Achim Starke

Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients : Using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double‐blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l−1, i.v. insulin infusion of 0.2 mU kg−1 min−1 throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate‐rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l−1 *240 min−1; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l−1; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l−1 (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.

Action profile of the rapid acting insulin analogue : human insulin B28Asp

The time‐action profile of the human insulin analogue B28Asp, which displays faster absorption rates from subcutaneous tissue compared to soluble human insulin, was studied under euglycaemic glucose clamp conditions (blood glucose 5.0 mmol l−1) in 14 healthy male volunteers. Subcutaneous injection of 0.15 U kg−1 body weight (range 9.5–14.3 U) of the insulin analogue or soluble human insulin resulted in half‐maximal glucose infusion rates (after subtraction of mean baseline glucose infusion rates) that were reached significantly earlier after injection of B28Asp (45 ± 11 (SD) min) as compared to human insulin (58 ± 25 min, p < 0.05). Forty‐five and 60 min after injection of human insulin, glucose infusion rates had increased by 3.4 ± 1.8 and 4.8 ± 2.3 mg min−1 kg−1 above baseline glucose infusion rates, reflecting 30 ± 15 and 42 ± 17% of maximal action of 10.6 ± 2.7 mg min−1 kg−1. Following the injection of B28Asp, glucose infusion rates increased by 6.3 ± 2.7 after 45 min and by 7.9 ± 2.8 mg min−1 kg−1 after 60 min above baseline glucose infusion rates, reflecting 64 ± 28% and 81 ± 26% of maximal action of human soluble insulin (p < 0.001). Peak glucose infusion rates after injection of B28Asp were significantly higher and were reached earlier than after subcutaneous injection of soluble human insulin (p < 0.05 and p < 0.001). The human insulin analogue B28Asp showed a significantly faster onset of action as compared to soluble human insulin.

The action profiles of human NPH insulin preparations

The complete time—action profiles of four subcutaneously injected human NPH insulin preparations (Protaphane HM/Novo; Insulatard Human/Nordisk; Huminsulin Basal/Eli Lilly; Basal H‐Insulin/Hoechst) have been investigated by means of the euglycaemic clamp technique (blood glucose 5.0 mmol I−1). Six normal male subjects were connected to a Biostator on five occasions in randomized order including a control study without insulin injection. A stable basal insulin level of about 10 mU I−1 was established by means of a low dose insulin infusion (0.1 mU kg−1 min−1) which subsequently suppressed C‐peptide by 35 ± 19% (mean ± SD) to levels of around 0.3 nmol I−1. Twelve units of NPH insulin were injected subcutaneously into the abdominal wall and glucose infusion rates were monitored for 19 h. In the control study, the mean glucose infusion rate was 1.11 ± 0.60 (range 0.32–1.95) mg kg−1 min−1. Maximal glucose infusion rates, reached 5–7 h after injection, were comparable (4.3–4.9 mg kg−1 min−1) for the four different preparations used. Glucose infusion rates returned to basal rates within the 19 h study period. Mean plasma free insulin levels peaked at 17.5–18.6 mU I−1 3–4.5 h after injection and returned to basal levels within 16 h. The time ranges of >90, >75, >50, and >25% of maximal insulin action (as estimated from glucose infusion rates) revealed no significant differences between the four insulin preparations tested. No significant insulin action was observed beyond 17 h after insulin injection of any preparation.

Malignant Metastatic Insulinoma—Postoperative Treatment and Follow-up

The rarity of malignant insulinoma limits reports on therapeutic strategies and outcome. The treatment and follow-up of 10 patients, all presenting an insulinoma with metastatic disease of the liver and newly diagnosed between 1992 and 2002, is reported. Pancreatic surgery with successful removal of the primary tumor preferentially located in the tail was performed in 7 women and 3 men, median age 55 years (range 36–82 years). If appropriate, 5 patients underwent additional hepatic surgery and lymph node resections. Liver metastases as the major cause of postoperatively persistent hypoglycemia were subsequently treated by repeated transarterial hepatic chemoembolization and chemoperfusion protocols using high-dose transhepatic streptozocin perfusions (3–4 g per session). The current median survival time for all 10 patients is 2.6 years (range: 1.6–9.7 years). Six patients are currently alive with a median survival of 3.7 years (1.7–9.7 years), five of them with stable disease and free of hypoglycemia. Four patients died after a median survival of 1.8 years (range: 1.6–7.5 years) from complications of unmanageable hypoglycemia. It is concluded that the necessity to treat debiliating and life-threatening hypoglycemia in metastatic malignant insulinoma warrants the option of radical endocrine surgery in combination with extended and repeated postoperative chemoembolization of liver metastases.

Reoperative Surgery for Organic Hyperinsulinism: Indications and Operative Strategy

Abstract. Organic hyperinsulinism has a good chance of cure by operation, although patients with diffuse or multiple disease run a high risk of recurrence or persistence of disease. Surgical management and outcome in these patients are presented and discussed. Between 1986 and April 1997 a total of 62 patients were operated on for organic hyperinsulinism [solitary 48, multiple 3, multiple endocrine neoplasia type I (MEN-I) 2, diffuse 4, malignant 5]. Persistence or recurrence occurred in 10 patients (16%). Among the six that persisted, four were malignant and two benign. All four of those that recurred were benign. Patients with benign disease presented with multiple tumors (n= 3), MEN-I syndrome (n= 1), and diffuse/nodular hyperplasia (n= 2). The duration between diagnosis and reintervention ranged from 1 to 10 years. Preoperative diagnosis was able to localize tumors in three patients (computed tomography 1, angiography 2, calcium stimulation 1). Operative procedures were multiple enucleations in two patients with sporadic disease, subtotal resection plus enucleation in the case of MEN-I syndrome, subtotal resection for diffuse hyperplasia, left resection for adenomatosis, and tumor extirpation after multiple previous operations. Long-term clinical and biochemical cure was achieved in five of six patients (mean follow-up 5 years). Octreotide therapy shows good symptomatic control in the patient with operative failure. Reintervention for organic hyperinsulinism is successful (80% cure) and requires preoperative imaging and individual surgical management.

Spezielle diagnostische und therapeutische Aspekte beim Insulinom

Summary. Insulinomas are rare tumors and account for 90 % of all endocrine pancreatic tumors. They typically present as a solitary tumor, but may occur in multiple sites (e.g. multiple endocrine neoplasia type I) or as a malignant disease in 10 % of cases and rarely as nesidioblastosis or islet cell adenomatosis. Neuroglucopenic symptoms lead to the diagnosis; inadequate high insulin and C-peptide secretion with hypoglycemia in the fasting test confirm the diagnosis. Preoperative localization is not necessary prior to the first operation. The standard operation is enucleation or, depending on size and location, resection. The treatment of multiple tumors and islet cell hyperplasia with a high risk of recurrence is problematic. Subtotal resection plus enucleation seems to be better than selective tumor resection. In malignant insulinomas, mostly presenting with liver metastases, aggressive surgical therapy with hepatectomy and debulking, chemoembolization and systemic chemotherapy are the modalities of choice.Zusammenfassung. Das Insulinom ist ein seltener Tumor und betrifft 90 % der endokrinen Pankreastumoren. Grundlage des Hyperinsulinismus ist typischerweise ein solitärer Tumor, in jeweils 10 % multiple Tumoren (z. B. multiple endokrine Neoplasie Typ I) und malignes Insulinom sowie selten die Nesidioblastose oder Inselzelladenomatose. Wegweisend ist die klinische Symptomatik mit Neuroglucopenie, beweisend die inadäquat hohe Insulin- und C-Peptidsekretion bei Hypoglykämie im Hungertest. Präoperative Lokalisationsdiagnostik beim Ersteingriff ist obsolet. Standardoperation ist die Enucleation des Tumors oder in Abhängigkeit von Größe und Lage die Resektion. Problematisch ist die Behandlung von multiplen Tumoren und Inselzellhyperplasie, die mit einer hohen Rezidivrate belastet sind. Subtotale Resektion plus Enucleation scheinen selektiver Tumorentfernung überlegen. Beim malignen Insulinom, meist mit Lebermetastasen, stehen aggressive chirurgische Therapie mit Leberresektion und Debulking, Chemoembolisation und systemische Chemotherapie zur Wahl.

Simulated postaggression metabolism in healthy subjects: metabolic changes and insulin resistance.

Postaggression metabolism (PAM) is difficult to study in critically ill patients. The objective of this study was to simulate PAM in healthy subjects to quantify insulin sensitivity under these conditions. Six healthy men (age, 24 +/- 1 years; body mass index, 22.0 +/- 0.7 kg/m2 [mean +/- SE]) received an intravenous (i.v.) infusion of insulin-counteracting hormones (epinephrine 100 ng/kg/min, glucagon 16 ng/kg/min, hydrocortisone 5 microg/kg/min, and growth hormone [GH]-releasing hormone 50 microg/h) for 4 hours in addition to glucose (270 mg/kg/h). Control experiments used glucose only. In additional experiments, insulin sensitivity was measured by a two-step hyperinsulinemic glucose clamp with and without concomitant hormone infusion (insulin infusion rate, 2.5 and 5.0 mU/kg/min for hormone infusion or 1.0 and 2.5 mU/kg/min for control experiments). Plasma stress hormones reached levels comparable to severe PAM (epinephrine, 1,085 +/- 89 pg/mL; glucagon, 1,100 +/- 114 pg/mL; cortisone, 1,004 +/- 32 ng/mL; and GH, 20.6 +/- 6.1 pg/mL) in the hormone infusion experiment. This resulted in hyperglycemia and hyperinsulinemia (steady-state blood glucose, 19.7 +/- 0.4 mmol/L; serum insulin, 352 +/-8 pmol/L) in comparison to the control experiments with glucose infusion only (maximal blood glucose 7.2 +/- 0.8 mmol/L; serum insulin, 110 +/- 16 pmol/L). The insulin sensitivity index (S(I)) was 88% +/- 6% lower during hormone infusion (0.6 +/- 0.4 mL/min/m2/microU/min) compared with the control experiments (4.5 +/- 1.3 mL/min/m2/microU/min). Infusion of insulin-counteracting hormones at high doses allows simulation of the changes in carbohydrate metabolism observed in PAM in healthy subjects. The observed profound decrease in insulin sensitivity explains the hyperglycemia observed in nondiabetic critically ill patients. With this experimental setup, standardized investigations of therapeutic interventions in PAM should be possible.

Comparative dose-related time-action profiles of glibenclamide and a new non-sulphonylurea drug, AG-EE 623 ZW, during euglycaemic clamp in healthy subjects.

SummaryInsulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3–3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25–40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per μmol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions.

Differentiation of insulin secretion patterns in insulinoma.

BackgroundIn patients with insulinoma, biochemical proof of inappropriately elevated insulin secretion during hypoglycemia is required prior to surgery. Because circulating insulin levels usually vary widely, we have used the combined OGTT-fasting test to define new normative criteria for a retrospective systematic analysis.MethodsWe retrospectively analyzed insulin concentrations from OGTT-fasting tests of 64 patients with surgically removed insulinomas. In addition, the response to intravenous somatostatin infusions was estimated. Normative criteria were defined to obtain comparable estimates of insulin concentrations: basal, glucose-stimulated maximum, postglucose plateau, and secretory bursts.ResultsThree types of insulin secretion patterns were identified: (1) the autonomous secretion pattern (type 1, N = 17) with basal and post-OGTT plateau insulin concentrations of approximately 50 mU/L, suppression after OGTT by 41%, virtual absence of distinctive secretory bursts, and resistance to somatostatin-mediated suppression (25 %); (2) the inadequate suppression pattern (type 2, N = 28) with moderately elevated basal and post-OGTT insulin concentrations of approximately 20 mU/L, suppression after OGTT by 73%, absence of secretory bursts, and incomplete somatostatin-induced suppression (56 %); (3) the late-burst secretion pattern (type 3, N = 19) with similar basal and post-OGTT insulin concentrations of 17 mU/L, suppression after OGTT by 76%, true insulin bursts of Δ 13 ± 11 mU/L (184%), and nearly complete somatostatin-induced suppression by 64%.ConclusionsBy means of a new normative analysis of the combined OGTT-fasting test, three different patterns of insulin secretion can be described in patients with insulinoma: the autonomous secretion type, the inadequate suppression type, and the late-burst secretion type.

[Surgery for neuroendocrine tumors of the gastroenteropancreatic system (GEP-NET)].

Surgical treatment is still the only curative treatment proven for patients with neuroendocrine tumors (NET) of the gastroenteropancreatic system. In addition to the therapy of incidental findings, the treatment of NET with variable aggressiveness and often good long-term prognosis requires a thorough preoperative assessment and a surgical procedure that is based on each individual case. Treatment can be surgery alone (if the disease is locally confined) or can be combined with other therapies. Early NET of the stomach and rectum can be cured endoscopically without further diagnostics, while early findings of the appendix can be treated by an appendectomy. Functionally active pancreatic NET and NET of the small intestine are often preoperatively diagnosed based on symptoms. Thus, it is possible to refer the patient to a NET center, if necessary. Stratification of the necessary treatment combination can be made early. An alternative to radical surgical treatment is the operative reduction of the tumor size and hormone production in metastasized NET, which can lead to improved life expectancy and quality of life. Combination with other treatment forms is absolutely necessary in these patients. It has been proven useful to divide the large group of NET based on the different tumor locations, hormone activity, and the degree of differentiation of the tumor. Early forms, locoregionally limited tumor stages, and tumor stages with distant metastases are considered separately.ZusammenfassungDie chirurgische Therapie ist weiterhin der einzige nachweislich kurative Therapieansatz für Patienten mit neuroendokrinen Tumoren (NET) des gastroenteropankreatischen Systems. Neben der Therapie von Zufallsbefunden verlangt die Therapie von NET bei variabler Aggressivität der Tumoren und oft guter Langzeitprognose eine eindeutige präoperative Einschätzung und ein individuelles chirurgisches Vorgehen. Die Behandlung kann allein chirurgisch (bei lokaler Ausprägung der Erkrankung) oder in Kombination mit anderen Therapien erfolgen.So werden frühe NET des Magens und Rektums ohne weiterführende Diagnostik allein endoskopisch kuriert, Frühbefunde der Appendix werden durch eine Appendektomie gesichert. Funktionell aktive pankreatische NET und NET des Dünndarms werden aufgrund der Symptome häufig präoperativ erkannt. So ist ggf. die Überweisung in ein NET-Zentrum möglich. Eine Stratifizierung der notwendigen Therapiekombination kann frühzeitig erfolgen.Alternativ zum radikalen chirurgischen Vorgehen kann bei metastasierten NET durch die operative Reduktion der Tumormasse und Hormonproduktion eine Verbesserung der Lebenserwartung und -qualität erreicht werden. Eine Kombination mit anderen Therapieformen ist bei diesen Patienten prinzipiell notwendig.Es hat sich als sinnvoll erwiesen, die große Gruppe der NET nach der unterschiedlichen Lokalisation des Primärtumors, der hormonellen Aktivität und dem Differenzierungsgrad des Tumors zu unterteilen. Frühe Formen, lokoregionär begrenzte Tumorstadien und Tumorstadien mit Fernmetastasierung werden getrennt betrachtet.AbstractSurgical treatment is still the only curative treatment proven for patients with neuroendocrine tumors (NET) of the gastroenteropancreatic system. In addition to the therapy of incidental findings, the treatment of NET with variable aggressiveness and often good long-term prognosis requires a thorough preoperative assessment and a surgical procedure that is based on each individual case. Treatment can be surgery alone (if the disease is locally confined) or can be combined with other therapies.Early NET of the stomach and rectum can be cured endoscopically without further diagnostics, while early findings of the appendix can be treated by an appendectomy. Functionally active pancreatic NET and NET of the small intestine are often preoperatively diagnosed based on symptoms. Thus, it is possible to refer the patient to a NET center, if necessary. Stratification of the necessary treatment combination can be made early.An alternative to radical surgical treatment is the operative reduction of the tumor size and hormone production in metastasized NET, which can lead to improved life expectancy and quality of life. Combination with other treatment forms is absolutely necessary in these patients.It has been proven useful to divide the large group of NET based on the different tumor locations, hormone activity, and the degree of differentiation of the tumor. Early forms, locoregionally limited tumor stages, and tumor stages with distant metastases are considered separately.