Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Evidence that even "normal" albuminuria may denote incipient GFR reduction in patients with type 2 diabetes mellitus.

AIMS: In patients with diabetes and microalbuminuria, small changes of GFR could have been missed, due to the lack of sensitive methodology for GFR determination in clinical practice (creatinine based calculations). Therefore we explored the relation of the degree of albumin excretion with Cystatin C, which has been recently proved to be a better marker of GFR, compared to serum creatinine. METHODS: We studied 179 patients with type 2 diabetes, in whom renal function and microalbuminuria were evaluated. RESULTS: In patients with normal renal function, GFR/MDRD>or=60 ml/min/1.73 m(2), (n=79), urinary albumin concentration (UAC) was significantly correlated with Cystatin C, both in patients with normoalbuminuria (r=0.547, p<0.023) or microalbuminuria (r=0.305, p<0.035), while it was not correlated either with serum creatinine or calculated creatinine clearance. In patients with GFR/MDRD<60 ml/min/1.73 m(2), (n=100), UAC was significantly correlated with Cystatin C, also both in patients with normoalbuminuria (r=0.536, p<0.032) or microalbuminuria (r=0.340, p<0.016), while it was significantly correlated with serum creatinine and calculated creatinine clearance only in those with microalbuminuria. CONCLUSIONS: Subtle changes in renal function, as judged by Cystatin C concentration, may parallel the degree of albuminuria, even in the normoalbuminuric stage. This finding needs further confirmation by more appropriate methodology in prospective follow up studies.

Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature.

Among specific diabetes subtypes secondary to pancreatopathies, hereditary hemochromatosis is an inherited disorder of iron metabolism resulting in excessive iron overload and tissue damage in various organs. We here report the case of a man with the young-onset form of the disease and describe his glycaemic status before and during venesection therapy. A 25-year old man visited our clinic in Athens, Greece, with hypogonadotropic hypogonadism due to hereditary hemochromatosis. Genetic analysis revealed that he was suffering from the juvenile aggressive form and treatment was initiated with frequent phlebotomies in conjunction with androgen substitution. Within 18 months of therapy ferritin level was normalized and hypogonadism was fully restored. Despite severe iron overload, glucose tolerance remained normal during the various stages of the disease, although alterations in both insulin secretion and sensitivity were detected. Present data indicate that in juvenile hemochromatosis, the efficacy of the chelation therapy and probably the chronic interval required to restore normal iron concentration both play important roles in the formation of glucose metabolism characteristics.

A high carbohydrate versus a high monounsaturated fatty acid diet lowers the atherogenic potential of big VLDL particles in patients with type 1 diabetes.

The objective of the present study was to compare the effects of two diets on the atherogenic potential of two VLDL subfractions harvested from fasting subjects by measuring the number and composition of particles and the amount of esterified cholesterol accumulated in macrophages. A high (25%) monounsaturated fatty acid (Mono) diet and a high (61%) carbohydrate (CHO) diet were provided for 4 wk in a randomized crossover design to 19 normolipidemic, nonobese patients with type 1 diabetes. The two diets were matched for protein, polyunsaturated/saturated fatty acids, cholesterol and fiber content. The number of circulating big VLDL (S:(f) 100-400) particles was greater during the high Mono than during the high CHO diet based on the levels of apolipoprotein B (means +/- SEM): 31.4 +/- 7.4 versus 20.0 +/- 3.8 mg/L (P: < 0.025, paired t test). The following variables did not differ during the diet periods: number of small VLDL (S:(f) 20-100) particles, esterified cholesterol accumulated in THP-1 macrophages incubated with the same number of big and small VLDL particles and particle composition. We conclude that a high CHO diet might be preferable to a high Mono diet, on the basis of the premise that more big VLDL particles could increase the atherosclerotic risk in patients with diabetes.

Effects of simvastatin on fasting and postprandial triglyceride-rich lipoproteins in patients with type I diabetes mellitus.

To assess the effect of simvastatin on fasting and postprandial triglyceride (TG)-rich lipoproteins in subjects with type 1 diabetes and elevated LDL cholesterol levels, eight patients participated in a simvastatin versus placebo, randomized, crossover study. At the end of each drug period fasting and postprandial lipoprotein studies were undertaken. Fasting plasma total and LDL cholesterol and apolipoprotein B (apo B) were significantly lower on simvastatin compared to placebo. Postprandial studies: simvastatin versus placebo consistently decreased the area under the curve (AUC, mean+/-SEM) of TG in plasma (12.52+/-9.07 versus 18.70+/-10.48 mmol x h/L, p = 0.02). Similarly, TG AUC was lower: in the chylomicron subfraction (Sf > 400) 3.24+/-2.71 versus 5.27+/-4.61 mmol x h/L p = 0.03; and in the [chylomicron remnant + VLDL] subfraction (Sf 20-400) 3.98+/-2.51 versus 7.04+/-3.88 mmol x h/L, p = 0.01. This was due to decreased particle n umber rather than size, as shown by a decrease in the AUC of apo B in Sf 20-400 (600+/-360 versus 980+/-600 mg x h/L, p = 0.02) and the lack of change in the ratio of TG/apo B. Intestinal lipoproteins contributed to the simvastatin effect, as shown by the lower AUC of retinyl esters in both subfractions. Chylomicrons: 627.61+/-363.43 versus 948.19+/-568.34 nmol x h/L, p = 0.02 and remnants: 129.23+/-67.12 versus 208.49+/-92.11 nmol x h/L, p = 0.04. Our data suggest an additional mechanism by which simvastatin can decrease the risk of atherosclerosis in patients with type I diabetes: a decrease of the number of circulating intestinal and hepatic postprandial TG-rich lipoprotein particles.

Differences in the metabolism of postprandial lipoproteins after a high-monounsaturated-fat versus a high-carbohydrate diet in patients with type 1 diabetes mellitus.

There is little information comparing the effects of a high-monounsaturated (Mono)-fat versus a high-carbohydrate (CHO) diet in patients with type 1 diabetes mellitus. In the present study, the effects of these diets on a number of metabolic parameters were compared. Seventeen normolipidemic, nonobese patients with type 1 diabetes were provided with the diets for 4 weeks each in a randomized, crossover design. The percentages of Mono fat of the two diets were 25 Mono versus 9 CHO, with a corresponding total fat content of 40% versus 24% and a total CHO content of 45% versus 61%. At the end of each dietary period, parameters of glycemic control, coagulation factors, and fasting and postprandial lipoproteins were assessed. There were no differences in weight, glycemia, insulin dose, fasting lipid profile, or coagulation factors between the two diets. However, the metabolism of postprandial lipoproteins after a fat load differed; viz, after the Mono diet compared with the CHO diet, mean plasma triglyceride levels over 10 hours were higher (P=.0025, by repeated-measures ANOVA). The levels of triglyceride (P=.0045) and retinyl esters (P=.0046) in chylomicrons (Sf>400) and chylomicron remnants (Sf 100 to 400) (P=.0047 and P=.043, respectively), and the total particle number (apolipoprotein B levels) in chylomicron remnants (P=.001) and small, very low density lipoprotein (Sf 20 to 100, P=.016) were also higher. Our data suggest that in patients with type 1 diabetes, a CHO diet might be preferable to a Mono diet, since adherence to the former results in a lower number of circulating postprandial lipoprotein particles that are potentially atherogenic.