Alberto Bruno

Deflazacort vs Prednisone: Effect on Blood Glucose Control in Insulin-Treated Diabetics

Glucocorticoid treatment produces a deterioration of blood glucose control in diabetics. Recent reports have indicated that deflazacort is less diabetogenic than prednisone in healthy subjects. Ten insulin-treated diabetics who required steroid drugs were treated with deflazacort (30 mg/d for four weeks) and prednisone (25 mg/d for four weeks) in randomized, double-blind design after a pretreatment period of four weeks. At the end of each treatment, plasma glucose profile (five determinations per day), hemoglobin A1 level, and insulin requirements were compared. Mean (+/- SEM) plasma glucose level (139 +/- 28 vs 169 +/- 32 mg/dL [7.7 +/- 1.5 vs 9.4 +/- 1.8 mmol/L]) and hemoglobin A1 values (8.81% +/- 1.19% vs 10.71% +/- 1.17% of total hemoglobin) were significantly lower after deflazacort than after prednisone. Also, insulin requirement was significantly lower after deflazacort than after prednisone (29.3 +/- 11.6 vs 47.3 +/- 2.0 U/d). These results indicate that deflazacort, when employed in an anti-inflammatory dose equivalent to prednisone, should prove advantageous in insulin-treated diabetics who require steroid treatment.

Insulin resistance shows selective metabolic and hormonal targets in the elderly.

Abstract. There has been no simultaneous evaluation of different aspects of insulin action in ageing. We studied 12 elderly (77 ± 2 years) and 12 young (26 ±1 years) subjects with normal glucose tolerance and matched for sex, body mass index, lean body mass (LBM), blood pressure and physical activity, using a euglycaemic‐hyperinsulinaemic clamp at about 350 pmol L‐1 in combination with [3H]‐glucose infusion. In the elderly group, hepatic glucose production was normal, fasting serum insulin and C‐peptide were significantly increased (P= 0.001) and glucose utilization (34.4 ±2.4 vs. 44.4± 3.2 μmol kg‐1 LBM min‐1, P= 0.02) and the percentage maximal suppression of C‐peptide (58 ± 6% vs. 79 ±5%, P= 0.02) during the clamp were reduced. Fasting plasma free fatty acid (FFA) and glycerol levels were similar in the two groups, but their percentage maximal suppression during the clamp was reduced in the elderly group (FFA 45± 5% vs. 77 ± 6%, P= 0.001; glycerol 43 ± 5% vs. 76± 3%, P= 0.001). Branched‐chain amino acids (valine, leucine, isoleucine) and glucagon levels were similar in the two groups, both while fasting and during the clamp. Thus, insulin resistance in ageing appears selective on glucose utilization, inhibition of lipolysis and feedback inhibition of the B‐cell secretion.

Serum glucose, insulin and C-peptide response to oral glucose after intravenous administration of hydrocortisone and methylprednisolone in man

Glucocorticoid-induced glucose intolerance and insulin resistance are dependent on the type of steroid, its dose and route of administration. Although the intravenous (i.v.) route is used mainly, the effects of different steroids have so far been compared using the oral route. The present study was therefore planned to compare the effects on glucose metabolism of hydrocortisone (HC) and methylprednisolone (MP) administered i.v. at equivalent antiinflammatory doses in healthy subjects.Eighteen healthy volunteers with normal glucose tolerance, divided into three groups (A,B,C) matched for age, sex and body mass index were subjected to oral glucose tolerance tests (oGTT) 12 h after HC or MP i.v. injection. The two tests were performed at a 1-month interval and in random sequence. Group A received low doses (HC 100 mg, MP 20 mg), group B intermediate doses (HC 200 mg, MP 40 mg) and group C high doses (HC 400 mg, MP 80 mg). Serum glucose, insulin and C-peptide were measured during both fasting and oGTT.Serum glucose values were not significantly different after HC or MP, during both fasting and oGTT. However, there was a positive correlation between fasting serum glucose or the area under the glucose curve and the dose·kg−1 body weight of HC (r=0.748; r=0.462) and MP (r=0.708; r=0.736). Serum insulin values were significantly higher after MP than after HC when fasting (A: 115 vs 223; B: 95 vs 215, C: 158 vs 268 pmol·l−1) and as area under the oGTT curve (A: 57.8 vs 87; B: 48.5 vs 92.1; C: 57.8 vs 94.5 pmol·l−1·2 h). In contrast, serum C-peptide values were not significantly different after HC or MP, neither fasting nor as area under the insulin curve. Fasting C-peptide/insulin molar ratio was significantly lower after MP than HC at the three doses administered.In conclusion the dose-related decreases in glucose tolerance are more marked after a single i.v. injection of MP than HC at the same anti-inflammatory dose, MP 20 or 40 mg as well as HC 100 or 200 mg do not impair glucose tolerance, but the former is associated with higher serum insulin levels, suggesting insulin resistance. MP-induced hyperinsulinaemia seems to be mainly due to reduced hepatic insulin extraction.

Comparison of acute and subacute effects of deflazacort and prednisone on glucose metabolism in man

SummaryCorticosteroid treatment produces glucose intolerance with insulin resistance. Recent reports have indicated that deflazacort (DF) is significantly less diabetogenic than prednisone (PN). A euglycaemic hyperinsulinaemic (100 µU/ml) glucose clamp (EHGC) and 3H-glucose infusion for 240 min were performed in 6 healthy volunteers (HV) after administration of 15 mg PN or 18 mg DF, 12 h and 2 h before test. The glucose metabolic clearance rate (MCR) was significantly (p=0.02) higher after DF (4.75±0.58 ml/min·kg) than after PN (3.31±0.27 ml/min·kg). Basal hepatic glucose production (HGP) was significantly (p=0.003) lower after DF (3.58±0.33 mg/kg·min) than after PN (4.44±0.23 mg/kg·min). A similar pattern was obtained for glucose volume (GV) and glucose pool (GP). The kinetic parameters of insulin were not significantly different after the two drugs. After 7 day of PN 30 mg/day or DF 36 mg/day, EHGC and 3H-glucose infusion for 240 min were performed in 10 HV. Glucose MCR values were significantly (p=0.03) higher after DF (5.03±0.91 ml/min·kg) than after PN (2.80±0.26 ml/min·kg). HGP values did not different significantly after the two drugs. GV (p=0.001) and GP (p=0.002) were significantly lower after DF than after PN. Insulin kinetics were not significantly different after the two drugs. It is concluded that on acute and 7-day administration to healthy subjects DF, in an anti-inflammatory dose equivalent to PN, shows significantly less influence on glucose metabolism.

Feedback inhibition of insulin and glucagon secretion by insulin is altered in abdominal obesity with normal or impaired glucose tolerance

We investigated the feedback inhibition of insulin and glucagon secretion during euglycemic-hyperinsulinemic clamp at about 350 pmol/l in 16 patients with abdominal obesity [8 with normal glucose tolerance (oNGT), 8 with impaired glucose tolerance (oIGT)] and 8 normal-weight subjects matched for age, sex and blood pressure. In oNGT and oIGT, fasting plasma C-peptide levels were twice those in the controls (962±51 and 915±85 vs 439±28 pmol/l,P<0.001) and their suppression was lower than in the controls, both in absolute terms (155±19 and 185±17 vs 274±18 pmol/l,P<0.001) and as a percentage decline from basal levels (16±2% and 21±2% vs 63±2%,P<0.001). Fasting plasma glucagon levels were similar in the patients and in the controls, but were less suppressed during clamp in oNGT and oIGT, both in absolute terms (7.0±0.9 and 5.6±0.6 vs 13.2±1.2 pmol/l,P<0.001) and as a percentage change from basal levels (23±3% and 19±2% vs 44±4%,P<0.001). These results suggest that the insulin feedback on B and A cells is impaired in abdominal obesity, and that this defect is of similar degree in oNGT and oIGT. These alterations could be implicated in the pathogenesis of hyperinsulinemia in obesity.

Change in glucose metabolism after long-term treatment with deflazacort and betamethasone

SummaryWe have compared the long-term effects of different corticosteroids on glucose metabolism by carring out a 75 g oral glucose tolerance test in 27 subjects before and after the administration of deflazacort or betamethasone for two months in random balanced sequence. Fasting plasma glucose and insulin concentrations were significantly higher after betamethasone, whereas deflazacort increased only fasting plasma insulin.After oral glucose there were significant increases in blood glucose and insulin after betamethasone compared with deflazacort. These results suggest that the degree of glucose intolerance and insulin resistance depends on the steroid used and on the dose given, although long-term treatment with deflazacort has a smaller effect on glucose metabolism than betamethasone.

The glucoregulatory and antilipolytic actions of insulin in abdominal obesity with normal or impaired glucose tolerance: an in vivo and in vitro study

Abstract. To evaluate the effects of obesity and impaired glucose tolerance on insulin sensitivity, we performed a euglycaemic‐hyperinsulinemic clamp at about 350 pmol 1‐1, combined with 3H‐glucose infusion, in 14 obese patients, BMI 36.5 ± 1.2 and in 12 matched controls, BMI 23.9 ± 0.4. Six obese patients had normal glucose tolerance (oNGT), and eight had impaired glucose tolerance (oIGT). The ability of insulin to inhibit lipolysis in isolated adipocytes was also studied. Insulin‐mediated glucose utilization was more severely impaired in oIGT than in oNGT with respect to the controls (621 ± 51 vs. 897 ±83 vs. 1298 ± 55 μmol m‐2 min‐1, P<0.001). Plasma gly‐cerol was higher in oIGT than in oNGT and in the controls, both fasting (238 ±12 vs. 179 ± 14 vs. 112 ± 8 μmo1 1‐1, P < 0.001) and during the clamp (175 ± 21 vs. 120 ± 12 vs. 36 ± 6/μmiol1‐1, P<0.001). The correlation between glucose utilization and the percent reduction of plasma glycerol during the clamp was significant in the study group as a whole (r = 0.809, P=0.0001), and in each of the groups separately (oIGT: r = 0.929, P = 0.002; oNGT: r = 0.943, P = 0036; controls: r = 0.902, P = 0.0001). Inhibition by insulin of noradrenaline‐stimulated lipolysis in isolated adipocytes was more severely impaired in oIGT than in oNGT compared with the controls (P < 0.001). We conclude that impaired as opposed to normal glucose tolerance in obesity is associated with more severe impairment in both glucose utilization and insulin inhibition of lipolysis.

Urinary excretion of glycated albumin in insulin-dependent diabetic patients with normal urinary albumin excretion.

SummaryGlycation involves both circulating proteins, such as albumin, and structural proteins, such as the components of the glomerular basement membrane. A preferential excretion of glycated albumin (more anionic at physiological pH compared with unmodified plasma albumin) has been reported by some authors, but not by others. We therefore investigated the selectivity index (renal clearance of non-glycated albumin/clearance of glycated albumin) in 25 insulin-dependent diabetic patients with normal urinary albumin excretion and in 19 well-matched control subjects. The selectivity index was significantly higher in diabetic patients than in control subjects: 1.38±0.05 SEMvs 0.98±0.02, p<0.0001. This result is not consistent with a preferential urinary excretion of glycated albumin, at least in normoalbuminuric uncomplicated insulin-dependent diabetic patients.

Resistant Hypertriglyceridemia in a Patient With High Plasma Levels of Apolipoprotein CII

To the Editor: Human apolipoprotein CII (apo CII) consists of 79 amino acid residues and is required as a cofactor in the hydrolysis of triacylglycerides of chylomicrons and VLDL by lipoprotein lipase.1 2 Familial apo CII deficiency is an autosomal recessive genetic disorder characterized by fasting hypertriglyceridemia and an accumulation of chylomicrons in the plasma.3 Shachter et al4 generated transgenic mice overexpressing human apo CII, and these authors reported the unexpected observation of marked hypertriglyceridemia with an accumulation of triglyceride-enriched VLDL in the plasma. We are the first to report a case of resistant hypertriglyceridemia in a young man with high plasma levels of apo CII (turbidimetric method …

Dietary guar gum supplementation does not modify insulin resistance in gross obesity

SummaryObesity is considered an insulin resistant state. Dietary guar gum supplementation is able to reduce blood glucose and plasma insulin response to a carbohydrate meal. In order to evaluate whether guar is able to reduce hyperinsulinemia and insulin resistance in gross obesity, we studied 9 obese patients, >50% overweight with impaired glucose tolerance before and after 4+4 g/day guar for 6 weeks. Six patients repeated the treatment with 8+8 g/day guar after a 3-month interval. Guar was added to the usual diet in order to maintain the body weight constant. Pre-treatment and post treatment study included: total specific insulin binding on circulating monocytes; 3H-glucose infusion and euglycemic hyperinsulinemic clamp at ∼100 µU/ml. The differences between post-treatment and pre-treatment values were not significant for any of the parameters studied. Fasting glucose production was: 2.17±0.33 SEM (pretreatment)vs 2.18±0.18 (4+4 g/day)vs 2.28±0.14 (8+8 g/day) mg/kg/min; glucose utilization was: 3.52±0.43vs 3.22±0.44vs 3.49±0.63 mg/kg/min; total specific insulin binding was: 2.80±0.20vs 2.75±0.25vs 2.78±0.31%; body weight was: 101.4±5.4vs 100.2±6.2vs 100.5±7.0 kg. These results indicate that dietary guar gum supplementationper se is unable to reduce insulin resistance in gross obesity if overweight is maintained constant.