W H Hackeng

Publications (11)70.47 Total impact

• Article: An improved method for the determination of islet amyloid polypeptide levels in plasma.

  K L van Hulst, W H Hackeng, J W Höppener, B C van Jaarsveld, M G Nieuwenhuis, M A Blankenstein, C J Lips
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  ABSTRACT: We describe an improved method for the determination of islet amyloid polypeptide (IAPP) levels in plasma. Plasma is first extracted with acid-acetone, followed by a specific and sensitive radioimmunoassay (RIA) for IAPP using rabbit-anti-human-IAPP serum. Recovery of synthetic IAPP from plasma was 82 +/- 6% (n = 16). Standard samples, prepared in 'hormone-free' serum, were also extracted with acid-acetone. Displacement curves of serially diluted acid-acetone extracted plasma samples were parallel to the standard curve. The lower detection limit of the RIA was 2.3 +/- 0.1 fmol/sample (n = 5). Intra-assay variations for IAPP concentrations of 4, 17 and 32 pM were 16.3% (n = 10), 9.2% (n = 10) and 6.2% (n = 10); interassay variations were 35.9% (n = 14), 19.9% (n = 15) and 15.4% (n = 15), respectively. Non-stimulated IAPP levels ranged from 2.4 to 12 pM (mean 6 +/- 4 pM, n = 10) in healthy control subjects. IAPP was not detectable in type 1 (insulin-dependent) diabetic patients before and after glucagon administration. In type 2 (non-insulin-dependent) diabetic patients basal levels ranged from 2.2 to 14.5 pM and glucagon-stimulated levels ranged from 2.2 to 38.9 pM. The increase in IAPP varied from 0 to 24.4 pM. The anti-human-IAPP serum had full cross-reactivity with rat IAPP (= mouse IAPP). Transgenic mice overexpressing the human IAPP gene showed elevated plasma IAPP levels as compared to (non-transgenic) control mice. It is concluded that the method presented for the determination of IAPP in plasma is reliable and easy to perform, yielding reproducible results.(ABSTRACT TRUNCATED AT 250 WORDS)
  Annals of Clinical Biochemistry 04/1994; 31 ( Pt 2):165-70. · 2.17 Impact Factor
• Article: Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia.

  J W Höppener, J S Verbeek, E J de Koning, C Oosterwijk, K L van Hulst, H J Visser-Vernooy, F M Hofhuis, S van Gaalen, M J Berends, W H Hackeng
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  ABSTRACT: Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
  Diabetologia 01/1994; 36(12):1258-65. · 6.81 Impact Factor
• Article: Plasma concentrations of islet amyloid polypeptide after glucagon administration in type 2 diabetic patients and non-diabetic subjects.

  B C van Jaarsveld, W H Hackeng, C J Lips, D W Erkelens
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  ABSTRACT: Islet amyloid polypeptide (IAPP) is the main constituent of pancreatic islet amyloid, observed in the pancreases from patients with Type 2 diabetes mellitus. IAPP is synthesized by the pancreatic beta-cells. In order to study the secretion characteristics of IAPP in Type 2 diabetes mellitus, plasma IAPP was measured during a provocation test with glucagon in 33 Type 2 diabetic patients and 18 non-diabetic subjects. The median fasting IAPP level was 5.7 (range 1.1-13.1) pmol l-1 in the 27 patients treated with oral hypoglycaemic agents and 2.7 (1.9-5.9) in the 6 patients on insulin. In the non-diabetic group fasting IAPP was 5.7 (2.2-10.1). Six minutes after glucagon administration median IAPP rose to 9.4 (1.7-31.0) and 6.1 (5.1-10.2) in the respective diabetic groups, and to 16.8 (4.0-41.0) in the non-diabetic subjects (p < 0.05). The correlation coefficient between change in IAPP and change in C-peptide was 0.68 in the diabetic group. We conclude that intravenous administration of glucagon stimulates IAPP release from the beta-cell. This provocation test is easy to perform and can be used on a large scale in the study of IAPP secretion in Type 2 diabetes mellitus.
  Diabetic Medicine 06/1993; 10(4):327-30. · 2.90 Impact Factor
• Article: Calcitonin gene-related peptide, the menstrual cycle and premenstrual syndrome.

  J S van Leeuwen, H P Koppeschaar, W J Kop, E R te Velde, W H Hackeng, A A Haspels
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  ABSTRACT: Calcitonin gene-related peptide plasma levels were measured during four different phases of ovulatory menstrual cycles, in eight women suffering from the premenstrual syndrome and in eight controls. No significant fluctuations in calcitonin gene-related peptide levels occurred during the menstrual cycle. Neither were there significant differences in calcitonin gene-related peptide levels between the premenstrual syndrome and control groups.
  Gynecological Endocrinology 10/1992; 6(3):199-204. · 1.58 Impact Factor
• Article: Long-term follow-up in four large MEN 2 families in The Netherlands.

  C J Lips, M J Berends, J Brouwers-Smalbraak, R A Geerdink, W H Hackeng, J M Jansen-Schillhorn van Veen, A Struyvenberg, T J van Vroonhoven
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  ABSTRACT: Results of follow-up studies in four large multiple endocrine neoplasia type 2A families (total of 95 patients affected) have shown a positive effect on the course of the disease since early screening and intervention were initiated in 1974.
  Henry Ford Hospital medical journal 02/1992; 40(3-4):256-7.
• Article: Islet-amyloid polypeptide in human plasma.

  B C van Jaarsveld, W H Hackeng, M G Nieuwenhuis, D W Erkelens, R A Geerdink, C J Lips
  The Lancet 02/1990; 335(8680):60. · 38.28 Impact Factor
• Article: Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration. A study of 15 kindreds in The Netherlands.

  H F Vasen, A C Nieuwenhuijzen Kruseman, H Berkel, E K Beukers, C C Delprat, R G Van Doorn, R A Geerdink, H R Haak, W H Hackeng, H P Koppeschaar
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  ABSTRACT: Since 1975, 10 families with the multiple endocrine neoplasia (MEN)-2A syndrome and five with the MEN-2B syndrome, making a total of 101 patients, have been identified in The Netherlands. Twenty-three of the MEN-2A patients died before the start of the screening program. The average age of the patients whose death was due to pheochromocytoma (n = 11) or medullary thyroid carcinoma (n = 12) was 34.9 and 49.2 years, respectively. Eighty-seven patients with the MEN-2A syndrome and eight with the MEN-2B syndrome underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma. Eighteen patients had signs or symptoms caused by MEN-2A (group A), 60 were relatives of these patients who had been found to be affected at the first screening of the family (group B), and nine relatives had had negative screening results that later became positive (group C). Five patients had signs or symptoms due to MEN-2B (group A) and three were relatives of these patients who had been found to be affected at the initial screening (group B). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic medullary thyroid carcinoma at thyroidectomy and the results of the postoperative calcitonin tests. Among the MEN-2A families, 72 percent of group A, 33 percent of group B, and none of group C were found to have metastatic medullary thyroid carcinoma at surgery. In the MEN-2B families, all five patients in group A and one of the three patients in group B had metastatic disease. The "cure rates" in these three groups with MEN-2A, as determined by stimulated calcitonin assessment, were 11, 57, and 100 percent, respectively. One of the five patients with MEN-2B in group A and two of the three patients in group B showed normalization of the stimulated calcitonin value after surgery. From these results, it may be concluded that screening can lead to the detection of medullary thyroid carcinoma in an earlier stage, which in turn may permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to promote periodic examination and to guarantee the continuity of such screening is discussed.
  The American Journal of Medicine 12/1987; 83(5):847-52. · 5.43 Impact Factor
• Article: Thyroid C-cell hyperplasia and micronodules in close relatives of MEN-2A patients: pitfalls in early diagnosis and reevaluation of criteria for surgery.

  C J Lips, J R Leo, M J Berends, W H Minder, A P Blok, R A Geerdink, W H Hackeng, J M Roelofs, H F Vasen, J K Vette
  Henry Ford Hospital medical journal 02/1987; 35(2-3):133-8.
• Article: Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome).

  K J Lips, J Van der Sluys Veer, A Struyvenberg, A Alleman, J R Leo, P Wittebol, W H Minder, C J Kooiker, R A Geerdink, P F Van Waes, W H Hackeng
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  ABSTRACT: Two kindreds with the multiple endocrine neoplasia type 2A syndrome were studied. Of one of these we examined 150 members, 20 of whom were treated with thyroidectomy for medullary carcinoma and nine with bilateral adrenalectomy for pheochromocytoma. Of the second kindred 50 members were examined, seven of whom were thyroidectomized and seven treated with bilateral adrenalectomy. Pheochromocytomas were invariably found on both sides, even in four cases in which the adrenals on one side appeared to be completely normal, not only at preoperative roentgenologic examination but also on inspection during the operation. The microscopic finding of micronodules and a cluster of abnormal medullary cells identical with those found in pheochromocytomas in one of the apparently normal adrenals represents a first stage in the development of diffuse medullary hyperplasia as well as nodular hyperplasia. This is in accordance with the fact that in the MEN type 2A syndrome pheochromocytomas are always multicentric and multiple in origin. On the basis of these findings we conclude that all patients with the MEN 2A syndrome who show symptoms and signs of active pheochromocytoma should be subjected to bilateral adrenalectomy, even when one or both of the adrenals appear to be normal at roentgenologic investigation.
  The American Journal of Medicine 06/1981; 70(5):1051-60. · 5.43 Impact Factor
• Article: Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome) in a large family in the Netherlands. Diagnostic and therapeutic implications.

  C J Lips, W H Minder, J R Leo, A Alleman, W H Hackeng
  The American Journal of Medicine 05/1978; 64(4):569-78. · 5.43 Impact Factor
• Article: Calcitonin gene-related peptide in human obesity.

  P M Zelissen, H P Koppeschaar, C J Lips, W H Hackeng
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  ABSTRACT: We studied plasma calcitonin gene-related peptide (CGRP) levels in obese women before (n = 24) and after (n = 13) weight loss, and in normal weight controls (n = 15). Furthermore, the influence of two isocaloric meals (high carbohydrate vs. high fat) on plasma CGRP concentrations was studied. The CGRP concentration in the obese group (32.26 +/- 2.01 pg/ml) was significantly (p less than 0.0001) higher than in the control group (21.64 +/- 0.15 pg/ml). After weight loss (14.3 +/- 0.72% of original weight) CGRP concentrations remained unchanged. Only the high-fat meal caused a significant (p less than 0.02) rise in CGRP levels. Our results indicate that elevated plasma CGRP levels may constitute a primary phenomenon in obese women, and that fat intake may be associated with increased CGRP secretion.
  Peptides 12(4):861-3. · 2.43 Impact Factor