Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy.

Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = -0.282, p = 0.021), and SBP (r = -0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.

Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein axis constituents. The potential link between ANGPTL8 and IGFBPs in DN has not been explored before. Here, we assessed changes in the circulating ANGPTL8 levels in patients with DN and its association with IGFBP-1, -3, and -4. Our data revealed a significant rise in circulating ANGPTL8 in people with DN, 4443.35 ± 396 ng/mL compared to 2059.73 ± 216 ng/mL in people with T2D (p < 0.001). Similarly, levels of IGFBP-3 and -4 were significantly higher in people with DN compared to the T2D group. Interestingly, the rise in ANGPTL8 levels correlated positively with IGFBP-4 levels in T2DM patients with DN (p < 0.001) and this significant correlation disappeared in T2DM patients without DN. It also correlated positively with serum creatinine and negatively with the estimated glomerular filtration rate (eGFR, All < 0.05). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and IGFBP4 was 0.76 (0.69-0.84), p < 0.001, and the specificity was 85.9%. In conclusion, our results showed a significant increase in ANGPTL8 in patients with DN that correlated exclusively with IGFBP-4, implicating a potential role of both proteins in the pathophysiology of DN. Our findings highlight the significance of these biomarkers, suggesting them as promising diagnostic molecules for the detection of diabetic nephropathy.

Association of significantly elevated plasma levels of NGAL and IGFBP4 in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression. METHODS: In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants. RESULTS: Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN (ρ = .620, p <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN. CONCLUSION: The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.

ANGPTL4: A Predictive Marker for Diabetic Nephropathy.

BACKGROUND: ANGPTL4 is a glycoprotein that is involved in regulating triglyceride metabolism by inhibiting LPL activity under fasting conditions. Additionally, ANGPTL4 has been suggested as a link between hypertriglyceridemia and albuminuria in the nephrotic syndrome. In this study, we examined levels of circulating ANGPTL4 in people with diabetic nephropathy (DN) and its association with established DN-associated proteins such as IGFBP1 and IGFBP4. METHODS: We quantified circulating ANGPTL4, IGFBP1, IGFBP3, and IGFBP4 in fasting plasma samples of 122 Kuwaiti participants using a multiplexing assay. The study involved 36 controls, as well as 86 people with type 2 diabetes (T2D) including 37 people with normal kidney function and 49 people with DN. RESULTS: ANGPTL4 level was increased in people with DN (241.56 ± 14.1 µg/ml) compared to the control group (178.43 ± 24.09 µg/ml). The increase in ANGPTL4 correlated with clinical parameters of DN including albumin-to-creatinine ratio (r = 0.271, P = 0.002), serum creatinine (r = 0.381, P = 0.0001), and eGFR (r = -0.349, P < 0.0001). Furthermore, ANGPTL4 correlated positively with both IGFBP1 (r = 0.202, P = 0.026) and IGFBP4 (r = 0.364, P < 0.0001). Multiple regression analysis showed increased IGFBP1 and TG as predictors of higher ANGPTL4 in people with DN. In people with T2D, only IGFBP1 acted as a positive predictor of a rise in ANGPTL4. CONCLUSION: In this study, our data showed a significant increase in circulating ANGPTL4, IGFBP1, and IGFBP4 in patients with DN. The elevation in ANGPTL4 correlated significantly with clinical markers of DN such as ACR, serum creatinine, and eGFR, as well as IGFBP1 and IGFBP4. Altogether, this suggests a potential role for ANGPTL4 in DN perhaps through its role in inhibiting LPL activity and promotes ANGPTL4 as a biochemical marker for the detection of a diabetic kidney disease in patients with T2D.

Association between apolipoprotein E-polymorphism and Ischemic heart disease patients with or without type 2 diabetes mellitus: a preliminary study in Kuwait.

BACKGROUND: We investigated the association between apolipoprotein E polymorphism and ischemic heart disease with or without type 2 diabetes in Kuwait and examined the impact of apolipoprotein E polymorphism in diabetic patients. METHODS: The present study was conducted from January 2005 to June 2006 in the Diabetic Clinic of Al-Amiri and Al-Sabah Hospitals in Kuwait City. Apolipoprotein E polymorphism was assessed in 250 subjects of which 83 were ischemic heart disease patients (41 diabetic and 42 non-diabetic) and 105 were diabetic patients without ischemic heart disease. Results were compared with 62 healthy controls. Apolipoprotein E polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Apolipoprotein E3 allele was the most commonly occurring form. The frequency of apolipoprotein E4 was higher in ischemic heart disease patients with type 2 diabetes (39%) and the non-diabetic (31%) group, but lower in the diabetic (20%) and control groups (16%). CONCLUSION: Apolipoprotein E4 allele may be related to the development of ischemic heart disease in patients with or without type 2 diabetes in Kuwait.  However, future studies with larger population sizes are needed to establish such relationship.

Cardiac tests in asymptomatic type 2 diabetics.

OBJECTIVE: To evaluate the use of noninvasive procedures for the detection of myocardial ischemia and its relation with other coexistent clinical factors in patients with asymptomatic type 2 diabetes mellitus. SUBJECTS AND METHODS: A total of 42 patients with type 2 diabetes mellitus, aged 41-72 years with no clinical history suggestive of coronary heart disease, were evaluated for silent myocardial ischemia by stress cardiac exercise tolerance test (ETT), 12-lead electrocardiography (ECG), transthoracic echocardiography and stress myocardial perfusion scan using technetium-99m tetrofosmin. RESULTS: Eleven patients (26.2%) showed an ischemic pattern on ETT, the resting ECG was suggestive of ischemia in only 2 (4.8%), echocardiography showed diastolic dysfunction in 9 (21.4%), and the stress myocardial perfusion scan was ischemic in 3 (7.3%). For subjects over the age of 57, a significant difference was found between age and ischemic ETT (p = 0.026) and diastolic dysfunction by echocardiography (p = 0.044). Patients with microalbuminuria and/or diastolic dysfunction were more likely than others to have ischemic ETT (p = 0.036 and 0.024, respectively) and patients with diastolic dysfunction had a higher prevalence of ischemic ETT. There was no relation between ischemic ETT and other major cardiac risk factors (hypertension, dyslipidemia, smoking, sex, duration of diabetes, BMI, and glycated hemoglobin levels). CONCLUSION: The cardiac ETT was most helpful for detecting myocardial ischemia in asymptomic type 2 diabetics. For equivocal ETT findings, echocardiography is recommended. The prevalence of myocardial ischemia was high in patients with type 2 diabetes mellitus.