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The objective was to test whether chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas.We determined CgA, NSE, PP, insulin, C-peptide, and proinsulin in blood samples obtained during the ASVS test in 19 patients with insulinomas. Levels following calcium injection into the arteries supplying the tumor were compared with levels following calcium stimulation of arteries supplying healthy pancreatic tissue.After calcium injection into the artery supplying the insulinoma, a significant 8-fold increase in insulin (range, 2.3-117; P0.001), a 3.8-fold increase in C-peptide (1.7-32.4; P0.001), and a 1.9-fold increase in proinsulin (0.7-5.3, P0.001) were detectable whereas NSE and CgA did not increase. No significant increases in insulin, C-peptide, proinsulin, CgA, and NSE concentrations were found after calcium injection into control arteries. Pancreatic polypeptide increased 1.5-fold (0.8-4.5; P = 0.017) after calcium injection into the tumor artery and 2.4-fold (0.8-7.9; P = 0.016) after injection into the control artery.Insulin, C-peptide, and proinsulin are released by insulinoma cells in response to arterial calcium stimulation, whereas CgA and NSE are not released. Also from our study it seems that PP may be released by healthy islet cells after calcium stimulation.

INTRODUCTION Basal insulin dose requirements in patients with type 1 diabetes may be derived from the course of glucose concentrations in the fasting state; i. e. by skipping meals. The present study examined whether fasting tests could be replaced by carbohydrate-free meals. MATERIAL AND METHODS 16 adult patients with type 1 diabetes (10 male) on intensive insulin therapy participated in this prospective intervention study. Mean age (+/-SD) was 44+/-12 years, BMI 24+/-3 kg/m (2), mean HbA1c was 7.5+/-0.6% and duration of diabetes 15+/-12 years. All participants skipped dinner and plasma glucose concentrations were hourly monitored from 7 p.m. to 11 p.m. This blood glucose profile was compared with three test meals given at 7 p.m. at day 2-4, consumed either in the hospital (meal 1) or at home (meal 2 and 3). No insulin injection (except to basal insulin) was allowed. Test meals consisted of 2.5 g carbohydrate, 32.4 g protein, 52.0 g fat (according to 612 kcal). RESULTS During 16 fasting tests plasma glucose concentration remained stable between 7.2+/-2.4 mmol/l at 7 p.m. and 6.8+/-2.8 mmol/l at 11 p.m. (p=0.461). Following the intake of near carbohydrate-free meals (48 tests), plasma glucose concentrations rose within 4 h from 6.7+/-2.0 at 7 p.m. to 9.8+/-3.4 mmol/l at 11 p.m. (p

OBJECTIVE—To compare the effect of acute psychosocial stress on glucose concentrations in the fasting state and following food intake in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—In study 1, 20 patients were exposed to moderate psychosocial stress by means of the Trier Social Stress Test (TSST) in the fasting state. In study 2, the TSST was applied to 20 additional patients 75 min after intake of a standard meal. Glucose concentrations (by continuous glucose monitoring system), blood pressure, and heart rate were monitored on the control day and on the stress testing day. RESULTS—In both studies, blood pressure increased in response to TSST from 122/77 ± 14/9 mmHg at baseline to a maximum of 152/93 ± 21/13 mmHg (P < 0.001), and heart rate increased from 80 ± 11 to 99 ± 19 bpm (P < 0.001). In the fasting state (study 1), glucose concentrations remained unchanged during the control day as well as during the stress testing day. In study 2, glucose concentrations were similar on both days before and up to 75 min after the intake of the standard meal. However, a significant delay (of 45 min) in the decrease of glucose concentrations was induced by psychological stress. A two-factor repeated-measures ANOVA revealed a significant difference of glucose concentrations over time (F = 646.65/P < 0.001). CONCLUSIONS—In the postprandial period, acute psychological stress induced a significantly delayed decrease of glucose concentrations, whereas in the fasting state, no effect on poststress glucose concentrations was observed.

BACKGROUND: Debate surrounds the relative importance of impaired beta-cell secretory function versus insulin resistance in type 2 diabetes. We therefore defined insulin secretion and sensitivity in patients with impaired glucose homoeostasis of varying aetiology and duration. METHODS: 126 consecutive patients undergoing an oral glucose tolerance test (OGTT) between 1999 and 2003 were included. Whole-body insulin sensitivity index (ISI) and insulinogenic index derived from the OGTT were determined in 32 healthy controls, 65 type 2 diabetic patients, 15 patients with acromegaly, 10 patients with insulinoma, and 4 patients with HAIRAN syndrome. RESULTS: Median ISI (quartiles Q25-Q75) of healthy controls and of patients with insulinoma were similar (3.5 [2.8-5.6] and 3.2 [1.7-4.2] respectively) but significantly decreased in patients with acromegaly, type 2 diabetes, and HAIRAN syndrome (2.8 [1.8-3.3], 1.9 [1.4-3], and 0.8 [0.6-1.3] respectively). Despite the decrease in ISI, patients with HAIRAN syndrome and acromegaly maintained normal glucose tolerance by adapting insulin secretion as reflected in the insulinogenic index (106.5 [90.4-127.5] and 49 [24.4-89] in HAIRAN and acromegaly respectively, versus 46.9 [27.3-66.7] in controls). In contrast, type 2 diabetic patients failed to adapt and displayed severely hampered insulin secretion (insulinogenic index of 7.6 [3.8-14.7]). Furthermore, the level of the insulinogenic index correlated significantly with duration of diabetes and HbA1c, which was not the case for the ISI. Insulinoma patients had a decreased insulinogenic index (38.7 [32-83.8]), leading to impaired glucose tolerance despite normal ISI. CONCLUSIONS: The data are compatible with the notion that beta-cell function rather than insulin sensitivity determines the evolution of hyperglycaemia.

To the Editor: Obesity, type 2 diabetes, insulin resistance and hyperinsulinaemia are associated with an increased risk of some types of cancer, and recent epidemiological data have refuelled discussions on the safety of insulin therapy [1]. The data published in the last issue of Diabetologia raise concern but do not provide evidence that any of the specific insulin preparations cause harm; there are too many confounders for which adjustment remains imperfect. Whether the potential risks of insulin preparations with increased affinity to type 1 IGF receptors are acceptable remains a matter of debate. We wish to point out that (apart from the intrinsic properties of an insulin preparation) higher levels of continuous insulin exposure resulting from the choice of insulin preparation should also be considered as a potential drawback. A similar (unit-based) glucose-lowering efficacy of NPH insulin and the long-acting analogues has been suggested, but it remains unclear whether this is also true for obese patients with type 2 diabetes. In our recently published prospective study comparing the effect of NPH insulin, insulin detemir (NN304) [B29Lys(e-tetradecanoyl),desB30 human insulin] and insulin glargine (A21Gly,B31Arg,B32Arg human insulin) injected at bedtime in patients with type 2 diabetes [2], each patient was sequentially treated with all three longacting insulin preparations. Comparable predefined glucose targets were achieved at midnight (00:00 hours) and in the morning (at 07:00 hours) with all three insulin preparations tested; none of them could totally prevent the rise of glucose between 05:00 and 08:00 hours. As mentioned (but not shown) in our communication, a trend for increased analogue (compared with NPH) insulin dose requirements (especially in obese patients on high total doses) to reach glucose targets was observed. The difference was significant in patients with a BMI of >30 kg/m, as shown in Table 1. In patients with type 2 diabetes, it has previously been reported that a higher dose of insulin analogues relative to NPH insulin is required to achieve similar glucose control, e.g. in the Treat-to-Target Trial, in which doses of insulin glargine were higher than those of NPH [3]. An increased insulin dose requirement compared with NPH insulin in patients with type 2 diabetes has also been reported for insulin detemir [4, 5]. Whereas such differences have not been found in all studies (e.g. in the LANMET study [6]), to the best of our knowledge, the opposite, i.e. a lower insulin dose requirement of the long-acting analogues compared with NPH insulin in patients with type 2 diabetes, has not been reported. Good glycaemic control and prevention of cardiovascular disease remain major goals when treating patients with type 2 diabetes. Lifestyle changes are difficult to achieve, C. Schmid Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland

A negative 72-h fast is usually considered to preclude the diagnosis of insulinoma. The aim of this study was to describe the functional and morphological properties of two exceptional patients with an insulinoma who had exhibited pre-operatively a negative 72-h fast. Despite the ability of tumor cells to turn off insulin secretion in response to low plasma glucose during 72 h of fasting, hyperinsulinemic hypoglycemia occurred in both patients in response to stimulation by classical secretagogues. Pre-operatively, both patients underwent oral and iv glucose challenge tests and iv glucagon stimulation test. Insulin secretion was rapidly stimulated by these secretagogues to an exaggerated extent and thereby caused hypoglycemia due to an insulin mass effect. In contrast to the common functional features during suppression and stimulation tests, the tumors differed widely with regard to insulin and proinsulin response to calcium during ASVS tests and morphological properties. In patient 1, the immunohistochemical proinsulin distribution pattern resembled that of normal beta-cells, i.e. the staining was restricted to the perinuclear area; insulin and proinsulin were not stimulated by calcium during the ASVS test. In patient 2, the proinsulin staining pattern was abnormal, i.e. proinsulin was also found in the periphery of tumor cells; insulin and proinsulin were stimulated by calcium. We conclude that normal or exaggerated rather than defective glucose sensing may explain hypoglycemia in these exceptional insulinoma patients. Different functional characteristics of these tumors can be correlated with distinct morphological properties.