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or macrovascular complications
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Abstracts/Netherlands Journal of Medicine 47 (1995) A59-A64
not differ significantly between ACE inhibition and placebo treatment (%Adiameter: + 8.6 [6.7] vs. +5.1 [7.4]%; p = 0.33). The response to nitroglycerin was similar during ACE inhibition and placebo treatment (+13.4 [9.5] vs. +10.6 [3.6]%; p = 0.78). These results suggest that the endothelium-dependent and the endothelium-independent vasodilatation are not improved by ACE inhibition for 5 weeks in uncomplicated diabetes mellitus. Development and applications of a radioimmunoassay for islet amyioid polypeptide (IAPP): studies in man and transgenie mice. K.L van Hulst 1,2 J.W.M. Hfppener 1.3 C. Oosterwijk 1,3 M.G. Nieuwenhuis 1, M.A. Blankenstein 2, J.A. Fischer 4, C.J.M. Lips 1. Departments of 1 Internal Medicine, 2 Endocrinology and 3 Pathology, University of Utrecht, Utrecht, Netherlands; 4 Research Laboratory for Calcium Metabolism, Department of Orthopedic Surgery and Medicine, Zurich University, Zurich, Switzerland. IAPP is the major constituent of pancreatic islet amyloid deposits in type 2 diabetic patients. It is synthesized by pancreatic fl-cells and co-secreted with insulin. To determine circulating IAPP levels, an IAPP radioimmunoassay was developed. In one study, 14 healthy volunteers ingested a carbohydrate-rich meal. A statistically significant increase in plasma IAPP/C-peptide ratio was found 1 h after the meal compared to the fasted situation, which suggests different production a n d / o r clearance rates of these peptides. In another study, glucagon was administered intravenously to 12 type 2 diabetic patients. Both the increase in plasma IAPP levels after glucagon administration and fasting plasma IAPP/C-peptide ratios decreased with aging. This might be explained by progressive islet amyloid formation, causing selective deposition of IAPP. In human lAPP overproducing transgenic mice (up to 15-fold), HPLC analysis revealed that transgenic human IAPP was properly processed from prepro-IAPP by proteolyric enzymes. As assessed by cAMP stimulation in T47D cells, transgenic human lAPP had similar bioactivity to that of endogenous mouse IAPP. No hyperglycaemia, hyperinsulinaemia or obesity was observed, so IAPP overproduction is unlikely to induce peripheral insulin resistance. However, IAPP may contribute to the progression of type 2 diabetes by impairing/3-cell function via islet amyloid formation, induced by insulin-resistance-associated /3-cell hyperactivity. This will be investigated by crossing human IAPP transgenic mice with ob and db mice, which develop genetically determined obesity/diabetes. Determinants of hypertension in non-insulin-dependent diabetic (NIDDM) patients in primary care. E.K. Hoogeveen t, F.E.E.v.d. Does 1, C.D.A. Stehouwer 2, R.J. Heine 1,2. 1 Institute for Research in Extramural Medicine, Free University, van der Boechorststraat 7, 1081 BT Amsterdam, 2 Department of lnternal Medicine, Free University, De Boelelaan 1117, 1081 H V Amsterdam, Netherlands NIDDM is associated with hypertension. The determinants of hypertension in NIDDM may differ according to the epidemiological setting: e.g., population-based versus primary
care-based (i.e. treated by a general practitioner). We investigated the determinants of hypertension (systolic blood pressure [BP] > 160 mmHg a n d / o r diastolic BP > 95 mmHg a n d / o r use of antihypertensive drugs) in 274 NIDDM patients in primary care (127 men, 40-78 yr, mean known diabetes duration 4.2 yr, HbAlc 7.2%). Hypertension was present in 128 (47%) patients. In univariate analysis, the presence of hypertension was related to body mass-index (BMI; OR 1.1 [95%] 1.05-1.2) and to the presence of microalbuminuria (urinary albumin/creatinine > 2.5 mg/mmol; OR, 1.9 [1.03-3.4]), but not to age, sex, waist-hip ratio, smoking, duration of NIDDM, insulin use, triglycerides, total or HDL-cholesterol, fasting glucose, HbAlc and creatinine. Multivariate analysis confirmed these results. At 1 year of followup the cumulative incidence of hypertension was 15% (22 out 146). The development of hypertension was associated with microalbuminuria (RR 1.8 [0.8-4.0]), and insulin treatment (RR 1.9 [0.8-4.5]) at baseline, but not with the above-mentioned factors. Conclusion: In NIDDM patients in primary care, hypertension is positively related to BMI and microalbuminuria. Microalbuminuria may also predict the development of hypertension. Tissue factor pathway inhibitor (TFPI) in IDDM patients with and without micro- and/or macrovascular complications. P.B, Leurs, R.v. Oerle, K. Hamulyak, B.H.R. Wolffenbuttel. Department of Internal Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 A Z Maastricht, Netherlands. TFPI, a coagulation inhibitor, is produced by and mainly bound to the vascular endothelium. Its release can be stimulated by heparin. Plasma TFPI activity was demonstrated to b e increased in IDDM patients without:secondary complications. We investigated whether TFPI activity can be used as a marker for endothelial dysfunction. Nineteen ( d : ? = 11:8) IDDM patients (group I) without, and 30 ( 4 : 9 = 15:15) 1DDM patients with vascular complications (19 with retinopathy [Group II], 11 with retinopathy and micro/macroalbuminuria [Group III]), were studied. Blood samples were taken, before and after 5000 IU of heparin i.v. TFPI activity was measured chromogenically. In addition, von Willebrand factor, t-PA, PAI-1 and thrombomodulin were measured. Mean age (40_+ 9 yr), BMI (24.2 + 2.6 kg/m2), HbAlc (8.8_+ 1.3), and blood pressure (94_+ 15 mmHg) were similar in the three groups. Basal TFPI activity was 116_+ 12% in Groups I I + I I I and 110_+13% in Group I (p=0.05). Basal TFPI activity was higher in Group III (125___14%) than in Group 1I (111 _+8%) or Group I (p < 0.001). Post-heparin TFPI activity was also higher in Group IIl (AUC 65 _+6 vs. 61 _+5 [Group II] and 59 _+4 [Group I]; p < 0.01). This was independent of basal TFPI activity. Only thrombomodulin was also higher in Group III (42_+ 22 vs. 26 _+6 [Group II] and 28_+9 n g / m l [Group I]; p < 0.01). Conclusion: Basal and post-heparin TFPI activity is increased in patients with retinopathy and albuminuria. This suggests that TFPI activity can be regarded as a marker of endothelial dysfunction.
Abstracts/Netherlands Journal of Medicine 47 (1995) A59-A64
not differ significantly between ACE inhibition and placebo treatment (%Adiameter: + 8.6 [6.7] vs. +5.1 [7.4]%; p = 0.33). The response to nitroglycerin was similar during ACE inhibition and placebo treatment (+13.4 [9.5] vs. +10.6 [3.6]%; p = 0.78). These results suggest that the endothelium-dependent and the endothelium-independent vasodilatation are not improved by ACE inhibition for 5 weeks in uncomplicated diabetes mellitus. Development and applications of a radioimmunoassay for islet amyioid polypeptide (IAPP): studies in man and transgenie mice. K.L van Hulst 1,2 J.W.M. Hfppener 1.3 C. Oosterwijk 1,3 M.G. Nieuwenhuis 1, M.A. Blankenstein 2, J.A. Fischer 4, C.J.M. Lips 1. Departments of 1 Internal Medicine, 2 Endocrinology and 3 Pathology, University of Utrecht, Utrecht, Netherlands; 4 Research Laboratory for Calcium Metabolism, Department of Orthopedic Surgery and Medicine, Zurich University, Zurich, Switzerland. IAPP is the major constituent of pancreatic islet amyloid deposits in type 2 diabetic patients. It is synthesized by pancreatic fl-cells and co-secreted with insulin. To determine circulating IAPP levels, an IAPP radioimmunoassay was developed. In one study, 14 healthy volunteers ingested a carbohydrate-rich meal. A statistically significant increase in plasma IAPP/C-peptide ratio was found 1 h after the meal compared to the fasted situation, which suggests different production a n d / o r clearance rates of these peptides. In another study, glucagon was administered intravenously to 12 type 2 diabetic patients. Both the increase in plasma IAPP levels after glucagon administration and fasting plasma IAPP/C-peptide ratios decreased with aging. This might be explained by progressive islet amyloid formation, causing selective deposition of IAPP. In human lAPP overproducing transgenic mice (up to 15-fold), HPLC analysis revealed that transgenic human IAPP was properly processed from prepro-IAPP by proteolyric enzymes. As assessed by cAMP stimulation in T47D cells, transgenic human lAPP had similar bioactivity to that of endogenous mouse IAPP. No hyperglycaemia, hyperinsulinaemia or obesity was observed, so IAPP overproduction is unlikely to induce peripheral insulin resistance. However, IAPP may contribute to the progression of type 2 diabetes by impairing/3-cell function via islet amyloid formation, induced by insulin-resistance-associated /3-cell hyperactivity. This will be investigated by crossing human IAPP transgenic mice with ob and db mice, which develop genetically determined obesity/diabetes. Determinants of hypertension in non-insulin-dependent diabetic (NIDDM) patients in primary care. E.K. Hoogeveen t, F.E.E.v.d. Does 1, C.D.A. Stehouwer 2, R.J. Heine 1,2. 1 Institute for Research in Extramural Medicine, Free University, van der Boechorststraat 7, 1081 BT Amsterdam, 2 Department of lnternal Medicine, Free University, De Boelelaan 1117, 1081 H V Amsterdam, Netherlands NIDDM is associated with hypertension. The determinants of hypertension in NIDDM may differ according to the epidemiological setting: e.g., population-based versus primary
care-based (i.e. treated by a general practitioner). We investigated the determinants of hypertension (systolic blood pressure [BP] > 160 mmHg a n d / o r diastolic BP > 95 mmHg a n d / o r use of antihypertensive drugs) in 274 NIDDM patients in primary care (127 men, 40-78 yr, mean known diabetes duration 4.2 yr, HbAlc 7.2%). Hypertension was present in 128 (47%) patients. In univariate analysis, the presence of hypertension was related to body mass-index (BMI; OR 1.1 [95%] 1.05-1.2) and to the presence of microalbuminuria (urinary albumin/creatinine > 2.5 mg/mmol; OR, 1.9 [1.03-3.4]), but not to age, sex, waist-hip ratio, smoking, duration of NIDDM, insulin use, triglycerides, total or HDL-cholesterol, fasting glucose, HbAlc and creatinine. Multivariate analysis confirmed these results. At 1 year of followup the cumulative incidence of hypertension was 15% (22 out 146). The development of hypertension was associated with microalbuminuria (RR 1.8 [0.8-4.0]), and insulin treatment (RR 1.9 [0.8-4.5]) at baseline, but not with the above-mentioned factors. Conclusion: In NIDDM patients in primary care, hypertension is positively related to BMI and microalbuminuria. Microalbuminuria may also predict the development of hypertension. Tissue factor pathway inhibitor (TFPI) in IDDM patients with and without micro- and/or macrovascular complications. P.B, Leurs, R.v. Oerle, K. Hamulyak, B.H.R. Wolffenbuttel. Department of Internal Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 A Z Maastricht, Netherlands. TFPI, a coagulation inhibitor, is produced by and mainly bound to the vascular endothelium. Its release can be stimulated by heparin. Plasma TFPI activity was demonstrated to b e increased in IDDM patients without:secondary complications. We investigated whether TFPI activity can be used as a marker for endothelial dysfunction. Nineteen ( d : ? = 11:8) IDDM patients (group I) without, and 30 ( 4 : 9 = 15:15) 1DDM patients with vascular complications (19 with retinopathy [Group II], 11 with retinopathy and micro/macroalbuminuria [Group III]), were studied. Blood samples were taken, before and after 5000 IU of heparin i.v. TFPI activity was measured chromogenically. In addition, von Willebrand factor, t-PA, PAI-1 and thrombomodulin were measured. Mean age (40_+ 9 yr), BMI (24.2 + 2.6 kg/m2), HbAlc (8.8_+ 1.3), and blood pressure (94_+ 15 mmHg) were similar in the three groups. Basal TFPI activity was 116_+ 12% in Groups I I + I I I and 110_+13% in Group I (p=0.05). Basal TFPI activity was higher in Group III (125___14%) than in Group 1I (111 _+8%) or Group I (p < 0.001). Post-heparin TFPI activity was also higher in Group IIl (AUC 65 _+6 vs. 61 _+5 [Group II] and 59 _+4 [Group I]; p < 0.01). This was independent of basal TFPI activity. Only thrombomodulin was also higher in Group III (42_+ 22 vs. 26 _+6 [Group II] and 28_+9 n g / m l [Group I]; p < 0.01). Conclusion: Basal and post-heparin TFPI activity is increased in patients with retinopathy and albuminuria. This suggests that TFPI activity can be regarded as a marker of endothelial dysfunction.