantar pressures are considered to play a major role in the pathologies of neuropathic ulcers in the diabetic foot. The purpose of this study was to classify the plantar pressure distribution in normal and type 2 diabetes subjects with and without neuropathy. Foot scans were obtained using the F-Scan (Tekscan, USA) in-shoe pressure measurement system. Various pedobarographic parameters such as the total plantar force, total contact area, peak pressures, and percentage medial impulse (PMI) were evaluated. These parameters were subjected to analysis of variance (ANOVA) test with a >95% confidence interval, giving excellent p-values in all of the categories. When these extracted parameters were presented to the artificial neural network (ANN) for classification, the neural network classifier was seen to be correct in more than 90% of the test cases.

Elevation of a Novel Angiogenic Factor, Leucine-Rich-α2-Glycoprotein (LRG1), Is Associated With Arterial Stiffness, Endothelial Dysfunction, and Peripheral Arterial Disease in Patients With Type 2 Diabetes

CONTEXT Increased arterial stiffness and endothelial dysfunction are associated with peripheral arterial disease (PAD). Leucine-rich-α2-glycoprotein (LRG1) is a proangiogenic factor involved in regulation of the TGFβ signaling pathway. OBJECTIVE This study in patients with type 2 diabetes mellitus explored the associations of plasma LRG1 with arterial stiffness, endothelial function, and PAD. DESIGN Based on the ankle brachial index (ABI), patients were classified as having PAD (ABI ≤ 0.9) or as being borderline abnormal (ABI, 0.91-0.99) or normal (ABI, 1.00-1.40). LRG1 was measured by immunoassay; arterial stiffness, by carotid-femoral pulse-wave velocity and augmentation index; and endothelial function, by laser Doppler flowmetry. RESULTS A total of 2058 patients with type 2 diabetes mellitus were recruited. Mean age (1 SD) was 57.4 (0.2) years. Patients with PAD (n = 258) had significantly higher LRG1 compared to patients with borderline ABI and patients without PAD (19.00 [13.50] vs 17.35 [13.30] and 15.28 [10.40] μg/mL, respectively; P < .0001). Multiple regression analysis revealed that female gender (P < .0001), non-Chinese ethnicity (P < .0001), higher waist circumference (P = .017), lower estimated glomerular filtration rate (P < .0001), higher urine albumin-creatinine ratio (P = .009), lower ABI (P < .0001), higher pulse wave velocity (P = .040), and poorer endothelium-dependent vasodilation (P = .007) were independent significant predictors of higher plasma LRG1 levels. A generalized linear model showed that a 1-SD increase in log LRG1 was associated with an odds ratio of 4.072 (95% confidence interval, 1.889-8.777; P < .0001) for prevalence of PAD, after adjustment for traditional risk factors. CONCLUSIONS Higher LRG1 is a significant predictor for arterial stiffness, endothelial function, and PAD. The pathobiological basis and the temporal relationships of these associations need to be explored by further mechanistic and prospective studies to understand the clinical significance of these findings.