Jian-Jun Liu

Lower circulating irisin is associated with type 2 diabetes mellitus

AIMSnIrisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients.nnnMETHODSnIn this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression.nnnRESULTSnCirculating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p < 0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p < 0.01), BMI (r = 0.387, p < 0.01), total cholesterol (r = 0.341, p < 0.01), total triglycerides (r = 0.299, p < 0.05), fasting blood glucose (r = 0.430, p < 0.01) and diastolic blood pressure (r = 0.306, p < 0.05). Multiple linear regression model revealed that BMI (β = 0.407, p = 0.012) and FBG (β = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didnt reveal significant association between circulating irisin and major markers of metabolic phenotype.nnnCONCLUSIONSnCirculating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.

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

AIMSnChronic 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.nnnMETHODSnCirculating irisin and body composition were measured in 365 T2DM subjects across a wide range of renal function.nnnRESULTSnCirculating 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.nnnCONCLUSIONnOur 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.

The role of fibroblast growth factor 21 in diabetes and its complications: A review from clinical perspective

Fibroblast growth factor 21 (FGF21) has been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases. The level of endogenous FGF21 is elevated in patients with impaired glucose tolerance and progressively increased from patients with overt type 2 diabetes to those with micro- and macro-vascular complications, presumably as a compensation or response to the deterioration of metabolic imbalance. A few exploratory in vivo studies, including a recent clinical trial, showed that exogenous FGF21 mimetics targeting FGF21 signaling can attain beneficial metabolic effects not with-standing the already elevated ambient FGF21 levels. In addition, some clinically available pharmacologic agents such as fenofibrates and metformin may modulate energy and macronutrients metabolism by acting through FGF21. This review mainly focuses on the role of FGF21 in development, progression and treatment of type 2 diabetes from a clinical perspective.

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.

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

CONTEXTnIncreased 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.nnnOBJECTIVEnThis study in patients with type 2 diabetes mellitus explored the associations of plasma LRG1 with arterial stiffness, endothelial function, and PAD.nnnDESIGNnBased 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.nnnRESULTSnA 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.nnnCONCLUSIONSnHigher 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.

Obesity is a determinant of arterial stiffness independent of traditional risk factors in Asians with young-onset type 2 diabetes.

OBJECTIVEnType 2 diabetes (T2DM) among the young population has become a serious concern globally, presumably due to the rising trend of obesity. Compared to other forms of diabetes, young-onset T2DM experiences more cardiovascular events and other vascular complications although the underlying mechanisms remain largely unknown. Increased arterial stiffness is a hallmark of vasculopathy. We aim to study the clinical and metabolic determinants of arterial stiffness in a cohort of multi-ethnic Asians with young-onset T2DM.nnnMETHODSn179 subjects with T2DM onset age below 30 years old were selected in this cross sectional study. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV).nnnRESULTSnPWV was correlated with age, duration of diabetes, systolic blood pressure, alanine aminotransferase, urinary albumin-to-creatinine ratio (ACR) and eGFR in bivariate correlation analysis. However, PWV was only significantly correlated with body mass index (BMI), waist circumference, urinary ACR and eGFR after adjustment for age. Overweight individuals with young-onset T2DM had significantly higher PWV levels compared to their lean counterparts (7.3xa0±xa02.4xa0m/s vs 6.4xa0±xa02.3xa0m/s, pxa0=xa00.072 and pxa0<xa00.0001 without and with adjustment for age, respectively). Multivariable regression models revealed that age, BMI, eGFR and usage of insulin were independently associated with PWV. These 4 variables explained 35.5% variance in PWV levels.nnnCONCLUSIONnAge, BMI, renal function and insulin usage are the main determinants of PWV levels in Asians with young-onset T2DM. Notably, obesity is a modifiable determinant of arterial stiffness independent of high blood pressure, dyslipidemia and hyperglycemia in this population.

Vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, is associated with diabetic kidney disease in Asians with type 2 diabetes

BACKGROUND AND AIMSnThe association of adhesion molecules ICAM-1 and VCAM-1 with cardiovascular diseases has been well-studied. However, their roles in diabetic kidney disease (DKD) are incompletely understood. We aim to study the association of plasma ICAM-1 and VCAM-1 with DKD in Asians with type 2 diabetes (T2DM).nnnSUBJECTS AND METHODSnA total of 1950 Asians with T2DM were included in this cross-sectional study. Plasma ICAM-1 and VCAM-1 were measured by immunoassays.nnnRESULTSnRenal filtration function (eGFR) declined and urinary albumin-to-creatinine ratio (ACR) levels increased progressively with the increase in plasma VCAM-1 levels. In contrast, no significant changes in eGFR and ACR were observed in subjects across different plasma ICAM-1 levels. Both ICAM-1 and VCAM-1 were correlated with ACR (rho = 0.153, p < 0.001 for VCAM-1 and ACR; rho = 0.053, p = 0.020 for ICAM-1 and ACR) in bivariate correlation analysis. However, only VCAM-1 was correlated with eGFR (rho = -0.228, p < 0.001). Multivariable linear regression models revealed that VCAM-1, but not ICAM-1, was independently associated with eGFR and albuminuria. Backward linear regression suggested that plasma VCAM-1 variability was mainly determined by eGFR whereas plasma ICAM-1 level was mainly determined by C-reactive protein in patients with T2DM.nnnCONCLUSIONSnPlasma VCAM-1 level, but not ICAM-1 level, was independently associated with prevalent DKD in Asians with T2DM. High level of ICAM-1 may be indicative of systemic inflammation and portends increase risk of incipient DKD.

Association of plasma soluble α-klotho with pro-endothelin-1 in patients with type 2 diabetes

OBJECTIVESnTo study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).nnnSUBJECTS AND METHODSnIn this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.nnnRESULTSnPlasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.nnnCONCLUSIONSnPlasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.