Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy.

We recently observed that the course of glomerular filtration rate (GFR) rapidly declines in a subgroup of Type 2 diabetic patients (D) with abnormalities of albumin excretion rate (AER) and typical diabetic nephropathy, despite tight blood pressure control. The aim of this study was to evaluate whether amelioration of blood glucose control, using insulin, improves the course of GFR. GFR decay was measured by spline modeling analysis of the plasma clearance rate of 51CR-EDTA, assessed every 6 months. We identified two groups of D using morphometric analysis of renal biopsy, who had values of glomerular basement membrane (GBM) and fractional mesangial volume (Vv mes/glom) respectively below (Group A: 38) or above (Group B: 50) the mean+2SD of values found in 27 kidney donors (GBM: 389 nm; Vv mes/glom: 0.25), as previously described in detail. Median AER was similar at base line in the 2 groups (109 microg/min, 29-1950, in Group A, 113 microg/min, 37-1845, in Group B; n.s.). Conventional metabolic therapy (sulphonylureas and/or biguanides) was used both in Group A and B during a 3 year follow-up period (Period 1). Group B was further divided in two subgroups with body mass index below (Group B, a) and above (Group B, b) the value of 30 kg/m2. Mean +/- SD HbA1c was 8.2 +/- 1.6% in Group A, 8.3 +/- 1.7% in Group B (a) (n.s.) and 9.1 +/- 1.7% in Group B (b) (n.s.). Tight blood pressure control was achieved and maintained using angiotensin converting enzyme inhibitors and/or beta blockers and/or calcium antagonists and/or thiazides. The mean arterial blood pressure (MAP) was 92 +/- 3 mmHg in Group A and 91 +/- 4 mmHg in Group B (n.s.). GFR decay was significantly greater in Group B than in Group A (Group A vs B: +1.21 +/- 0.71 vs -5.86 +/- 1.61 ml/min/1.73 m2/year). Median AER significantly rose in Group B (177 microg/min, p<0.05 vs base line) but not in Group A (134 microg/min, n.s.) during the third year of follow-up. Groups A and B were then followed over 4.1 years (range 3.1-4.4) (Period 2) maintaining the above described antihypertensive regimen, resulting in MAP values similar to those described during Period 1. Group A patients were treated with the same conventional glycemic control during Period 2. Group B (a) was conversely treated with intensive insulin therapy to achieve a HbA1c value below 7.5% (3 daily injections of regular and 1 or 2 daily injections of intermediate acting insulin associated with metformin 500 mg twice daily in 64% of the patients). Group B (b) patients were only treated by metformin (850 mg thrice daily) to achieve a HbA1c value below 7.5%. HbA1c decreased below the 7.5% target value in Group B (a) (7.0 +/- 1.6%, p<0.01 vs Period 1), but not in Group B (b) (8.0 +/- 1.6%, p<0.05 vs Period 1) and in Group A (8.3 +/- 1.7%, n.s. vs Period 1). The GFR decay of Group B, a during Period 2 was lower than that during Period 1 (Period 1 vs Period 2: -5.9 +/- 1.8 vs -1.8 +/- 0.7 ml/min/1.73 m2/year, p<0.01). GFR decay during Period 2 was similar to that observed during Period 1 in Group A (Period 1 vs Period 2: +1.21 +/- 0.71 vs +0.7 +/- 0.6 ml/min/1.73 ml/year, n.s.) and in Group B (b) (Period 1 vs Period 2: -4.4 +/- 0.71 vs -4.2 +/- 0.6 ml/min/1.73 m2/year, n.s.). Median AER did not significantly change in the fourth year of Period 2 , either in Group A or B (Group A vs B: 141 vs 152 microg/min, n.s.). In conclusion, our findings seem to suggest that amelioration of blood glucose control is attained both by insulin and metformin intensive treatment, but only insulin decreases and maintains HbA1c levels below 7.5%. These pattens of HbA1c appear to be a threshold value in order to significantly blunt GFR decay in a subgroup of Type 2 diabetic patients with typical diabetic glomerular lesions, who are less responsive to tight blood pressure control alone. Conversely, the cohort of patients with less severe diabetic glomerulopathy steadily show constant GFR patterns, despite similar abnormalities of albumin excretion rate, and HbA1c average values above 7.5%.

Atorvastatin for the management of Type 2 diabetic patients with dyslipidaemia. A mid-term (9 months) treatment experience.

Dyslipidaemia, particularly increased triglycerides (TG) and low HDL-cholesterol (HDL-C), represents an important risk factor for Type 2 diabetes (T2DM) macrovascular complications. Our aim was to evaluate the effects of atorvastatin in a population of T2DM patients according to their cardiovascular risk: evidence of myocardial or coronary lesions (group A); evidence of familiar hypercholesterolaemia (group B); evidence of stable cardiovascular risk (group C). The mean age was 64+/-7 yr, mean disease duration 9.5+/-3 yr, the mean body mass index (BMI) 27.7+/-1.3 kg/m2, mean HbA1c 8+/-0.6%; total cholesterol 256+/-24 mg/dl in group A, 298+/-30 and 244+/-31 in groups B and C, respectively (p<0.05 B vs. A and C). Moreover, mean HDL-C values were about 45+/-7 mg/dl, TG 225+/-20 mg/dl, systolic and diastolic blood pressure 144+/-7 mm Hg and 84+/-8 mm Hg, respectively; fibrinogen values 330+/-23 mg/dl and microalbuminuria 58+/-9 mg/l. Lipid profile improved significantly during the treatment with personalised doses of atorvastatin (generally 10 mg/day) designed to achieve the therapeutic goals: the reduction of total cholesterol, TG (p<0.01), LDL-cholesterol (LDL-C) (p<0.01) and an increase of HDL-C were measured. The treatment with atorvastatin induced significant reduction of microalbuminuria and fibrinogen levels (p<0.01). Moreover, in the subgroup of patients with hypertension, diastolic blood pressure values were reduced without modification of antihypertensive treatment. This preliminary study suggests that the management of hypercholesterolaemia with atorvastatin in T2DM patients may be useful both for the primary and secondary prevention of chronic complications of T2DM.

Renal function in noninsulin-dependent diabetes mellitus patients treated with angiotensin-converting enzyme inhibitors and calcium channel blockers.

BACKGROUND: Data have not shown consistent effects with calcium channel blockers on the course of renal function in patients with noninsulin-dependent diabetes mellitus (NIDDM) who have hypertension alone or in association with renal damage. The differences between the antiproteinuric effects of subclasses or formulations of calcium channel blockers and the heterogeneity of renal lesions may contribute to the discrepancy in these data. Clinical studies conducted by the authors and other recent data that describe the course of renal dysfunction in hypertensive NIDDM patients treated with antihypertensive agents are reviewed. Renal structural changes were also evaluated. RESULTS: Most available data indicate that angiotensin-converting enzyme inhibitors and dihydropyridine and nondihydropyridine calcium channel blockers produce similar effects on glomerular filtration rate. In one study of patients achieving intensified, strict control of blood pressure (target<140/85 mmHg) with either cilazapril or amlodipine, glomerular filtration rate declined by 2.03+/-0.66 ml/ min/1.73 m2 per year and 2.01+/-0.71 ml/min/1.73 m2 per year, respectively, in the subgroup with normoalbuminuria and by 2.15+/-0.69 ml/min/1.73 m2 per year and 2.33+/-0.83 ml/min/ 1.73 m2 per year, respectively, in the subgroup with microalbuminuria. Renal lesions in NIDDM patients were found to be structurally heterogeneous and glomerular filtration rate appeared to decline only in patients with renal structural changes typical of NIDDM. CONCLUSIONS: The extent of blood pressure control, rather than the method by which this is accomplished, is the most important factor in determining the evolution of incipient nephropathy in hypertensive NIDDM. The kidneys of microalbuminuric NIDDM patients are structurally heterogeneous with less than one-third of patients having 'typical' diabetic nephropathology.

Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.

BACKGROUND/AIMS: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. METHODS: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. RESULTS: There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group. CONCLUSIONS: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Therapeutic effect of benfluorex in type II diabetic patients on diet regimen alone.

A randomized double-blind study of benfluorex (150 mg x 3 daily) versus placebo was conducted over 3 months in 32 type II diabetic patients (24 men and 8 women, aged 52 +/- 8.4 years) with mild stable obesity [body-mass index (BMI) 27 +/- 1.6 kg/ m2], moderate fasting hyperglycemia (fasting blood glucose 9 +/- 0.5 mmol/L, HbA1c 6.7 +/- 0.9%) and moderate hyperinsulinemia (18.6 +/- 3.0 microU/mL) when on treatment with diet alone. After a 1-month placebo run-in period, subjects were randomized to benfluorex or placebo three tablets daily. Inclusion parameters and end-of-study measures were body weight, BMI, fasting blood glucose, glycemic profile, HbA1c, fasting insulinemia, basal and stimulated C-peptide, and an insulin tolerance test (0.1 U/kg). The groups were homogeneous at baseline, except for glycemic profile (higher postprandial glycemia in the group randomized to benfluorex). At the end of the study, the groups did not differ in body weight or BMI; however, HbA1c decreased more with benfluorex (6.0 +/- 1.0% versus 6.8 +/- 0.9%, p = 0.024), as did the mean glycemic profile (7.8 +/- 1.4 versus 8.5 +/- 1.7 mmol/L, p < 0.001), including a particular decrease in postprandial glycemia. The decreases in fasting blood glucose and insulinemia appeared larger with benfluorex (7.7 +/- 1.3 versus 8.4 +/- 1.6 mmol/L and 13.5 +/- 4.5 versus 16.1 +/- 5.1 microU/mL, respectively), but were not statistically significant. The increase in the insulin sensitivity index (Kitt) was greater with benfluorex (+0.54 +/- 1.4 versus +0.25 +/- 1.3%/mn), but the difference was not statistically significant. The same was observed for the stimulated C-peptide. In type II diabetics with mild obesity and hyperglycemia previously managed with diet alone, benfluorex has significant long-term effect on HbA1c and mean daily blood glucose, and tends to lower insulinemia.

Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients.

Contrasting information has been reported concerning the course of renal function in NIDDM with hypertension alone or in association with renal damage. The aim of the present study was to elucidate the course of the glomerular filtration rate (GFR) in hypertensive NIDDM patients during antihypertensive therapy. Furthermore, we compared the effects of ACE inhibitors (cilazapril, Inibace, Roche, Milan, Italy) and Ca(2+)-channel blockers (amlodipine, Norvasc, Pfizer, Rome, Italy). Of the hypertensive NIDDM patients attending the outpatient's clinic of the internal medicine departments of the University of Padova and Sassari, 44 participated in the present study. Of these patients, 26 were normoalbuminuric and 18 microalbuminuric. They were randomly treated with either cilazapril or amlodipine. The target of antihypertensive treatment was a value < 140 mmHg for systolic and 85 mmHg for diastolic blood pressure (BP). Microalbuminuria was defined as an albumin excretion rate (AER) between 20 and 200 micrograms/min. GFR was measured by plasma clearance of 51Cr-labeled EDTA at baseline and every 6-12 months during a 3-year follow-up interval. A significant decrease was observed in the values of GFR, AER, and systolic and diastolic BP in normoalbuminuric and microalbuminuric patients during antihypertensive therapy. The GFR fall in the overall population of NIDDM patients was significantly and inversely related to the decrease of mean BP (diastolic + 1/3 pulse pressure) (r = -0.80, P < 0.0001) but not to that of HbA1c, triglycerides, and BMI. The GFR decline (mean +/- SE) per year in the normoalbuminuric patient was 2.03 +/- 0.66 ml.min-1 x 1.73 m-2 (95% CI 0.92-3.17) during cilazapril and 2.01 +/- 0.71 ml.min-1 x 1.73 m-2 (95% CI 0.82-3.11) during amlodipine therapy. The GFR decline per year in the microalbuminuric patient was 2.15 +/- 0.69 ml.min-1 x 1.73 m-2 (95% CI 0.86-3.89) during cilazapril and 2.33 +/- 0.83 ml.min-1 x 1.73 m-2 per year (95% CI 1.03-3.67) during amlodipine therapy. Cilazapril and amlodipine lowered AER to a similar extent in normoalbuminuric and microalbuminuric patients. No significant changes were observed concerning other clinical and biochemical features between the two antihypertensive therapies and particularly HbA1c, BMI, triglycerides, and cholesterol plasma values. These results support the tenet that arterial hypertension plays a pivotal role in contributing to renal damage in NIDDM, even when AER is normal. However, the degree of BP control, with both cilazapril and amlodipine, can successfully delay the slope of GFR decline in hypertensive NIDDM patients with or without incipient nephropathy.

[Median-term (4 months) treatment with glibenclamide + metformin substituting for glibenclamide + fenformin lowers the lacticemia levels in type-2 diabetics (NIDDM)]. / Il trattamento a medio termine (4 mesi) con glibenclamide + metformina in sostituzione al trattamento con glibenclamide + fenformina abbatte i livelli di lattacidemia in soggetti diabetici tipo II (NIDDM).

60 NIDDM patients, mean age (68 +/- 3 years), BMI (25 +/- 5.1 kg/m2), fasting blood glucose (FG) (170 +/- 10 mg/dl), mean daily blood glucose (MDBG) (180 +/- 10 mg/dl), daily glycosuria (GLU) (15.6 +/- 9 g/24 hours), HbA1c (7.9 +/- 0.6%), basal (1.2 +/- 0.2 ng/ml) and stimulated (3.89 +/- 1.3 mg/ml) C peptide (CP) treated by ASS (7.5 +/- 75 mg), after a strict 4 months follow-up period, were assigned to G + M treatment (7.5 +/- 1.500 mg) during a 4 months period. During G+M treatment FG (171 +/- 13 at t0 to 165 +/- 11 mg/dl: p < 0.01 at t4) varied significantly. MDBG (180 +/- 10 at t0 to 175 +/- 12 mg/dl at t4:p < 0.05), GLU (16 +/- 9 at t0 to 11 + 6 g/24 hours at t4; p < 0.01), HbA1c (8.1 +/- 0.4 at t0 to 7.6 +/- 0.3% at t4; p < 0.01). Basal CP remained unchanged in G+M period and varied significantly during ASS period (1.3 +/- 0.3 ng/ml at t4; p < 0.01) and stimulated CP (unchanged during ASS) was reduced during G+M (4.19 +/- 0.4 to 4.04; p < 0.05). Highly significant variations were observed for LAC (28.4 +/- 2.1 at t0 to 14.9 +/- 0.6 mg/dl: p < 0.01 during G+M treatment). G+M therapy was found to be more effective and safer than ASS therapy in regard to glucose metabolism and lactate production in a selected group of NIDDM patients.

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)