Monica Vedovato

Insulin Resistance and Microalbuminuria: A Cross-Sectional, Case-Control Study of 158 Patients With Type 2 Diabetes and Different Degrees of Urinary Albumin Excretion

Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was ∼25% lower in micro- than in normoalbuminuric patients (5.20 ± 1.91 vs. 6.86 ± 2.88 mg · kg−1 · min−1, P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg · kg−1 · min−1 decrease predicting ∼40% increased prevalence (odds ratio 1.37 [95% CI 1.14–1.70]). Microalbuminuria was threefold more frequent in patients with GDR ≤7.50 ± 2.56 mg · kg−1 · min−1 than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 ± 2.56 vs. 5.16 ± 1.61 mg · kg−1 · min−1) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications.

Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.

Objective In type 2 diabetes, prevalence of nonalbuminuric renal impairment is increasing worldwide, though its clinical significance remains unclear. This large-cohort study aimed at evaluating the association of this phenotype with cardiovascular risk factors and other complications. Methods Type 2 diabetic patients from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study (n = 15 773), visiting consecutively 19 hospital-based Diabetes Clinics in years 2007–2008, were examined. Serum creatinine was assessed by the Jaffe method; albuminuria was measured by immunonephelometry or immunoturbidimetry. Results Of patients with renal impairment, as identified by an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2, 56.6% were normoalbuminuric, 30.8% were microalbuminuric, and 12.6% were macroalbuminuric. Percentages were similar when GFR was estimated using the more accurate Chronic Kidney Disease Epidemiology Collaboration equation instead of the simplified Modification of Diet in Renal Disease formula, and were independent of age, thus indicating that the increasing prevalence of this phenotype does not reflects misclassification of elderly patients. Nonalbuminuric renal impairment was not associated with HbA1c and correlated less strongly with retinopathy and hypertension than albuminuria, either alone or associated with reduced eGFR. It was associated with a higher prevalence of cardiovascular disease (CVD) than albuminuria alone, but lower than albuminuric renal impairment. Female sex correlated with nonalbuminuric renal impairment and male sex with the albuminuric forms. Conclusions These data show that type 2 diabetic patients with nonalbuminuric renal impairment exhibit distinct clinical features, suggesting predominance of macroangiopathy as underlying renal pathology, and that this phenotype is associated with significant CVD burden.

Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study

Poorer control of risk factors for cardiovascular disease (CVD) has been reported in diabetic women, as compared with diabetic men. It has been proposed that this finding is due to gender disparities in treatment intensity. We investigated this hypothesis in a large contemporary cohort of subjects with type 2 diabetes.

Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: The renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

OBJECTIVE Although a reduced estimated glomerular filtration rate (eGFR) was shown to be a powerful independent predictor of cardiovascular disease (CVD), other studies suggested that it confers a much lower risk than albuminuria alone, whereas the combination of the two abnormalities is associated with multiplicative risk. This study aimed at assessing the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria and chronic kidney disease (CKD) phenotypes. RESEARCH DESIGN AND METHODS This cross-sectional study evaluated 15,773 patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study in 19 outpatient diabetes clinics in years 2007–2008. Albuminuria was assessed by immunonephelometry or immunoturbidimetry. GFR was estimated by the simplified Modification of Diet in Renal Disease Study and the Chronic Kidney Disease-Epidemiology Collaboration equation. CKD was defined as an eGFR <60 mL/min/1.73 m2 or micro- or macroalbuminuria. Major acute CVD events were adjudicated based on hospital discharge records or specialist visits. RESULTS CVD risk increased linearly with eGFR decline and albuminuria and became significant for values <78 mL/min/1.73 m2 and ≥10.5 mg/24 h, respectively. Beyond traditional CVD risk factors, total CVD showed an independent association with albuminuria alone (odds ratio 1.20 [95% CI 1.08–1.33]), reduced eGFR alone (1.52 [1.34–1.73]), and both abnormalities (1.90 [1.66–2.19]). However, coronary events were associated predominantly with reduced eGFR alone, whereas cerebrovascular and peripheral events showed a stronger correlation with the albuminuric CKD phenotypes. CONCLUSIONS These data, although cross-sectional, show that reduced eGFR, irrespective of albuminuria, is associated with significant CVD, particularly in the coronary district.

Nitric Oxide Synthesis Is Reduced in Subjects With Type 2 Diabetes and Nephropathy

OBJECTIVE Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied. RESEARCH DESIGN AND METHODS We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[15N2-guanidino]-arginine infusion, and use of precursor–product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic (∼1,000–1,200 pmol/l) clamp. RESULTS In type 2 diabetes, NOx FSR was reduced both under basal (19.3 ± 3.9% per day, vs. 22.9 ± 4.5% per day in control subjects) and hyperinsulinemic states (24.0 ± 5.6% per day, vs. 37.9 ± 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 ± 0.06 vs. 0.89 ± 0.34 mol per day; hyperinsulinemia, 0.35 ± 0.07 vs. 1.15 ± 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 ± 3.2% per day) and the ASR (0.03 ± 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 ± 2.9% per day and 0.25 ± 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 ± 0.05% vs. 0.65 ± 0.25%; hyperinsulinemia, 0.32 ± 0.06% vs. 1.03 ± 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA). CONCLUSIONS In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.

Reproducibility of albuminuria in type 2 diabetic subjects. Findings from the Renal Insufficiency And Cardiovascular Events (RIACE) study

BACKGROUND Measurement of urinary albumin excretion (UAE) shows important intra-individual variability suggesting the need for multiple assessments. This study aimed at investigating the reproducibility of UAE in type 2 diabetes. METHODS UAE was obtained from two to three samples collected in a 3- to 6-month period from 4062 of the 15 773 type 2 diabetic subjects participating in the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study in 2007-08. UAE was assessed as albumin excretion rate (AER) in 24-h urine collections from 833 subjects and albumin:creatinine ratio (A/C) in early-morning urine samples from 3229 patients. Albuminuria was measured by immunonephelometry or immunoturbidimetry. RESULTS The median coefficient of variation (CV) was 32.5% (interquartile range: 14.3-58.9). Concordance rate between a single UAE and the geometric mean of multiple measurements was 94.6% for normoalbuminuria, 83.5% for microalbuminuria, 91.1% for macroalbuminuria and 90.6% for albuminuria (micro + macro). CV was significantly higher (P < 0.01) for AER measurement than for A/C and with immunoturbidimetry than with immunonephelometry, whereas concordance rates were similar between the two modalities of urine collection and the two assay methods. Receiver-operating characteristic (ROC) plots demonstrated a good performance of single UAE in predicting the geometric mean of multiple measures at the cut-off level of both microalbuminuria (ROC(AUC) 0.926; 95% confidence interval: 0.915-0.937) and macroalbuminuria (ROC(AUC) 0.950; 95% confidence interval: 0.927-0.973). CONCLUSIONS Data from this large cohort indicate that, in type 2 diabetic subjects, a single UAE value, thought to be encumbered with high intra-individual variability, is an accurate predictor of nephropathy stage for clinical and epidemiological purposes.

Age, Renal Dysfunction, Cardiovascular Disease, and Antihyperglycemic Treatment in Type 2 Diabetes Mellitus: Findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study

To assess the distribution of antihyperglycemic treatments according to age and renal function and its relationship with cardiovascular disease in type 2 diabetes mellitus (T2DM).

Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study

BackgroundPrevious reports have clearly indicated a significant relationship between hemoglobin (Hb) A1c change from one visit to the next and microvascular complications, especially nephropathy (albuminuria and albuminuric chronic kidney disease, CKD). In contrast, data on macrovascular disease are less clear. This study was aimed at examining the association of HbA1c variability with cardiovascular disease (CVD) in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study.MethodsSerial (3–5) HbA1c values obtained during the 2-year period preceding recruitment, including that obtained at the enrolment, were available from 8,290 subjects from 9 centers (out of 15,773 patients from 19 centers). Average HbA1c and HbA1c variability were calculated as the intra-individual mean (HbA1c-MEAN) and standard deviation (HbA1c-SD), respectively, of 4.52±0.76 values. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. Diabetic retinopathy (DR) was assessed by dilated fundoscopy. CKD was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate, as calculated from serum creatinine.ResultsHbA1c-MEAN, but not HbA1c-SD, was significantly higher (P<0.0001) in subjects with history of any CVD (n. 2,133, 25.7%) than in those without CVD (n. 6,157, 74.3%). Median and interquartile range were 7.78 (7.04-8.56) and 7.49 (6.81-8.31), respectively, for HbA1c-MEAN, and 0.47 (0.29-0.75) and 0.46 (0.28-0.73), respectively, for HbA1c-SD. Logistic regression analyses showed that HbA1c-MEAN, but not HbA1c-SD (and independent of it), was a significant correlate of any CVD. Similar findings were observed in subjects with versus those without any coronary or cerebrovascular event or myocardial infarction. Conversely, none of these measures were associated with stroke, whereas both correlated with any lower limb vascular event and HbA1c-SD alone with ulceration/gangrene. All these associations were independent of known CVD risk factors and microvascular complications (DR and CKD).ConclusionsIn patients with type 2 diabetes, HbA1c variability has not a major impact on macrovascular complications, at variance with average HbA1c, an opposite finding as compared with microvascular disease, and particularly nephropathy.Trial registrationClinicalTrials.Gov NCT00715481

Insulin resistance of amino acid and protein metabolism in type 2 diabetes

Although insulin resistance in T2DM (type 2 diabetes mellitus) is usually referred to glucose and lipid metabolism, the question whether such a resistance affects also amino acid and protein metabolism is both relevant and not easy to be answered. Available data indicate a reduced response to insulin in the inhibition of proteolysis at low, near basal hormone levels, whereas such a response appears to be normal at high physiological doses. In most studies in T2DM subjects the stimulation of whole-body protein synthesis in the presence of hyperinsulinemia and euaminoacidemia appears to be normal, although one single study reported lower rates in male T2DM subjects with obesity. The response to insulin of plasma protein synthesis (albumin and fibrinogen) is also normal. However, some metabolic steps of amino acids related to vascular complications (methionine and arginine) exhibit a defective response to insulin in T2DM subjects with nephropathy. In summary, although gross alterations in the response of whole-body protein turnover are not evident in T2DM, specific investigations reveal subtle abnormalities in metabolic steps of selected amino acids. Furthermore, the effects of interaction between diabetes (with the associated insulin resistance) and older age in the pathogenesis of sarcopenia in the elderly deserve more specific studies.

Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria

We assessed blood pressure (BP), body weight, renal hemodynamics, and insulin sensitivity (by euglycemic-hyperinsulinemic clamp) in nine normoalbuminuric and seven microalbuminuric IDDM patients after 6 days on a low-sodium diet (20 mEq) and after 6 days on a high-sodium diet (250 mEq). In microalbuminuric but not in normoalbuminuric IDDM patients, switching from a low to a high-sodium diet was associated with a significant increase in mean BP (from 92 +/- 3 to 101 +/- 4 mmHg; P < 0.001) and in body weight (2.91 +/- 0.63 vs. 1.47 +/- 0.26 kg; P < 0.05). Moreover, under high-sodium conditions, angiotensin II infusion (3 ng x kg(-1) x min(-1)) caused a greater increase in mean BP (14 +/- 2 vs. 7.4 +/- 1 mmHg; P < 0.05) and a smaller reduction in renal plasma flow (-122 +/- 29 vs. -274 +/- 41 ml x min(-1) x 1.73 m2; P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Under low sodium conditions, aldosterone increments after angiotensin II infusion were lower (P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Insulin-mediated glucose disposal was not affected by sodium dietary content, but it was lower in microalbuminuric (P < 0.05) than in normoalbuminuric IDDM patients. The salt-induced changes in mean BP were related to insulin sensitivity (r = -0.78; P < 0.001). In conclusion, in IDDM patients, microalbuminuria is associated with 1) an increased responsiveness of BP to salt intake and angiotensin II, 2) impaired modulation of renal blood flow, and 3) insulin resistance. Therefore, salt sensitivity in IDDM patients clusters with other factors that are likely to play an important role in the pathogenesis of diabetic nephropathy and its cardiovascular complications.