Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular (CV) disease. Several large clinical trials have shown that the risk for patients with diabetes of developing CV complications is only partially reduced by early, intensive glycaemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles (i.e. exosomes and microvesicles) could be harnessed to restore a 'physiological' signature capable of preventing or delaying the harmful systemic effects of T2DM.

Clinical implications of oxidative stress and potential role of natural antioxidants in diabetic vascular complications.

AIMS: The possible link between hyperglycaemia-induced oxidative stress (OxS) and diabetic complications is suggested by many in vitro studies. However, not much attention has been paid to the clinical evidence supporting this hypothesis, as well as to their possible therapeutic implications. DATA SYNTHESIS: Some prospective studies show a direct correlation between an increase in OxS biomarkers and the appearance of diabetes complications. This is consistent with the evidence that any acute increase of glycaemia, particularly post-prandial, and hypoglycaemia causes endothelial dysfunction and inflammation, through the generation of an OxS. However, the detection of free radicals is difficult as they are highly reactive molecules with a short half-life. Instead, the metabolites of OxS are measured. Interventional trials with supplemented antioxidants have failed to show any beneficial effects. Conversely, natural foods show very promising results. CONCLUSIONS: The "new antioxidant" approach includes the possibility of controlling free radical production and increasing intracellular antioxidant defence, a concept different from the old one, when antioxidant activities implied scavenging the free radicals already produced. A synergistic action in this respect could convincingly be obtained with a balanced 'Mediterranean Diet' (MedD) type. Early intensive glucose control is still the best strategy to avoid OxS and its associated diabetes complications.

Randomized, double-blind, placebo-controlled trial to evaluate the effect of Helicobacter pylori eradication on glucose homeostasis in type 2 diabetic patients.

BACKGROUND AND AIMS: Literature data suggest an association between Helicobacter pylori infection and glucose homeostasis. However, a causative link between them has not been demonstrated yet. The aim of this study is to investigate the effect of H. pylori eradication on glucose homeostasis in patients with type 2 diabetes. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled trial was conducted to investigate the effect of H. pylori eradication on glucose homeostasis in 154 patients with type 2 diabetes and who tested positive for H. pylori infection (mean age (SD), 63.1 (8.1) years). Subjects were assigned to H. pylori eradication treatment or placebo. Metabolic and inflammatory parameters were measured in all subjects at baseline and 4 weeks after the treatment. H. pylori eradication led to an improvement in glucose homeostasis, measured by HOMA-IR (p < 0.001) and KITT (0 = 0.041), due to the decrease in fasting insulin levels (p = 0.004). The results also showed that lower levels of inflammatory parameters were present after eradication. CONCLUSION: To our knowledge this is the first randomized, double blind, controlled study where the effect of H. pylori eradication on glucose homeostasis in subjects with type 2 diabetes has been investigated. Our findings demonstrate that H. pylori eradication improves glucose homeostasis in patients with type 2 diabetes through a decrease in pro-inflammatory factors. TRIAL REGISTRATION NUMBER: ACTRN12609000255280 (https://www.anzctr.org.au/).

Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Glycemic index, glycemic load and glycemic response: An International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).

BACKGROUND AND AIMS: The positive and negative health effects of dietary carbohydrates are of interest to both researchers and consumers. METHODS: International experts on carbohydrate research held a scientific summit in Stresa, Italy, in June 2013 to discuss controversies surrounding the utility of the glycemic index (GI), glycemic load (GL) and glycemic response (GR). RESULTS: The outcome was a scientific consensus statement which recognized the importance of postprandial glycemia in overall health, and the GI as a valid and reproducible method of classifying carbohydrate foods for this purpose. There was consensus that diets low in GI and GL were relevant to the prevention and management of diabetes and coronary heart disease, and probably obesity. Moderate to weak associations were observed for selected cancers. The group affirmed that diets low in GI and GL should always be considered in the context of diets otherwise understood as healthy, complementing additional ways of characterizing carbohydrate foods, such as fiber and whole grain content. Diets of low GI and GL were considered particularly important in individuals with insulin resistance. CONCLUSIONS: Given the high prevalence of diabetes and pre-diabetes worldwide and the consistency of the scientific evidence reviewed, the expert panel confirmed an urgent need to communicate information on GI and GL to the general public and health professionals, through channels such as national dietary guidelines, food composition tables and food labels.

Hyperglycemia following recovery from hypoglycemia worsens endothelial damage and thrombosis activation in type 1 diabetes and in healthy controls.

BACKGROUND AND AIMS: Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation. METHODS AND RESULTS: In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production. CONCLUSION: This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.

Oxidative stress after a carbohydrate meal contributes to the deterioration of diastolic cardiac function in nonhypertensive insulin-treated patients with moderately well controlled type 2 diabetes.

The prevalence and prognostic importance of diastolic dysfunction in type 2 diabetes has only recently been appreciated. We tested the hypothesis that in insulin treated type 2 diabetes (D), carbohydrate consumption induces oxidative stress resulting in further impairment of diastolic function beyond structural myocardial stiffness. The effects of a pure carbohydrate breakfast (48 g) on oxidative stress and cardiac function were studied in the fasting and postmeal states in subjects without hypertension or overt cardiac disease (moderately well controlled D, n=21 and controls without D, n=20). Studied variables included systolic and early diastolic (E') myocardial velocities, traditional metabolic and hemodynamic parameters, serum nitrotyrosine, and sVCAM-1. In D compared to control subjects, the postmeal increase (∆) in glucose (1.44±2.78 vs. 0.11±0.72 mmol/l, p=0.04) and ∆nitrotyrosine (0.34±0.37 vs. -0.23±0.47 nM/l, p<0.001) were significantly higher. sVCAM-1 was higher in fasting and postmeal (p=0.02). E' was significantly lower in postmeal (7.3±1.3 vs. 9.6±1.3 cm/s, p<0.001) and fasting (p<0.001) whereas the rate pressure product was significantly higher (9 420±1 118 vs. 7 705±1 871 mm Hg/min, p<0.001). Multivariable regression models of the pooled data demonstrated that independent predictors for postmeal E' were ∆nitrotyrosine and septal thickness (R² 0.466) and for fasting E' age, ∆nitrotyrosine, and septal thickness (R² 0.400). In insulin requiring type 2 diabetes, carbohydrate consumption may induce oxidative stress that is associated with worsening diastolic function, indicating that this metabolic factor is an important determinant of diastolic dysfunction in the diabetic heart beyond the increase in structural myocardial stiffness.

A prediction model to assess the risk of egfr loss in patients with type 2 diabetes and preserved kidney function: The amd annals initiative.

OBJECTIVE: To develop and validate a model for predicting 5-year eGFR-loss in type 2 diabetes mellitus (T2DM) patients with preserved renal function at baseline. RESEARCH DESIGN AND METHODS: A cohort of 504.532 T2DM outpatients participating to the Medical Associations of Diabetologists (AMD) Annals Initiative was splitted into the Learning and Validation cohorts, in which the predictive model was respectively developed and validated. A multivariate Cox proportional hazard regression model including all baseline characteristics was performed to identify predictors of eGFR-loss. A weight derived from regression coefficients was assigned to each variable and the overall sum of weights determined the 0 to 8-risk score. RESULTS: A set of demographic, clinical and laboratory parameters entered the final model. The eGFR-loss score showed a good performance in the Validation cohort. Increasing score values progressively identified a higher risk of GFR loss: a score ≥ 8 was associated with a HR of 13.48 (12.96-14.01) in the Learning and a HR of 13.45 (12.93-13.99) in the Validation cohort. The 5 years-probability of developing the study outcome was 55.9% higher in subjects with a score ≥ 8. CONCLUSIONS: In the large AMD Annals Initiative cohort, we developed and validated an eGFR-loss prediction model to identify T2DM patients at risk of developing clinically meaningful renal complications within a 5-years time frame.

Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells.

AIMS/HYPOTHESIS: Damage persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed 'metabolic memory'. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho-γ-histone H2AX and PKCδ) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest. METHODS: HUVECs were incubated for 3 weeks in 5 or 25 mmol/l glucose or oscillating glucose (24 h in 5 mmol/l glucose followed by 24 h in 25 mmol/l glucose) or for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous 25 mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24 h after high glucose exposure. RESULTS: High constant glucose upregulated phospho-γ-histone H2AX and protein kinase C (PKC)δ compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6 h after glucose exposure, showing a predicted oscillatory behaviour. CONCLUSIONS/INTERPRETATION: Exposure to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition.

Impact of acute hyperglycaemia on endothelial function and retinal vascular reactivity in patients with Type 2 diabetes.

AIM: In diabetes, endothelial dysfunction and an altered retinal blood flow have been reported and precede overt macrovascular and microvascular disease. Furthermore, an association between postprandial hyperglycaemia, retinopathy and cardiovascular disease has been observed. METHODS: Endothelial function and retinal vascular reactivity have been measured in baseline conditions in 10 healthy control subjects and 21 patients with Type 2 diabetes. In the patients with Type 2 diabetes, endothelial function and retinal vascular reactivity have been also measured every hour, for 4 h, during an oral glucose tolerance test. Endothelial function has been evaluated by measuring flow-mediated vasodilation of the brachial artery, while retinal vascular reactivity has been measured using a retinal vessel analyser, during a flicker. RESULTS: At 1 and 2 h after glucose ingestion, endothelial function decreased (P<0.05), while retinal vascular reactivity increased, even at 3 h (P<0.05), vs. the baseline values. CONCLUSION: Our data highlight that acute hyperglycaemia impacts on endothelial function simultaneously at both macrovascular and at microvascular levels, inducing functional change, which could contribute towards explaining the clinical evidence of a strong association between postprandial hyperglycaemia, cardiovascular disease and retinopathy.

Leukocyte telomere length is associated with complications of type 2 diabetes mellitus.

OBJECTIVE: The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type 2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type 2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type 2 diabetes. METHODS: This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type 2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR. RESULTS: Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42). CONCLUSIONS: The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications.

Meal-induced increases in C-reactive protein, interleukin-6 and tumour necrosis factor α are attenuated by prandial + basal insulin in patients with Type 2 diabetes.

AIM: To determine if a regimen with prandial + basal insulin compared with basal insulin attenuates post-meal inflammatory and glycative biomarkers in patients with Type 2 diabetes. METHODS: This test-meal sub-study in the USA is from a previously reported clinical trial comparing the effect on glycaemic control of 24 weeks of thrice-daily pre-meal insulin lispro mix 50 (50% insulin lispro, 50% insulin lispro protamine suspension) or bedtime insulin glargine, both plus metformin. In the sub-study, glucose, insulin, triglycerides, high-sensitivity C-reactive protein, tumour necrosis factor α, interleukin-6, methylglyoxal and 3-deoxyglucosone were measured during the post-meal period of a mixed-meal breakfast at the final visit. Prandial + basal (n = 25) and basal (n = 21) insulin were administered at the same times as during the previous 24 weeks. RESULTS: Post-meal, the prandial + basal insulin group had significantly higher insulin, lower glucose and triglycerides, as well as lower high-sensitivity C-reactive protein, tumour necrosis factor α and interleukin-6, than the basal insulin group. Glucose incremental area under the concentration curve significantly correlated with high-sensitivity C-reactive protein, tumour necrosis factor α, interleukin-6, methylglyoxal and 3-deoxyglucosone incremental area under the concentration curve. Insulin incremental area under the concentration curve correlated inversely with high-sensitivity C-reactive protein and tumour necrosis factor α incremental area under the concentration curve. However, after adjusting for glucose incremental area under the concentration curve, these inverse correlations were no longer significant. Triglyceride incremental area under the concentration curve was not correlated with any biomarker incremental area under the concentration curve. CONCLUSIONS: Controlling post-meal hyperglycaemia with prandial + basal insulin in patients with Type 2 diabetes attenuates meal-induced increases in high-sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor α compared with basal insulin. The rise in post-meal glucose, but not triglycerides, significantly correlated with the rise in post-meal inflammatory and glycative biomarkers.

Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials.

AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. METHODS: We conducted an electronic search for randomized controlled trials (RCTs) involving DPP-4 inhibitors through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more and reported the proportion of patients reaching the HbA1c target of <7%. RESULTS: A total of 43 RCTs reporting 52 comparisons met the selection criteria, which included 19 101 study participants evaluated for the primary endpoint, 10 467 treated with a DPP-4 inhibitor and 8634 treated with placebo or a comparator drug. DPP-4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40% of participants achieved the HbA1c goal of <7%: this was associated with weight neutrality and no greater hypoglycaemia. The reduction of the HbA1c level and the rate of HbA1c goal attainment was not different from comparator drugs, with similar hypoglycaemia, and different effect on weight owing to the nature of comparator (metformin, sulfonylurea or glitazones). Baseline HbA1c was the best predictor for achievement of A1C target (overall weighted r(2) value = 0.410, p < 0.001). CONCLUSIONS: A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with DPP-4 inhibitors compared to placebo, with no weight gain, and no hypoglycaemic risk when used alone; DPP-4 inhibitors were not different from comparator drugs.

Optimal dietary approaches for prevention of type 2 diabetes: a life-course perspective.

In recent years, several alternative dietary approaches, including high-protein and low-glycaemic-load diets, have produced faster rates of weight loss than traditional low-fat, high-carbohydrate diets. These diets share an under-recognised unifying mechanism: the reduction of postprandial glycaemia and insulinaemia. Similarly, some food patterns and specific foods (potatoes, white bread, soft drinks) characterised by hyperglycaemia are associated with higher risk of adiposity and type 2 diabetes. Profound compensatory hyperinsulinaemia, exacerbated by overweight, occurs during critical periods of physiological insulin resistance such as pregnancy and puberty. The dramatic rise in gestational diabetes and type 2 diabetes in the young may therefore be traced to food patterns that exaggerate postprandial glycaemia and insulinaemia. The dietary strategy with the strongest evidence of being able to prevent type 2 diabetes is not the accepted low-fat, high-carbohydrate diet, but alternative dietary approaches that reduce postprandial glycaemia and insulinaemia without adversely affecting other risk factors.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

'Glycaemic variability': a new therapeutic challenge in diabetes and the critical care setting.

Much attention has been paid recently to the possibility that oscillating glucose may superimpose on glycated haemoglobin (HbA(1c)) in determining the risk for diabetes complications. Furthermore, recent evidence suggests that glucose variability, particularly if accompanied by frequent hypoglycaemic episodes, may adversely alter the prognosis of acutely ill patients. In vitro and animal studies confirm that oscillating glucose is more dangerous than stable constant high glucose, particularly in activating the pathways involved in the pathogenesis of diabetes complications. The production of free radicals, accompanied by an insufficient increase in intracellular antioxidant defences, seems to account for this phenomenon. In humans, studies also confirm that fluctuating glucose levels produce an increase in free radicals as well as endothelial dysfunction, and that these changes are greater than those produced by stable high glucose. Avoiding glucose fluctuations in diabetic patients and in critically ill patients seems to be an emerging therapeutic challenge.

Effect of acute hyperglycaemia, long-term glycaemic control and insulin on endothelial dysfunction and inflammation in Type 1 diabetic patients with different characteristics.

OBJECTIVE: To investigate the possibility of reversing endothelial dysfunction and inflammation by glucose normalization, antioxidants and insulin per se, in different subgroups of Type 1 diabetic patients. METHODS: Three subgroups of Type 1 diabetic patients were studied: patients within 1 month of diagnosis (subgroup 1); patients with approximately 5 years' disease duration and with glycated haemoglobin (HbA(1c)) 7.0% since diagnosis (subgroup 3). Participants underwent four procedures: 2-h hyperglycaemic clamp followed by: (A) 12 h near-normalization of blood glucose, with the addition of vitamin C during the last 6 h; (B) 12-h vitamin C and near-normalization of blood glucose for the last 6 h; (C) both vitamin C and near-normalization of blood glucose for 12 h; (D) hyperglycaemic-hyperinsulinaemic clamp for 12 h, with the addition of vitamin C during the last 6 h. RESULTS: After 2 h of hyperglycaemia, markers of endothelial dysfunction, nitrotyrosine, 8-iso prostaglandin F2alpha, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, interleukin (IL)-6 and IL-18 were increased in all the subgroups. Levels were normalized, at all time points, by treatments A, B and C in the subgroups 1 and 2. In the third subgroup, levels were normalized only by the simultaneous normalization of blood glucose and vitamin C treatment. During treatment D, the levels were improved at 6 h in all the subgroups, but normalized at 12 h only after vitamin C in subgroups 1 and 2, but not in subgroup 3. CONCLUSIONS: This study suggests that different subgroups of Type 1 diabetic patients react identically to acute hyperglycaemia and insulin, but differently to glucose normalization.

Obesity and changes in urine albumin/creatinine ratio in patients with type 2 diabetes: the DEMAND study.

BACKGROUND AND AIMS: Obesity is a potential risk factor for renal disease in non-diabetic subjects. It remains unclear whether this also applies to diabetic patients. We investigated whether obesity predicted changes in albumin excretion rate in individuals with type 2 diabetes. METHODS AND RESULTS: Fifty Italian diabetes outpatient clinics enrolled a random sample of 1289 patients. A morning spot urine sample was collected to determine urinary albumin/creatinine ratio (ACR) at baseline and after 1 year from the study initiation. Progression of albumin excretion was defined as a doubling in ACR, while regression was defined as a 50% reduction. Multivariate logistic regression analyses were used to evaluate correlates of these outcomes. Data are expressed as odds ratios (OR) with 95% confidence intervals (CI). The risk of progression increased by 7% (OR=1.07; 95%CI 1.00-1.15) for every 5-cm increase in waist circumference measured at baseline, and by 17% (OR=1.17; 95%CI 1.03-1.33) for every one-unit increase in BMI during follow-up. The likelihood of regression was not independently associated with any of the variables investigated. The effect of obesity on progression of ACR was independent of metabolic control, blood pressure, treatment, and baseline level of albumin excretion. CONCLUSIONS: We found a tight link between obesity and changes in albumin excretion in diabetic subjects, suggesting potential benefits of interventions on body weight on end-organ renal damage.