Androgens and insulin resistance in type 1 diabetic men

OBJECTIVE In healthy men, both high and low serum testosterone concentrations are associated with insulin resistance, whereas low concentration of sex hormone binding globulin (SHBG) is related to reduced insulin sensitivity. The aim of our study was to examine the association of sex hormones, SHBG, dehydroeplandrosterone (DHEAS) and insulin-like growth factor binding protein-1 (IGFBP-1) on Insulin sensitivity in type 1 diabetic patients. PATIENTS We examined 23 male patients with the mean age of 29 ± 1 years, body mass index 22.9 ± 0.4 kg/m², Insulin dose 47 ± 3 units/day, glycosylated haemoglobin (HbA_1c) 7.8 ± 0.3% and duration of diabetes 13 ± 1 years. DESIGN Each patient was studied With a 4-hour euglycaemic (5.5 ± 0.1 mmol/l), hyperinsulinaemic (612 ± 26 pmol/l) clamp with indirect calorimetry. Muscle biopsies (quadriceps femoris) for the determination of glycogen synthase were performed In 15 patients before and at the end of the clamp. RESULTS insulin infusion reduced the concentrations of IGFBP-1 by 90% (P < 0.001), DHEAS by 11% (P < 0.001), and SHBG by 4% (P < 0.01), whereas free or bound testosterone levels remained unchanged. The fall in IGFBP-1 level was closely related to the basal concentration (r= 099, P < 0.001). Basal SHBG concentration Correlated directly with total (r= 0.51, P <0.05) and non-oxidative glucose disposal (r= 0.41, P < 0.05), and with the decrease in lipld oxidation (r= 0.47, P <0.05) during Insulin Infusion. The fall in SHBG was inversely related to the mean (30–240 min) FFA concentration durlng hyperinsulinaemia (r=-0.64, P < 0.001). The fractional activity of glycogen synthase at the end of insulin infusion correlated directly with fasting SHBG (r= 0.71, P <0.01) and DHEAS concentrations (r= 0.67, P <0.01). CONCLUSIONS In male type 1 diabetic patients: (1) acute hyperinsulinaemia decreases IGFBP-1, DHEAS and SHBG concentrations with the greatest decline in IGFBP-1, (2) SHBG concentration is positively associated with factors Indicating good insulin sensitivity, (3) association between fuel homeostasis and SHBG, DHEAS and insulin antagonists suggests a network of these factors In the regulation of insulin action in type 1 diabetic patients.     

Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance: Influence on muscle glycogen synthase and insulin receptor kinase activity

Fluoxetine (F) is a specific serotonin-reuptake inhibitor that has been shown to promote weight loss and improve glycemic control in obese diabetic patients. To study its long-term metabolic effect, 40 obese patients with non-insulin-dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT) were included in a 12-month, randomized, placebo-controlled study. Patients were assigned to receive either 60 mg F or placebo (P) daily in conjunction with a 5.0-MJ/d diet (> 50% carbohydrate). Both groups showed a significant weight loss, with a nadir after 6 months without group differences (mean ± SD: F, 10.1 ± 10.0 kg; P, 9.4 ± 11.5 kg). Fifteen patients from the F group and 14 from the P group completed the 12-month study without weight loss differences. Glycemic regulation improved along with the weight loss, but with a larger decline in plasma C-peptide and fasting glucose levels in the F group (P < .05). Total skeletal muscle glycogen synthase (GS) activity increased by 31% in the F group (P < .01) and by 17% in the P group (nonsignificant) after 6 months of treatment, but was still less than the activity in normal-weight controls (aged 28.0 ± 6.3 years; body mass index, 23.5 ± 2.2). After adjustment for fasting glucose, insulin, weight loss, and diabetic state, a positive effect of F remained on the total GS activity, which accounted for 27% of the variation (P < .05). The waist to hip ratio was reduced in P subjects as compared with F subjects (P < .05). Fat-free mass (FFM) tended to be more reduced in the F group as compared with P subjects (4.9 v 1.9 kg), although the difference did not reach statistical significance. In conclusion, F seems to improve insulin sensitivity beyond the effect mediated through weight loss by a possible effect on GS activity in skeletal muscle tissue.     

Islet cell antibodies are associated withβ-cell failure also in obese adult onset diabetic patients

To clarify the utility of islet cell antibodies (ICA) to correctly classify and predict insulin treatment in newly diagnosed diabetic subjects, ICA, body mass index (BMI), glycated hemoglobin (HbA_1c), and fasting plasma C-peptide values were evaluated at and 3 years after diagnosis in 233 new, consecutively diagnosed, adult diabetic patients classified as obese or nonobese (National Diabetes Data Group, NDDG criteria). Among the 233 patients, 31 were nonobese ICA-positive (mean age at diagnosis 43±3 years), 55 nonobese ICA-negative (mean age at diagnosis 58±2 years), 7 obese ICA-positive (mean age at diagnosis 57±5 years), and 139 obese ICA-negative (mean age at diagnosis 58±1 years). Fasting C-peptide decreased (P<0.05) in nonobese ICA-positive patients who after 3 years showed lower BMI (22.6±0.6 versus 24.5±0.4;P<0.05), lower fasting C-peptide (0.14±0.06 nmol/l versus 0.71±0.07 nmol/l;P<0.001), and higher frequency of insulin treatment [28/31 (90%) versus 6/45 (13%);P<0.001] than nonobese ICA-negative patients. In obese ICA-positive patients, fasting C-peptide also decreased ( C-peptide 0.17±0.04 nmol/l;P<0.05) after diagnosis, and 3 years after diagnosis, obese ICA-positive patients showed lower BMI (25.7±1.2 versus 29.8±0.4;P<0.01) and fasting C-peptide (0.08±0.04 nmol/l versus 1.06±0.05 nmol/l;P<0.001) and higher HbA_1c values (9.92%±0.68% versus 7.39%±0.21%;P<0.01) and a higher frequency of insulin treatment [7/7 (100%) versus 5/121 (4%);P<0.001] than obese ICA-negative patients. Therefore, ICA detected at diagnosis of diabetes in both obese and nonobese adult patients indicate -cell dysfunction, high HbA_1c levels, and progression to insulin dependency.     

Increased urinary albumin excretion is associated with a cluster of metabolic alterations in type 2 diabetes mellitus

The relationship between urinary albumin excretion rate (UAE) and some metabolic and haemodynamic characteristics was studied in 62 (50 male, 12 female) type 2 (non-insulin-dependent) diabetic patients, with (26 male, 5 female) and without (24 male, 7 female) ischaemic heart disease (IHD), free from overt diabetic nephropathy. The overall population was subdivided into quartiles on the basis of UAE values (mg/24h): group 1 (16 subjects), 3.3–7 (range); group 2 (15 subjects), 7.22–11.8; group 3 (15 subjects), 11.9–30; group 4 (16 microalbuminuric subjects), 31.7–226. The groups were comparable with regard to age, duration of diabetes and prevalence of smokers. From group 1 to group 4 we found increasing levels of body mass index (BMI) (24.2±0.6, 26.6±0.7, 27.6±0.7, 27.6±0.9 kg/m²;P=0.007), HbA_1c (5.99±0.2, 6.45±0.35, 7.02±0.41, 7.4±0.39%;P=0.017), total cholesterol (5.30±0.26, 5.51±0.34, 6.14±0.21, 6.32±0.26 mmol/l;P=0.026), triglycerides (1.37±0.20, 1.67±0.21, 2.07±0.29, 2.55±0.45 mmol/l;P=0.034) and prevalence of hypertension (50%, 67%, 67%, 81%;P=0.088). No significant differences were found between C-peptide, insulin resistance (K index of insulin tolerance test) and high-density lipoprotein (HDL)-cholesterol levels. Groups 1+2 had a lower prevalence of IHD in comparison with groups 3+4 (42% vs 58%,P=0.069). Using multiple regression analysis, only HbA_1c was independently associated with log₁₀ UAE in the overall population (P=0.002), including as independent variables age, duration of diabetes, BMI, total cholesterol, triglycerides and mean arterial pressure. In conclusion: (1) type 2 diabetic patients show higher BMI, HbA_1c, total cholesterol, triglyceride levels and prevalence of hypertension with increasing UAE, even in the normoalbuminuric range; (2) the prevalence of IHD is higher in the groups with elevated UAE; (3) glycaemic control is the only metabolic characteristic independently associated with UAE.     

FORT and FORD: two simple and rapid assays in the evaluation of oxidative stress in patients with type 2 diabetes mellitus

The aim of the study was to evaluate the levels of free oxygen radicals and free oxygen radicals defense in patients with newly diagnosed type 2 diabetes mellitus (T2DM). The disease seems to be involved strongly in the production of reactive oxygen species. Forty-five patients with newly diagnosed T2DM and 20 apparently healthy individuals (control group) were included in the study. Reactive oxygen species were determined using the free oxygen radicals (FORT) test, which is based on the Fenton reaction. In this method, the hydroperoxides reacted with the transition metal ions liberated from the proteins and were converted to alkoxy and peroxy radicals. The radical species produced by the reaction, which are directly proportional to the quantity of lipid peroxides, interact with an additive that forms a radical molecule. Similarly, the free oxygen radicals defense (FORD) test uses preformed stable and colored radicals and determines the decrease in absorbance that is proportional to the blood antioxidant concentration. We found that (a) FORT levels were increased in diabetic patients (2.86 ± 0.56 mmol/L H₂O₂) compared with controls (1.87 ± 0.26 mmol/L H₂O₂) (P < .0001) and (b) FORD levels were lower in diabetic patients (1.23 ± 0.18 mmol/L Trolox) compared with controls (1.34 ± 0.14 mmol/L Trolox) (P < .01). The intraassay and interassay coefficients of variation were 3.7% and 6.2%, respectively, for FORT and 4.2% and 6.6%, respectively, for FORD. Determination of free oxygen radicals and free oxygen radicals defense seems to play an important role in the generation and evaluation of oxidative stress, an imbalance between oxidants and antioxidants that can lead to oxidative damage and is involved in the pathogenesis of several diseases, such as T2DM.     

Sex hormone status and osteoporosis in postmenopausal women with rheumatoid arthritis

Sex hormones have important effects on bone, especially in postmenopausal women. These hormones may be of particular significance in patients with rheumatoid arthritis (RA), who have a high frequency of osteoporosis. To examine this, we measured estrogen and androgen concentrations and bone mineral density (BMD) in 49 postmenopausal women with RA and 49 normal postmenopausal women. Compared with the controls, postmenopausal RA patients had significantly reduced levels of estrone (median 18 pmoles/liter versus 49; P < 0.001), dehydroepiandosterone sulfate (DHEAS) (median 0.3 μmoles/liter versus 2.0; P < 0.001), testosterone (median 0.6 nmoles/liter versus 0.95; P < 0.001), and femoral BMD (mean 0.72 gm/cm² versus 0.80; P < 0.002). Prednisolone therapy in 22 patients (mean dosage 8 mg/day) was associated with reductions in estrone and testosterone levels; however, DHEAS and femoral BMD were also decreased in RA patients who were not receiving corticosteroids. Reduced DHEAS levels in postmenopausal women with RA may increase their risk of osteoporosis.     

Hyperglycaemia increases dipeptidyl peptidase IV activity in diabetes mellitus

Aims/hypotheses Chronic hyperglycaemia increases dipeptidyl peptidase IV (DPP-IV) activity in endothelial cells in vitro. The present study was designed to assess the effect of high glucose on circulating DPP-IV activity in patients with type 1 and type 2 diabetes.Methods Plasma DPP-IV activity was measured in 29 patients with type 1 diabetes and 29 age-, sex- and BMI-matched control subjects. We also assessed DPP-IV activity in 31 type 2 diabetic patients with HbA₁c >8.5% and in plasma from matched groups of 31 newly diagnosed diabetic subjects with HbA₁c <7.5%, 31 subjects with IGT and 62 subjects with NGT. In a further sample of 66 type 2 diabetic patients, a longitudinal study was also performed to evaluate variations in DPP-IV activity and HbA₁c over 3 months.Results DPP-IV activity in type 1 diabetic patients was not significantly different from that in control subjects; however, a significant correlation between DPP-IV and HbA₁c was observed in diabetic subjects (r=0.47; p<0.01). Type 2 diabetic patients with HbA₁c >8.5% showed significantly (p<0.05) higher DPP-IV activity (mean±SD 27.7±7.1 U/l) than newly diagnosed diabetic patients and subjects with IGT (22.1±6.0 and 18.8±8.8 U/l, respectively). Variations in DPP-IV activity over 3 months in type 2 diabetic patients showed a significant positive correlation with variations in HbA₁c (r=0.26; p<0.05).Conclusions/interpretation Chronic hyperglycaemia induces a significant increase in DPP-IV activity in type 1 and type 2 diabetes. This phenomenon could contribute to the reduction in circulating active glucagon-like peptide-1 and to the consequent postprandial hyperglycaemia in type 2 diabetic patients with poor metabolic control.     

Association between serum C-peptide levels and chronic microvascular complications in Korean type 2 diabetic patients

This study evaluated the association between serum C-peptide levels and chronic vascular complications in Korean patients with type 2 diabetes. Data for 1,410 patients with type 2 diabetes were evaluated cross-sectionally. Fasting and postprandial 2-hour serum C-peptide levels were analyzed with respect to diabetic micro- and macrovascular complications. In the group of patients with lower fasting serum C-peptide quartile, the prevalences of diabetic retinopathy and neuropathy were significantly higher (P = 0.035, P < 0.001, respectively). In the group of patients with lower delta C-peptide (postprandial − fasting C-peptide) quartile, the prevalences of diabetic retinopathy, nephropathy, and neuropathy were significantly higher (P < 0.001 for all). Low delta C-peptide quartile was also associated with increased severity of retinopathy and nephropathy. The age- and sex-adjusted odds ratios (ORs) for retinopathy, neuropathy, and nephropathy in the lowest versus the highest delta C-peptide quartile were 6.45 (95% confidence interval 3.41–12.22), 3.01 (2.16–4.19), and 2.65 (1.71–4.12), respectively. After further adjustment for the duration of diabetes, type of antidiabetic therapy, mean hemoglobin A1c, body mass index, and blood pressure, the ORs were reduced to 2.83 (1.32–6.08), 1.68 (1.12–2.53), and 1.61 (1.05–2.47), respectively, but remained significant. No significant difference was observed in the prevalence of macrovascular complications with respect to fasting or delta C-peptide quartiles. These results suggest that low C-peptide level is associated with diabetic microvascular, but not macrovascular complications in patients with type 2 diabetes mellitus.     

Altered adrenal and thyroid function in children with insulin-dependent diabetes mellitus

In 129 children, aged 12.6±3.8 years, affected by type 1 diabetes mellitus, the levels of dehydroepiandrosterone sulfate (DHEAS), cortisol, T₃, fT₃, T4, fT4, rT₃, TSH, cholesterol, and triglycerides were evaluated and compared with those of a control group of 458 healthy age-matched children. The results were also correlated with hemoglobin HbA_1C. The DHEAS-standard deviation score (DHEAS-SDS; –0.36±0.77) was significantly different from zero in diabetic children, while the cortisol serum level was higher than in control subjects (485±94 vs 359±132 nmol/l). Moreover, the DHEAS-SDS and DHEAS-SDS/cortisol ratio correlated negatively with HbA_1c. Diabetic patients also showed lower T₃ values (2.22 ± 0.4 vs 2.32±0.3 nmol/l) and a higher rT₃/T₃ ratio (0.17±0.09 vs 0.15±0.05) than controls. There was a negative correlation between T₃ and HbA_1C. Cholesterol (4.77±1.08 vs 4.51±0.76 mmol/l) and triglycerides (0.82 ±0.53 vs 0.63±0.37 g/L) levels were higher in diabetic children and positively correlated with HbA_1c, but not with DHEAS-SDS. We can therefore conclude that diabetes, particularly if poorly controlled, tends to induce a dissociation of cortisol and DHEAS secretion and a low T₃ syndrome, similar to that seen in other illnesses.     

Exercise is not associated with better diabetes control in type 1 and type 2 diabetic subjects

In the clinical setting, the impact of educational efforts on the amount of regular exercise and its effects on diabetes control are unclear. Fifty type 1 diabetic, 50 type 2 diabetic and 70 non-diabetic subjects were evaluated using a questionnaire for type, duration and intensity of exercise to assess weekly energy expenditure. Diabetic subjects did not exercise more than controls: 36% of the type 1, 46% of the type 2 and 46% of the control subjects admitted no physical activity, and those exercising regularly had similar energy expenditure: 1808±320, 2722±617, 2523±304 (mean±SEM) kcal/week respectively (P=NS). There was no correlation between the degree of activity and HbA_1c levels, or hypoglycaemic events. HbA_1c levels were less than 6,8% in 31% of non-active active patients versus 21% of active patients (P=NS). A negative correlation was found between physical activity and daily insulin usage (r=0.27,P<0.05), but differences between patients averaged only 4 IU/1000 kcal energy expenditure/day. We conclude that patients' attitude towards exercise was not improved by our educational methods and that physical exercise was not necessarily associated with good blood glucose control.     

Increased prothrombin fragment 1+2 and D-dimer in first-degree relatives of type 2 diabetic patients

To evaluate whether or not activated coagulation is present in the preclinical phases of type 2 diabetes mellitus, we studied 46 non-diabetic first-degree relatives of type 2 diabetic patients and 21 matched controls with no family history of diabetes. We determined the plasma levels of prothrombin fragment 1+2, D-dimer, fibrinogen, plasminogen activator inhibitor type 1, tissue plasminogen activator, von Willebrand factor and coagulation factors VII and VIII. Glucose tolerance, beta-cell function and insulin sensitivity were assessed in all subjects by a continuous glucose infusion of 5 mg·kg ideal body weight^–1·min^–1 for 60 min with model assessment of glucose, insulin and C-peptide values. Plasma levels of prothrombin fragment 1+2 (median 1.24 vs 0.68 nmol·1^–1;P=0.0001) and D-dimer (331 vs 254 g·l^–1 UEF;P=0.018) were higher in relatives, without significant differences in the other haemostatic variables. Relatives showed higher fasting (5.5 vs 4.9 mmol·l^–1,P=0.004) and post-infusion (9.3 vs 8.3 mmol·l^–1,P=0.02) serum glucose, no differences in insulin or C-peptide levels, lower beta-cell function (122% vs 147%;P=0.02) and no significant differences in insulin sensitivity. Fifteen relatives were glucose-intolerant and had lower beta-cell function and insulin sensitivity than glucose-tolerant relatives. Both subsets of relatives exhibited higher levels of prothrombin fragment 1+2 and D-dimer than control subjects. Thus, first-degree relatives of type 2 diabetic patients present an activated coagulation, even in the absence of minor degrees of glucose intolerance. These abnormalities can play a role in the pathogenesis of cardiovascular diseases frequently seen at diagnosis of type 2 diabetes.This work was presented at the 31 st meeting of the European Association for the Study of Diabetes in Stockholm, Sweden, 12–16 September 1995, and published in an abstract form:Diabetologia (1995) 38:A257     

Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency

The effects of 6 months' treatment with recombinant human growth hormone (rhGH) on serum lipids and lipoproteins were assessed in 24 adult patients with GH deficiency in a double-blind, placebo-controlled trial. Compared with age-, weight-, and sex-matched controls, the patients had significantly higher serum concentrations of total cholesterol (P = .002), low-density lipoprotein (LDL) cholesterol (P < .001), apolipoprotein B ([apoB] P = .011), and triglyceride (P = .017), and lower concentrations of high-density lipoprotein (HDL) cholesterol (P < .001). The prevalence of elevated serum cholesterol, triglyceride, LDL cholesterol, and apo B levels was 39%, 26%, 39%, and 25%, respectively; 75% of patients had decreased concentrations of HDL cholesterol. Treatment with rhGH (0.07 U/kg daily) resulted in decreases in total cholesterol level (5.8 ± 0.3 to 5.1 ± 0.3 mmol · L⁻¹ over 6 months; P = .01 compared with placebo), LDL cholesterol level (4.22 ± 0.25 to 3.19 ± 0.23 mmol · L⁻¹; P = .0003), LDL:HDL cholesterol ratio (5.57 ± 0.47 to 3.29 ± 0.33; P = .03), apo B level (1.07 ± 0.06 to 0.84 ± 0.07 g · L⁻¹; P = .003), and apo B: A-1 ratio (0.73 ± 0.05 to 0.69 ± 0.05; P = .01). HDL cholesterol and apo A-1 levels did not change following rhGH treatment. The changes in lipid and lipoprotein levels were not significantly related to changes in insulin, thyroid hormones, insulin-like growth factor-1 (IGF-1), or indices of adiposity. The data suggest that (1) adults with GH deficiency may be at increased risk of cardiovascular (CVS) disease due to hyperlipidemia, and (2) long-term treatment with rhGH improves lipid and lipoprotein profiles. Alterations in CVS mortality following long-term rhGH treatment remain to be assessed.     

Elevated serum angiotensin I converting enzyme activity in type I,insulin-dependent diabetic subjects with persistent microalbuminuria

Angiotensin I-converting enzyme (ACE), which is synthesized by vascular endothelial cells, is sometimes elevated in diabetic subjects. To determine whether serum ACE is elevated in subjects at high risk of malignant microangiopathy, serum ACE activity in 34 normotensive, type 1 insulin-dependent diabetic subjects with persistent microalbuminuria (30–300 mg/24 h) was compared with that in 30 normotensive, normoalbuminuric type 1 diabetic subjects of the same age [37±15 (mean ±SD) vs 38±14 years], sex (21 M/13 F vs 15 M/15 F), stage of retinopathy (14 vs 16 nil/11 vs 7 background/6 vs 4 preproliferative/3 vs 3 proliferative) and HbA_1c (7.7±1.9 vs 8.2±1.0%). Serum ACE activity of diabetic subjects was also compared with 120 age and sex related healthy controls. Serum ACE activity was higher in subjects with microalbuminuria than in those with normoalbuminuria (406±114 vs 359±97 IU/l;P=0.03), or in controls (307±95 IU/l;P=0.0001). Normoalbuminuric subjects also had higher ACE activity than controls (P=0.02). Serum ACE activity was not related to diabetes duration (r=0.01; NS), HbA_1c (r=0.05; NS), or stage of retinopathy in diabetic subjects (r=0.06; NS), while stage of retinopathy was related to age (r=0.42;P=0.003) and to diabetes duration (r=0.74;P=0.0001) in these subjects. Elevated ACE activity occurs in type 1 diabetic subjects, especially in those with microalbuminuria. This may give early indication of lesions in vascular endothelial cells.This work was presented at the 27th meeting of the European Association for the Study of Diabetes in Dublin, Ireland, 10–14 September 1991, and published in an abstract form: Diabetologia (1991) 34: A17     

Effects of experimentally induced mild hyperthyroidism on growth hormone and insulin secretion and sex steroid levels in healthy young men

Although triiodothyronine (T₃) exerts major regulatory actions in both animals and humans, most clinical studies of T₃ administration have been relatively short-term. The present study examined the effects of more than 2 months (63 days) of low-dose T₃ treatment on overnight pulsatile growth hormone (GH) secretion, short-term insulin secretion, and of sex steroid levels in seven healthy, lean men studied at an inpatient metabolic unit. At baseline, there were strong correlations between sex hormone—binding globulin (SHBG) and several measures of GH production, including total GH production (r = .99), GH interburst interval (r = −.75, and GH mass (r = .82). SHGB was also inversely correlated with basal insulin secretion (r = −.74). There was a 42% increase in serum levels of total testosterone (18.5 ± 1.3 to 26.3 ± 1.8 nmol/L, P = .005) and a 150% increase in SHBG (18.0 ± 2.2 to 44.9 ± 7.0 nmol/L, P = .008) following T₃ treatment. Estradiol and free testosterone levels were unchanged by treatment, although free testosterone decreased from 142.8 ± 18.4 to 137.3 ± 19.5 pmol/L. T₃ treatment significantly reduced the GH interburst interval (P < .05) and produced slight increases in the measures of GH secretion. There were no statistically significant effects of T₃ treatment on insulin secretion, although insulin peak amplitude, mass secreted per burst, and total production all decreased. We conclude that experimentally induced T₃ excess in healthy men produces significant and sustained changes in sex hormone levels and GH secretion. Furthermore, there are strong associations between SHBG and both GH and insulin secretion independent of thyroid hormone excess that require additional study.     

Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty

To investigate the role of puberty on spontaneous clinical remission and on secretion of residual C-peptide during the first year of type 1 diabetes mellitus, we studied 77 pre-pubertal, 39 pubertal and 41 post-pubertal type 1 diabetic patients. Spontaneous partial clinical remission (HbA_1c within the normal range and insulin dose less than 0.3 U ⋅ kg^–1 body weight ⋅ day^–1 lasting for at least 10 days) decreased with duration of diabetes: months 3 vs 6 vs 12, respectively 13 vs 7 vs 4% (P<0.025). Remission was higher in post-pubertal than pubertal and pre-pubertal patients: month 6 respectively 20 vs 5 vs 1% (P<0.001). Secretion of C-peptide was significantly lower in pre-pubertal than the other two groups of patients. Basal and stimulated C-peptide secretion were higher in patients in clinical remission than in those who were not: basal value 0.4 (0.26–0.53) vs 0.28 (0.14–0.4) nmol/l (P<0.05); stimulated value 0.63 (0.5–0.95) vs 0.56 (0.31–0.74) nmol/l (P<0.05). Spontaneous remission is less frequent in children and adolescent patients than in adult post-pubertal patients, but different mechanisms may be involved. Low residual insulin secretion seems implicated in children meanwhile low insulin sensitivity could be more important in pubertal patients. Received: 11 April 1997 / Accepted in revised form: 30 April 1998     

Comparison of acute haemodynamic effects of nifedipine and isosorbide dinitrate in patients with heart failure following acute myocardial infarction

The acute haemodynamic effects of nifedipine (10 mg sublingually) and isosorbide dinitrate (5 mg sublingually) were compared in 13 patients with heart failure due to acute myocardial infarction. Nifedipine induced a significant reduction in systolic (from 122 ± 5 to 107 ± 3 mm Hg: mean ± SEM; P < 0.002) and diastolic blood pressure (from 85 ± 3 to 75 ± 2 mm Hg; P < 0.01). Heart rate did not change significantly, nor did mean right atrial pressure. The mean pulmonary arterial pressure was lowered from 31 ± 2 to 27 ± 2 mm Hg (P < 0.005). The left ventricular filling pressure decreased from 24 ± 1 to 19 ± 1 mm Hg (P < 0.0001). A significant increase in cardiac index (from 2.33 ± 0.13 to 2.69 ± 0.15 l/min per m²; P < 0.001) and in stroke volume index (from 24 ± 2 to 28 ± 2 ml/beats per m²; P < 0.005) was registered. Systemic vascular resistance fell from 1742 ± 145 to 1308 ± 85 dynes/sec per cm⁻⁵ (P < 0.00005). After isosorbide dinitrate was administered a significant reduction in mean right atrial pressure (from 9.5 ± 1.6 to 5.1 ± 1.2 mm Hg; P < 0.0001), in mean pulmonary arterial pressure (from 32 ± 1 to 23 ± 1 mm Hg; P < 0.00001) and in left ventricular filling pressure (from 23 ± 1 to 16 ± 1 mm Hg; P < 0.0001) was seen. No significant change in systolic and diastolic blood pressure, heart rate, cardiac index, stroke volume index and systemic vascular resistance was registered. No side-effects were seen after nifedipine and isosorbide dinitrate were administered.     

A simple clinical approach to discriminate between “true” and “pseudo” secondary failure to oral hypoglycaemic agents

To discriminate between true secondary failure (TF) and pseudo-secondary failure (PF) to oral hypoglycaemic agents, we studied 34 non-obese non-insulin-dependent diabetic patients who were being treated with these drugs. Nine were in good control (GC) with oral treatment, while 25 showed apparent SF. During a controlled hospital diet, fasting blood glucose remained persistently high in 15 of these patients (TF), while in the other 10 patients it clearly improved (PF). Fasting plasma glucose (FPG) and HbA_1c were higher and body mass index (BMI) was lower in TF patients than in PF patients (P<0.01). C-peptide concentrations differed significantly among the three groups both in the fasting state (TF 0.25±0.02 nmol/l, PF 0.70±0.03 nmol/l, GC 0.74±0.03 nmol/l;P<0.0001) and 6 min after glucagon injection (TF 0.50±0.04 nmol/l, PF 1.02±0.06 nmol/l, GC 1.14±0.07 nmol/l;P<0.0001). C-peptide and plasma insulin curves obtained after a standard mixed meal also showed significant differences (P<0.001). In particular, there was a statistically significant difference between GC and PF versus TF (P<0.05), while there was no statistical difference between PF and GC. We conclude that some patients with apparent SF can improve their metabolic control if they strictly adhere to a correct diet (PF); a single measurement of basal C-peptide concentration or examination of the C-peptide and insulin responses to a meal are useful indicators for distinguishing patients with PF from those with TF to oral hypoglycaemic agents. Lower BMI and higher fasting plasma glucose and HbA_1c are additional and simple indicators of TF.     

Characterization of alterations in glucose and insulin metabolism in Prader-Willi subjects

Obesity is a common component of non-insulin-dependent diabetes mellitus (NIDDM) and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi syndrome (PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. It has been assumed that the etiology for this increased rate of NIDDM is related to the morbid obesity and concomitant insulin resistance, but this remains controversial. To shed light on the glucoregulatory mechanisms in PWS, we studied both pediatric and adult PWS patients with normoglycemia. The objectives of our study were (1) to examine glucose, insulin, and C-peptide responses to oral (OGTT) and intravenous (IVGTT) glucose tolerance tests; (2) to characterize acute first- and second-phase insulin secretion during an IVGTT; (3) to assess hepatic insulin extraction (HIE) and insulin clearance (IC) in PWS subjects; and (4) to determine whether β-cell function in PWS is age-dependent. These results in PWS were compared with values obtained in age-, sex-, and body mass index (BMI)-matched non-PWS obese controls. Three groups were studied. Group I consisted of nine PWS subjects under the age of 13 years and 22 age-, sex-, weight-, and puberty stage-matched obese subjects who underwent OGTT. Group II consisted of 14 adult PWS subjects and 10 age-, weight-, and BMI-matched obese adults who underwent OGTT. Group III consisted of nine adult PWS subjects and eight age-, sex-, and weight-matched obese adults who underwent frequently sampled IVGTT (FSIVGTT). During the OGTT in the pediatric group, fasting (86 ± 3 v 89 ± 2 mg/dL), peak (144 ± 11 v 147 ± 4 mg/dL), and total area under the curve (AUC) (6,984 ± 1,320 v 6,963 ± 615 mg/dL · min) glucose levels were not significantly different in PWS versus obese children, respectively. In contrast, fasting (20 ± 6 v 37 ± 4 μU/mL), peak (114 ± 24 v 214 ± 23 • mU/mL), and total AUC (12,673 ± 2,176 v 26,734 ± 2,608 μU/mL μU/mL min) insulin levels were significantly lower in pediatric PWS. During the OGTT in the adult groups, neither fasting insulin (16.7 ± 2.8 v 13.5 ± 2.5 μU/mL) nor total AUC for insulin (10,664 ± 1,955 v 11,623 ± 1,584 μU/mL · min) were significantly different in adult PWS and obese groups. During the IVGTT in adults, both first-phase (138 ± 42 v 454 ± 102 μU/mL · min) and second-phase (295 ± 66 v 1,015 ± 231 μU/mL · min) insulin release were significantly reduced in PWS subjects despite similar glucose levels. Similarly, first-phase (8.6 ± 2.3 v 21 ± 4.6 ng/dL · min) and second-phase (47 ± 4.6 v 75 ± 14 ng/dL · min) C-peptide responses were also significantly reduced in PWS subjects. In contrast, mean HIE and IC was 33% higher in PWS subjects versus obese controls (15.4 ± 1.5 v 10.3 ± 1.6). Similarly, poststimulation HIE and IC was significantly greater (5.2 ± 0.8 v 2.4 ± 0.4) in the PWS group compared with the obese group (P < .01). In summary, this study demonstrates that nondiabetic PWS subjects manifest (1) a reduced β-cell response to glucose stimulation, (2) a significantly increased HIE compared with obese controls, and (3) a dissociation of obesity and insulin resistance, in contrast to normal obese subjects. We conclude that glucoregulatory mechanisms are different in obese PWS versus non-PWS subjects.     

Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy

Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n = 20, 10.38 ± 3.87 μg/ml) compared to the patients without it (n = 57, 7.68 ± 2.80 μg/ml) (p = 0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy.     

Secondary prevention with fluvastatin decreases levels of adhesion molecules, neopterin and C-reactive protein

Background: Treatment of hypercholesterolaemia with HMG-CoA reductase inhibitors results in an earlier reduction of morbidity and mortality than expected from trials using conventional cholesterol-lowering therapies. Possible explanations for this effect include stimulation of angiogenesis, improvement of endothelial function, plaque stabilisation, inhibition of coagulation and/or thrombocyte aggregation and inhibition of the inflammatory response associated with atherosclerosis. Methods: We investigated whether statins exert their effects by inhibition of endothelial activation, inflammation and/or monocyte/macrophage activation by measuring plasma levels of soluble cell adhesion molecules, neopterin and C-reactive protein upon treatment with fluvastatin for a period of 12 months in patients with established atherosclerosis and hypercholesterolaemia. Results: Blood samples were taken at baseline and at 3 and 12 months after starting treatment with fluvastatin 80 mg daily. Upon treatment, a reduction of s-ICAM-1 (956.3±123.6 vs. 745.4±127.4 vs. 674.9±70.8 ng/ml, P<0.05) and s-E-selectin (58.6±6.7 vs. 47.0±6.1 vs. 44.9±3.2 ng/ml, P<0.01) was observed. In addition, levels of neopterin decreased, albeit transiently (7.1±0.7 vs. 6.0±0.5 vs. 6.5±0.8 nmol/l, P=0.02), suggesting a reduction in monocyte/macrophage activity. Moreover, we found a decrease in levels of C-reactive protein during follow-up (5.21±2.0 vs. 3.18±0.7 vs. 1.95±0.3 mg/l, P<0.05), compatible with a reduction in inflammatory activity. Conclusion: We conclude that statins have a combined beneficial effect on monocyte/macrophage activity, endothelial function and systemic inflammatory activity.