Urban Rosenqvist and Suad Efendić
Suad Efendić, Peter Amer and Jan Östman
Mark Gutniak, Valdemar Grill, Arved Roovete and Suad Efendic
We have investigated the effects of hyperglycemia in Type II diabetic patients on the somatostatin response to oral glucose. In these patients hyperglycemia prevailed (11.8 ± 1.4 mmol/l) and was markedly increased to a maximum of 18.9 ±1.0 mmol/l following the ingestion of 75 g of glucose. The rise in blood glucose following glucose ingestion failed to induce a rise in plasma levels of somatostatin-like immunoreactivity. Biostator-regulated insulin infusion normalized fasting levels of blood glucose and reduced the hyperglycemia following glucose ingestion, i.e. blood glucose now rose from 4.6 ± 0.1 to a maximum of 7.3 ±0.8 mmol/l. This moderate rise in blood glucose was accompanied by a significant (p <0.05) rise in somatostatin-like immunoreactivity. Somatostatin-28 and somatostatin-14 were separated using a Sephadex G-50 fine column. Biostator treatment suppressed plasma levels of both peptides during fasting conditions. Treatment was also accompanied by a rise in both peptides during the first hour following glucose ingestion; this rise did not occur in the untreated state. In conclusion: lack of somatostatin response to glucose in non-insulin-dependent diabetes mellitus is associated with deranged metabolic control. Unresponsiveness to glucose entails the secretion of both somatostatin-28 and -14.
Suad Efendić, Franz Enzmann, Mark Gutniak, Anita Nylén and Manfred Zoltobrocki
HB 699 (100 μg/ml), almost identical with the left residue of the sulphonylurea glibenclamide, enhanced basal insulin and somatostatin release from the perfused rat pancreas. The compound also augmented both the early and the late insulin release stimulated by 6.7 mm glucose, while with 16.7 and 33.3 mm glucose only late insulin release was increased. Furthermore, HB699 enhanced both phases of glucose induced somatostatin release irrespective of whether 6.7, 16.7 or 33.3 mM glucose were used. As for glucagon release, HB 699 suppressed basal and arginine stimulated glucagon secretion.
The present findings imply that the sulphonylurea moiety of glibenclamide is not a prerequisite for its stimulatory action on insulin and somatostatin release. It is suggested that the enhanced somatostatin release mediates the inhibitory effect of the compound on glucagon release.
Ulf Eriksson, Arne Andersson, Suad Efendić, Robert Elde and Claes Hellerström
Streptozotocin (SZ) treated virgin female rats, classified as either manifest diabetic (MD) or subdiabetic (SD) according to intraperitoneal glucose tolerance tests, were mated. Normal untreated rats (N) were also mated and used as controls. On gestational day 20 the MD foetuses showed decreased litter sizes, elevated blood glucose values and glucose-to-insulin ratios, decreased body and pancreatic weights and markedly diminished pancreatic insulin contents. The MD pregnancy was prolonged by two days and about 50 per cent of the offspring died perinatally. Both the wet and dry carcass weights of the non-viable MD offspring were increased, but when correction was made for the prolonged gestational period both the viable and non-viable newborns were lighter than those of the other groups. In the viable newborns of MD mothers the blood glucose concentration was elevated and the pancreatic contents of insulin and somatostatin decreased while that of glucagon remained unchanged. The 20-day-old SD foetuses showed increased pancreatic insulin and somatostatin contents but were identical to N foetuses in all other respects. Similarly, the newborns of SD mothers remained indistinguishable from those of the N mothers.
It is concluded that, in the rat, severe SZ-diabetes induced before pregnancy causes foetal growth retardation and decreased pancreatic insulin stores. The observations suggest that excessive hyperglycaemia in the foetus hampers the normal development of the pancreatic B-cell. The absence of macrosomia and hyperinsulinism in both the MD and SD newborns suggests a difference between human and rat foetal development in diabetic pregnancy.
Erol Cerasi, Suad Efendic, Christina Thornqvist and Rolf Luft
The effect of two second generation sulphonylureas, gliquidone and glibenclamide, on insulin secretion has been studied in the basal state and in combination with glucose infusions in normal controls, patients with mild maturity-onset diabetes, and subjects with normal glucose tolerance but low insulin response. When injected intravenously, gliquidone caused rapid elevation of plasma insulin, peaking at 5 min in all groups, while glibenclamide induced a slow rise in insulin. Insulin response was somewhat smaller than normal in diabetics and low insulin responders. In all groups, 25 μg/kg glibenclamide and 200 μg/kg gliquidone were equipotent in generating an insulin response at the basal state.
Equipotent amounts of sulphonylureas were combined with glucose infusions at three different dose levels. The glucose-insulin dose relationships, established by giving glucose alone, demonstrated curves that were flatter, and shifted to the right of the control in diabetics and low insulin responders, the changes being more marked in the former group. Addition of sulphonylurea induced a left shift in the dose-response relationships in controls and low insulin responders; under these conditions the effect of glibenclamide was more pronounced than that of gliquidone. The doseresponse relation for glucose-induced insulin release was completely normalized in low responders when sulphonylureas were added. In the group of mild diabetics, insulin response to glucose was enhanced by sulphonylureas only to a modest extent, the dose-response curves remaining grossly abnormal.
It is concluded that, under acute experiments, sulphonylureas correct the deficient insulin response only in subjects with minimal abnormalities of the glucose tolerance; their effect in diabetics, even very mild ones, is marginal.
Nina Clausen, Per-Eric Lins, Ulf Adamson, Bertil Hamberger and Suad Efendić
Abstract. Hypothyroidism has been alleged to modulate insulin action and influence the secretion of growth hormone and catecholamines. We recently investigated the influence of hypothyroidism on glucose counterregulatory capacity and the hormonal responses to insulin-induced hypoglycaemia in 6 patients with primary hypothyroidism (age 32–52 years, TSH-values 66–200 mU/l). Hypoglycaemia was induced in the hypothyroid state and again when the subjects were euthyroid. After an overnight fast a constant rate infusion of insulin (2.4 U/h) was given for 4 h. Glucose was measured every 15 min and insulin, C-peptide, glucagon, epinephrine, norepinephrine, growth hormone and cortisol every 30 min for 5 h.
During insulin infusion somewhat higher concentrations of the hormone were obtained in the hypothyroid state and simultaneously glucose levels were 0.5 mmol/l lower. As expected, basal norepinephrine levels were higher in hypothyroidism. However, no increase in circulating norepinephrine during hypoglycaemia was registered in the two experiments. The responses of counterregulatory hormones showed an enhanced response of cortisol, similar responses of growth hormone and epinephrine while the glucagon response was paradoxically impaired. Our findings suggest that hypothyroidism alters insulin metabolism, and that the glucagon response to hypoglycaemia is impaired in this condition.
Moira S Lewitt, Agneta Hilding, Kerstin Brismar, Suad Efendic, Claes-Göran Östenson and Kerstin Hall
Low levels of IGF-binding protein 1 (IGFBP1) are associated with metabolic syndrome and predict diabetes development in men. The aim of this study was to determine the levels of IGFBP1 in women who later develop diabetes, in relation to abdominal obesity, and to compare these levels with those of men.
IGFBP1 levels were determined at baseline and after 8 years in a case–control, prospective study of Swedish women aged 35–56 years. Individuals with normal oral glucose tolerance test (OGTT) who developed abnormal glucose regulation (n=240) were pair matched to controls for age and family history of diabetes and also compared to men of the same age (n=355).
Low fasting IGFBP1 and increased waist measurement predicted development of diabetes in women (n=60; odds ratio (OR) 70, 95% confidence interval (CI) 8–661, lowest tertile and OR 27, 95% CI 5–141, highest tertile). In women developing diabetes, baseline IGFBP1 levels were lower than expected for fasting insulin values, were associated with impaired suppression after OGTT and increased during 8 years despite an increase in fasting insulin. All individuals in the highest tertile for waist and with ≤40% suppression of IGFBP1 developed diabetes within 8 years. Circulating IGFBP1 concentrations were higher in women compared to men. Women and men who developed diabetes had a similar degree of abdominal obesity, corrected for height.
We conclude that low IGFBP1 and elevated waist measurement predict diabetes development and that IGFBP1 production is suppressed by a novel factor(s) in women developing diabetes. Increasing levels of IGFBP1 during the emergence of diabetes in men and women suggest the emergence of hepatic insulin resistance.
Michael Alvarsson, Valdemar E Grill, Alexandre Wajngot, Erol Cerasi and Suad Efendic
We investigated the stability of the insulin response to glucose in healthy subjects by making retrospective comparisons of insulin responses after two 60 min glucose infusion tests performed many years apart. The subjects (N =49) were divided into two lower and two higher quartiles as assessed by the incremental 0–10 min insulin area during the initial glucose infusion test. Ages were initially 32.3±2.8 years in lower quartiles and 26.6±1.1 in higher quartiles and body mass indexes 21.6±0.6 kg/m2 and 21.8±0.5, respectively. The interval between the first and second glucose infusion tests was 8.1±2.8 years for lower quartiles and 10.4±1.3 for higher quartiles. In lower quartiles, the 0–10 min insulin area at first testing was 157.1±15.9 mU/l × 10 min and at follow-up 202.2±26.6 (+ 29%, NS). In higher quartiles, the insulin area decreased from 654.8±70.6 mU/l × 10 min at first testing to 489.8±53.6 at follow-up (−25%, p<0.05). The 0–60 min glucose area did not change significantly between glucose infusion tests in lower quartiles (+ 5%), but did increase by 12% (p<0.005) in higher quartiles. Only one subject of the lowest quartile at first testing changed to higher quartiles at follow-up. Predictable "regression toward the mean" at follow-up was moderate, hence the individual insulin response to glucose was relatively stable with time. This finding is compatible with the hypothesis that genetic factors are of major importance for the insulin response to glucose.
Claes-Göran Östenson, Bo Ahrén, Sven Karlsson, Jens Knudsen and Suad Efendic
Östenson C-G, Ahrén B, Karlsson S, Knudsen J, Efendic S. Inhibition by rat diazepam-binding inhibitor/ acyl-CoA-binding protein of glucose-induced insulin secretion in the rat. Eur J Endocrinol 1994;131:201–4. ISSN 0804–4643
Diazepam-binding inhibitor (DBI) has been localized immunohistochemically in many organs. In porcine and rat pancreas, DBI is present in non-B-cells of the pancreatic islets. Porcine peptide also has been shown to suppress insulin secretion from rat pancreas in vitro. Recently, acyl-CoA-binding protein (ACBP) was isolated from rat liver and shown to be identical structurally to DBI isolated from rat brain. Using this rat DBI/ACBP, we have studied its effects on glucose-stimulated insulin secretion in the rat, both in vivo and in isolated pancreatic islets. Infusion iv of rDBI/ACBP (25 pmol/min) during glucose stimulation induced a moderate and transient reduction of plasma insulin levels. Moreover, rDBI/ACBP suppressed insulin release from batch-incubated isolated islets, stimulated by 16.7 mmol/l glucose, by 24% at 10 nmol/l (p < 0.05) and by 40% at 100 nmol/l (p < 0.01). The peptide (100 nmol/l) also inhibited the insulin response to glucose (16.7 mmol/l) from perifused rat islets by 31% (p < 0.05), mainly by affecting the acute-phase response. Finally, incubation of isolated islets in the presence of rDBI/ACBP antiserum (diluted 1:100 and 1:300) augmented the insulin response to 16.7 mmol/l glucose (p < 0.05 or even less). We conclude that rDBI/ACBP, administered iv or added to the incubation media, suppresses insulin secretion in the rat but that the effect is moderate despite the high concentration used. It is therefore unlikely that the peptide modulates islet hormone release, acting as a classical hormone via the circulation. However, the occurrence of DBI/ACBP in the islets and the enhancing effect by the rDBI/ACBP antibodies on glucose-stimulated insulin release suggest that the peptide is a local modulator of insulin secretion.
C-G Östenson, Department of Endocrinology, Karolinska Hospital, S-171 76 Stockholm, Sweden