Ulrich Keller

Reduced Postprandial Hyperglycemia After Subcutaneous Injection of a Somatostatin-Analogue (SMS 201-995) in Insulin-dependent Diabetes Mellitus

The effect of a new octapeptide analogue of somatostatin (SMS 201-995) on blood glucose and gut hormone levels was studied in 10 C-peptide-negative, insulin-dependent diabetic (IDDM) subjects. On separate days, either 50 or 100 μg SMS or placebo was s.c. injected simultaneously with an identical insulin dose 30 min before a mixed meal. Postprandial blood glucose decreased after 100 μg SMS s.c. within 30 min from 8.9 ± 0.7 to 7.8 ± 0.6 mmol/L (P < 0.001) and remained at similar levels during 180 min. In contrast, postprandial blood glucose concentration increased after placebo from 9.9 ± 0.8 to 13.8 ± 0.9 mmol/L (SMS versus placebo P < 0.001). Plasma glucagon decreased rapidly after SMS to the limit of detection (P < 0.001) and remained lowered during 180 min; in contrast, glucagon levels increased after the meal during the placebo study (SMS versus placebo P < 0.001). Plasma growth hormone concentrations were significantly lower after SMS than after placebo (P < 0.05). SMS abolished completely the postprandial increase in plasma gastrin and pancreatic polypeptide (PP) concentrations. Plasma free fatty acid (FFA) and triglyceride concentrations decreased after SMS, reaching significantly lower levels than after placebo (P < 0.05 and P < 0.01), respectively). Plasma SMS concentration increased rapidly after s.c. administration of SMS; its appearance preceded that of plasma free insulin after s.c. insulin injection. Fifty micrograms SMS was similarly effective as 100 μg in decreasing blood glucose, triglycerides, glucagon, and gut hormone concentrations. The data demonstrate that in contrast to native somatostatin whose action is known to be relatively weak and shortlived after s.c. administration, this somatostatin analogue results in diminished postprandial blood glucose and plasma triglyceride concentrations and in prolonged suppression of gut hormone levels after s.c. injection.

Antihypertensive Therapy With Ca2+: Antagonist Verapamil and/or ACE Inhibitor Enalapril in NIDDM Patients

Objective To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. Results Verapamil or enalapril alone normalized blood pressure to < 90 mmHg diastolic in 30 patients; verapamil decreased mean ± SE blood pressure from 159/98 ± 3/1 to 146/87 ± 3/2 mmHg (n = 18, P < 0.001) and enalapril from 166/99 ± 5/2 to 146/86 ± 3/1 mmHg (n = 12, P < 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 ± 4/2 to 152/90 ± 4/2 mmHg (P < 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. Conclusions In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.

Hypoglycemia in response to glucose and glucagon in insulinoma patients with a negative prolonged fast: Functional and morphological properties

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 γ-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.

Delayed disappearance of human compared to porcine insulin in a patient with the insulin autoimmune syndrome

The insulin autoimmune syndrome is characterised by high titres of autoantibody to insulin, a high circulating concentration of total insulin and later, reactive hypoglycaemia. We have studied a patient with this syndrome whose insulin autoantibody bound exclusively human insulin. This permitted us to investigate the disappearance of bound (human) and unbound (porcine) insulin in the same patient, using i.v. injections of 0.075 U/g of each insulin on separate days. The peak plasma free insulin concentration following porcine insulin was four times greater than that following the same dose of human insulin. The plasma disappearance half-time of porcine insulin following injection was 11 min compared with 32 min following human insulin injection, and the area beneath the disappearance curve of free insulin during the 120 min of sampling was greater for porcine insulin by a factor of 3.15. The nadir in plasma glucose occurred at 45 min following porcine insulin and at 90 min following human insulin injection. The restoration of basal glucose concentration was correspondingly slower following human insulin, but the absolute fall in glucose achieved was no different. There was no evidence of insulin resistance. Insulin autoantibodies can seriously disturb the kinetics and effect of free insulin.