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Biomedical subjects

P Fioretto

Publications and source records attributed to P Fioretto.

80 records · Page 5Linked to original sources
PubMed1987

Glomerular filtration rate is increased in man by the infusion of both D,L-3-hydroxybutyric acid and sodium D,L-3-hydroxybutyrate.

A high glomerular filtration rate (GFR) is often found early in insulin-dependent diabetes mellitus (IDDM). It has been suggested that high circulating glucose, glucagon, and GH levels could play a role in this increase in GFR. On the other hand, patients with IDDM in poor metabolic control also have high circulating ketone body levels. This study was undertaken to determine whether exogenous D,L-3-hydroxybutyric acid at two infusion rates (40 and 30 mumol kg-1 min-1) for 180 min altered renal plasma flow (RPF), GFR, and the excretion rate of total protein, beta 2-microglobulin, and albumin in 11 normal (N) subjects and 11 IDDM patients in whom euglycemia was achieved and maintained using the insulin-glucose clamp technique. RPF and GFR were measured by a priming-continuous infusion of [125I]hippurate and [51Cr]EDTA, respectively. The 40 mumol kg-1 min-1 D,L-3-hydroxybutyric acid infusion increased RPF and GFR in both N and IDDM subjects. Mean RPF increased from 588 +/- 78 (+/- SD) to 706 +/- 129 mL min-1 1.73 m-2 in N and from 671 +/- 101 to 781 +/- 99 in IDDM. GFR increased from 121 +/- 11 to 151 +/- 15 ml min-1 1.73 m-2 in N and from 136 +/- 11 to 191 +/- 16 in IDDM. The filtration fraction also was significantly higher in IDDM than in N during the D,L-3-hydroxybutyric acid infusion. The 30 mumol kg-1 min-1 D,L-3-hydroxybutyric acid infusion increased RPF and GFR to a somewhat lesser extent in both groups. D,L-3-hydroxybutyric acid infusions increased the tubular reabsorption rate of ketone bodies and sodium. The increase in tubular sodium reabsorption rate was correlated significantly to that in the tubular ketone body reabsorption rate. A significant decrease in urinary pH was found during the D,L-3-hydroxybutyric acid infusion. D,L-3-Hydroxybutyrate sodium salt (30 mumol kg-1 min-1) also was infused in 5 of the 11 diabetic patients. A similar increase in GFR and RPF occurred. Both total protein and beta 2-microglobulin, but not albumin, excretion rates increased during D,L-3-hydroxybutyric acid (40 mumol kg-1 min-1) infusion in N and IDDM subjects. D,L-3-Hydroxybutyric acid infusion did not change plasma glucagon, GH, or renin activity.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxybutyric Acid↗
PubMed1987

Metabolic control of kidney hemodynamics in normal and insulin-dependent diabetic subjects. Effects of acetoacetic, lactic, and acetic acids.

Diabetes mellitus is associated with important changes in renal hemodynamics. The purpose of this study was to determine whether an increase in blood concentration patterns of ketone bodies and lactic acid, organic acids often elevated in poorly controlled insulin-dependent diabetes mellitus (IDDM), could contribute to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) regardless of changes in circulating levels of glucose and insulin. Six IDDM patients and six normal subjects were given a saline infusion (15 mumol.min-1.kg-1) for 2 h, an acetoacetic acid infusion (15 mumol.min-1.kg-1) for another 2 h, and then a saline infusion after an overnight fast during euglycemic insulin-glucose clamp. Acetoacetic acid infusion resulted in an increase of blood ketone bodies in the range of 0.7-1.5 mM from a basal value of 0.1-0.3 mM. GFR was 125 +/- 16 and 136 +/- 17 ml.min-1.1.73 m-2 in normal and IDDM subjects, respectively, during baseline saline infusion and 138 +/- 21 (P less than .01 vs. basal level) and 158 +/- 15 ml.min-1.1.73 m-2 (P less than .001 vs. basal level) during acetoacetic acid infusion. During the last saline infusion, renal hemodynamic patterns decreased again to baseline levels. Another six IDDM patients and six normal subjects were given saline, lactic acid, and saline infusions at the same rates of infusion after an overnight fast during euglycemic insulin-glucose clamp. Lactic acid concentration increased from approximately 0.5-0.8 to 1.0-1.5 mM in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1986

Type I diabetes is characterized by insulin resistance not only with regard to glucose, but also to lipid and amino acid metabolism.

Resistance to the metabolic effects of insulin has been reported with regard to glucose disposal in type I diabetic patients (IDDM) even when they were euglycemic. Our aim was to study glucose, lipid, and amino acid metabolism during glucose clamping at multiple levels of insulin in 10 normal (N) and 6 IDDM patients. Blood glucose was maintained constant (4.7 mmol/liter) at three insulin plateaus (160 min each) [42 +/- 6 (SD) 89 +/- 11, and 1255 +/- 185 microU/ml in N and 36 +/- 4, 80 +/- 13, and 1249 +/- 107 microU/liter in IDDM]. Mean glucose disposal was 34 +/- 11, 69 +/- 10, and 84 +/- 22 mumol kg-1 min-1 in N and 16 +/- 5, 40 +/- 18, and 65 +/- 27 in IDDM, respectively. Baseline concentrations of blood lactate, pyruvate, alanine, and branched chain amino acids were 560 +/- 130, 36 +/- 9, 212 +/- 44, and 451 +/- 19 mumol/liter, in N and 793 +/- 179 (P less than 0.05), 45 +/- 14, 195 +/- 50, and 439 +/- 33 in IDDM, respectively. The maximum percent change of lactate during the euglycemic clamp was +147 +/- 23% in N and +75 +/- 15% (P less than 0.05) in IDDM; that of branched chain amino acids was -61 +/- 5% in N and -48 +/- 7% (P less than 0.01) in IDDM. Baseline concentrations of glycerol, FFA, and adipate were 44 +/- 15, 449 +/- 152, and 8 - 8 mumol/liter in N and 39 +/- 14, 473 +/- 44, and 41 +/- 14 (P less than 0.01) in IDDM. The maximum percent change of glycerol during the euglycemic clamp was -50 +/- 8% in N and -16 +/- 8% (P less than 0.01) in IDDM, that of FFA -98 +/- 3% in N and -70 +/- 4% in IDDM (P less than 0.05). No significant differences were found between N and IDDM with regard to blood concentrations of ketone bodies, citrate, ketoglutarate, and hydroxymethylglutaryl coenzyme A both before and during the euglycemic clamp. The lactate percent increase was significantly correlated to glucose disposal rate (P less than 0.001). The lactate turnover rate increased during the euglycemic clamp and was lower in IDDM than in N. We conclude that during euglycemic-multiple insulin clamp studies the greater lactate increase suggests that the flux of glycolysis is higher in N than in IDDM, tricarboxylic acid concentrations are comparable in N and IDDM, and FFA, glycerol, and branched chain amino acid decreases were less in IDDM than in N, suggesting that IDDM patients are resistant to insulin with regard to lipid and protein metabolism. The higher adipate basal values demonstrate enhanced omega-oxidation in IDDM.

Adult↗
PubMedDate not supplied

Type I insulin-dependent diabetic patients show an impaired renal hemodynamic response to protein intake.

Human kidney responds to a meat meal with an increase in glomerular filtration rate (GFR), but the mechanisms regulating kidney hemodynamics following protein intake are poorly understood in Type I insulin-dependent diabetes. In the present study we investigated GFR response to protein intake (600 gr/1.73 m2 meat meal) in nine normal subjects and 21 Type I insulin-dependent diabetic patients with normal albumin excretion rates as well as proximal tubular sodium reabsorption rates and distal sodium delivery (PRNa and DDNa). The same study was reperformed in normal subjects and diabetic patients, with less than a 5 year diabetes duration, following one week of indomethacin treatment. Normal subjects showed a 38% increase in GFR following protein intake, whereas diabetic patients showed a significantly lower response (18%, p less than 0.01). The response of GFR to protein challenge was negatively related to diabetes duration but not to baseline glomerular filtration rate. Indomethacin treatment completely prevented the protein induced GFR increase in normal subjects but not in diabetic patients. Sodium reabsorption rate was increased following protein challenge both at the proximal and distal tubular level, as was net natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 1↗
PubMedDate not supplied

Vascular endothelial growth factor (VEGF) and VEGF receptors in diabetic nephropathy: expression studies in biopsies of type 2 diabetic patients.

Vascular endothelial growth factor (VEGF) is involved in the pathogenesis of diabetic retinopathy but its role in diabetic nephropathy is only speculative so far. It has been shown that in renal cortex of normal kidneys, glomerular and tubular epithelial cells express VEGF and that VEGF 165 is the predominant isoform. Two VEGF receptors, KDR (kinase domain region) and Flt-1 (fms-like tyrosine kinase) are co-expressed by glomerular and peritubular capillary endothelial cells. However, VEGF and VEGF receptors are predominantly expressed at glomerular level. We recently demonstrated that in type 2 diabetic patients glomerular qualitative and quantitative changes of VEGF mRNA expression are associated with functional and structural renal changes. In the present work we focused on the tubulo-interstitial compartment; by reverse transcription/polymerase chain reaction (RT/PCR) we evaluated the expression of VEGF, KDR, Flt-1 and the relationship between the two main type of VEGF isoforms, VEGF121 and VEGF165 in the tubulo-interstitium of type 2 diabetic patients. Patients were divided in three category on the basis of renal structure pattern: CI, with normal or near normal renal structure; CII, with glomerular and tubulo-interstitial lesions occurring in parallel (typical diabetic nephropathology); CIII, with atypical pattern of renal injury, i.e., more severe tubulo-interstitial and vascular than glomerular changes. Comparison between the two cortical compartments revealed that, both in glomeruli and in tubulo-interstitium. VEGF121 isoform exceed VEGF165 while Flt-1 was significantly lower in glomeruli. CIII patients had the lowest tubulo-interstitial level of VEGF and Flt-1 mRNAs. These results suggest that the transcriptional shifting from VEGF165 to VEGF121 isoform and the unbalanced FIt-1 expression between tubulo-interstitium and glomeruli could be involved in the pathogenesis of diabetic nephropathy. Furthermore, at least in CIII patients, down-regulation of the VEGF-Flt-1 system could be involved in the mechanisms leading to tubulointerstitial diabetic lesions.

Adult↗
PubMedDate not supplied

Role of mesangial expansion in the pathogenesis of diabetic nephropathy.

Glomerulopathy, characterized by thickening of the glomerular basement membrane (GBM) and mesangial expansion, is the most important renal structural change in type 1 diabetic patients with diabetic nephropathy. Morphological lesions develop concomitantly in the arterioles, tubules and interstitium. Mesangial fractional volume [Vv(mes/glom)], an estimate of mesangial expansion, is the structural parameter that best correlates with glomerular filtration rate (GFR) and it is also closely related to the presence of proteinuria and hypertension. Diabetic glomerulopathy has also been described in type 2 diabetic patients, but glomerular lesions are milder than in type 1 diabetic patients. In type 2 diabetes glomerular structural parameters are, on average, altered. However, despite persistent microalbuminuria or proteinuria, several patients have normal glomerular structure. Renal structure is, in fact, heterogeneous in type 2 diabetic patients: only a subset has typical diabetic glomerulopathy, while a substantial proportion has more advanced tubulo-interstitial and vascular rather than glomerular lesions, or has normal or near normal renal structure. Also in type 2 diabetes mesangial expansion is related to renal functional parameters, but although significant, these structural-functional relationships are less precise than in type 1 diabetes. Thus, both in type 1 and in type 2 diabetes, mesangial expansion is the most important structural change. Finally, we have recently demonstrated that, the lesions of diabetic glomerulopathy can be reversed in humans. This amelioration in glomerular structure was observed after long-term normoglycemia obtained by pancreas transplantation. This is a new concept in nephrology, and the understanding of the mechanisms involved in the glomerular architectural remodelling might have important clinical and therapeutic implications.

Diabetes Mellitus, Type 1↗