A randomized trial of iohexol versus amidotrizoate in endoscopic retrograde pancreatography

To evaluate whether a low-osmolar contrast medium could decrease hyperamylasemia after endoscopic retrograde pancreatography, a prospective randomized double-blind trial of 54 consecutive patients with suspected pancreatic disease referred for endoscopic retrograde pancreatography was performed. The low-osmolar contrast medium iohexol and high-osmolar amidotrizoate were used. No statistically significant differences with regard to rise in pancreatic-type amylase, pain reaction, or diagnostic information were found. No case of acute pancreatitis was observed.     

Chronic effect of fatty acids on insulin release is not through the alteration of glucose metabolism in a pancreatic beta-cell line (βHC9)

Summary Hyperinsulinaemia in the fasting state and a blunted insulin secretory response to acute glucose stimulation are commonly observed in obesity associated non-insulin-dependent diabetes mellitus. Hyperlipidaemia is a hallmark of obesity and may play a role in the pathogenesis of this beta-cell dysfunction because glucose metabolism in pancreatic beta cells may be altered by the increased lipid load. We tested this hypothesis by assessing the chronic effect of oleic acid on glucose metabolism and its relationship with glucose-induced insulin release in βHC9 cells in tissue culture. Our results show: (1) A 4-day treatment with oleic acid caused an enhancement of insulin release at 0–5 mmol/l glucose concentrations while a significant decrease in insulin release occurred when the glucose level was greater than 15 nmol/l; (2) Hexokinase activity was increased and a corresponding left shift of the dose-dependency curve of glucose usage was observed associated with inhibition of glucose oxidation in oleic acid treated βHC9 cells, yet the presumed glucose-related ATP generation did not parallel the change in insulin release due to glucose; (3) The rate of cellular respiration was markedly increased in oleic acid treated βHC9 cells both in the absence of glucose and at all glucose concentrations tested. This enhanced oxidative metabolism may explain the increased insulin release at a low glucose level but is clearly dissociated from the blunted insulin secretion at high glucose concentrations. We conclude that a reduction of oxidative metabolism in pancreatic beta cells is unlikely to be the cause of the dramatic effect that high levels of non-esterified fatty acids have on glucose-induced insulin release. [Diabetologia (1997) 40: 1018–1027] Received: 18 February 1997 and in revised form: 22 April 1997     

Isoamylases in diabetes mellitus

Summary We have evaluated the relationship between diabetes mellitus and exocrine pancreatic insufficiency in diabetic subjects by measuring a specific isoamylase arising from the pancreas. The pancreatic- and salivary-type isoamylase activity in serum and urine were evaluated and related to duration of disease, sex, age, weight, blood glucose level and glycosuria in 153 diabetics. In the insulin-dependent diabetics diagnosed between 15 and 24 years of age, a significant decrease in pancreatic isoamylase activity was found in serum and urine (means with 2 SD range, 50 U/l, 19–137 U/l, and 47 U/l, 4–607 U/l, respectively), as compared with control subjects (79 U/l, 45–140 U/l, and 183 U/l, 43–789 U/l, respectively). In this group of patients a low stimulated output of amylase into the duodenum was also observed (mean with range, 537 U, 87–1808 U), compared with controls (the lower limit of normal 2183 U). A significant positive correlation was found between stimulated output of amylase into the duodenum and pancreatic isoamylase activity in serum (r = 0.84, p < 0.01). In the non-insulin dependent diabetics, a significant negative correlation was found between blood glucose levels and pancreatic isoamylase activity in serum (r = -0.46, p < 0.01). In the diet-treated non-insulin dependent diabetics the pancreatic isoamylase activity in serum was increased compared with controls (mean and 2 SD range, 102 U/l, 49–211 U/l). In patients with blood glucose level above 12 mmol/l, however, a lowered pancreatic isoamylase activity in serum, and no apparent rise in serum immunoreactive insulin in glucose loading test was observed. The results suggest that production of pancreatic amylase is related to endocrine pancreatic function in diabetes mellitus.     

Effects of C-terminal fragments of cholecystokinin on exocrine and endocrine secretion from isolated perfused rat pancreas

The ability of various C-terminal fragments of cholecystokinin (CCK) to increase pancreatic exocrine and endocrine secretion was examined in the isolated perfused rat pancreas. CCK octapeptide (CCK-8) induced biphasic dose-response curves for stimulation of pancreatic juice and amylase secretion. Maximal pancreatic juice and amylase output were obtained with 100 pM CCK-8. Concentrations of CCK-8 that caused pancreatic exocrine secretion also increased insulin release in the presence of 8.3 mM glucose. The tetrapeptide of CCK also simultaneously stimulated both exocrine and endocrine secretion, but was about 100,000 times less potent than CCK-8. By contrast both deca- and tetradecapeptide of CCK at a concentration of 100 pM stimulated secretion of pancreatic juice and amylase, and elicited insulin release comparably to CCK-8. The complete CCK-8 sequence was required as deamidated CCK-8 was without effects on exocrine and endocrine pancreatic secretion at a concentration of 100 pM. The present observations suggest that the structural requirements for CCK-induced insulin secretion are the same as those for CCK-induced exocrine secretions, and that the amino acids in position 5-8 and the amidated residue on the C-terminus are required for physiological activity of CCK on both the exocrine and endocrine pancreas. It is concluded that C-terminal fragments of CCK with eight or more amino acid residues are potent potentiators of insulin release as well as pancreatic exocrine stimulants.     

Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta

Aims/hypothesis Several epidemiological data suggest that patients with postprandial hyperglycaemia are at high risk of cardiovascular disease. The aim of this study was to elucidate the effect of a glucose ‘spike’ on monocyte adhesion to rat aortic endothelial cells. Materials and methods Monocyte adhesion to endothelial cells in vivo was quantitated using an en face method for observation of endothelial surface after immunohistochemical staining for CD68 in the thoracic aortas of Sprague–Dawley rats after several kinds of blood glucose rises. Results The number of monocytes adhering to endothelial cells increased at 30 min after injection of glucose in 8-week-old Sprague–Dawley rats. The increased adhesion returned to the basal level at 120 min after glucose injection, concomitantly with the return of blood glucose levels to normal. The infusion of octreotide to inhibit endogenous insulin secretion did not prevent the glucose-induced increase in monocyte adhesion to endothelial cells. On the other hand, the number of monocytes adhering to endothelial cells did not increase in rats with streptozotocin-induced diabetes and sustained hyperglycaemia. Conclusions/interpretation Our data demonstrate that a temporary rise in blood glucose levels can in itself promote a reversible increase in monocyte adhesion to arterial endothelial cells.     

Syntaxin, but not soluble NSF attachment protein (SNAP), biosynthesis by rat pancreatic islets is regulated by glucose in parallel with proinsulin biosynthesis

Summary Recent studies have revealed that soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE)-related proteins, originally identified in neural tissues, are also expressed in pancreatic beta cells. In this study, we investigated the effect of glucose on syntaxin 1 and α/β SNAP biosynthesis in pancreatic beta cells and we demonstrated that syntaxin 1, but not α/β SNAP biosynthesis by rat isolated pancreatic islets was stimulated specifically by glucose nearly in parallel with proinsulin biosynthesis. Stimulation of syntaxin 1 and proinsulin biosynthesis by glucose was dose-dependent (K_m = ∼8 mmol/l) and reached the maximum (about 8–12 fold) at concentrations over 11 mmol/l. In contrast, 22 mmol/l glucose increased α/β SNAP biosynthesis about 2-fold only, similar to the increase in total protein synthesis. Stimulation of syntaxin 1 biosynthesis by glucose was also time-dependent, taking around 3 h to reach the maximum, and was not affected by actinomycin-D, suggesting regulation at the translational level. On the other hand, glucose had a similar stimulating effect on both syntaxin 1 and α/β SNAP biosynthesis by mouse insulinoma βTC3 cells as it did on proinsulin biosynthesis. The evidence showing coordinated stimulation of syntaxin 1 and proinsulin biosynthesis by glucose in rat islets suggested the critical functional role of syntaxin 1 in the insulin exocytotic mechanism. [Diabetologia (1997) 40: 1396–1402] Received: 16. April 1997 and in revised form: 19 August 1997     

The acute effect of insulin on heart rate,blood pressure,plasma noradrenaline and urinary albumin excretion

Summary The effect of intravenous insulin (7–8 U as a bolus injection) on renal haemodynamics and urinary excretion of albumin and beta-2-microglobulin was examined in five recent onset juvenile diabetics. Blood glucose concentration was maintained after insulin at unchanged or slightly increased levels by continuous intravenous glucose infusion (50 g/100 ml, 1.2 ml/min). Mean arterial blood pressure increased slightly but significantly from 94±8 mmHg to 99±10 (mean ± SD) after insulin. The rise in heart rate (16 versus 29 beats/min) and in plasma noradrenaline (from 0.16 to 0.32 ng/ml versus 0.20 to 0.49 ng/ml) was significantly greater in the tilted position after insulin. There was no decrease in glomerular filtration rate or renal plasma flow after insulin, in contrast to the findings after intravenous injection of insulin without maintenance of plasma glucose. Urinary albumin excretion was approximately doubled after insulin, from 6.8 to 12.5 g/min. Beta-2-microglobulin excretion decreased but this difference was not significant. — It is concluded that the rise in heart rate and plasma noradrenaline, and the increase in urinary albumin excretion, after insulin, are unrelated to changes in blood glucose concentration. It is suggested that increased albumin excretion after insulin is due to a direct effect of insulin on glomerular endothelial or epithelial cells.     

Influence of estrogen-progesterone sequential administration on pancreas cytology. Serum insulin and metabolic adjustments in female dogs

Summary In bitches in anestrus, artificial endometrial sex cycles were induced. Estrus was induced by 17β-estradiol benzoate administration; matched untreated and vehicle-treated controls were studied. Early metadiestrus (6th day after appearance of metestrum cells in vaginal smears) was induced by the sequential administration of 17β-estradiol benzoate and progesterone: matched studies with only one hormone or vehicles were also carried out. In different groups of animals, blood sugar (BS), serum immunoreactive insulin (IRI) and serum free fatty acids (FFA) in the basal conditions and during glucose and insulin tests were studied. Insulin was immunocytolocalized in sections of pancreas from a part of these animals. Size and insulin content in Langerhans islets were measured by morphometric and cytospectrophotometric computerized analysis. Extrapancreatic factors — space of distribution, t? in blood stream — regulating serum IRI and BS levels were calculated. The hypoglycemic effect of insulin was enhanced by estrogenization, together with insulin accumulation in Langerhans islets. Progesterone treatment caused mild insulin resistance together with depletion of pancreatic insulin stores in the long run. Glucose tolerance of progesterone-injected bitches was improved after estrogen priming with greater space of distribution of glucose. Furthermore, a high basal serum FFA levels in bitches receiving the hormone sequence was observed. We may therefore conclude that the metabolic and endocrine changes induced in bitches by artificial sex cycles converge towards excellent BS homeostasis leads to the replenishing of pancreatic insulin stores, so that estrogen-progesterone administration in sequence appears to be, in this experimental condition, non-diabetogenic. This study was partly presented at the XXIX Int. Congr. Physiol. Sci., Sydney, August 28–September 3, 1983 and II Congr. Endocrinol. Metabol, South Cone, Buenos Aires, November 11–14, 1985. Established Investigator, ‘Consejo Nacional de Investigaciones Científicas y Técnicas’ (CONICET): National Board of Scientific and Technical Research, Argentina. Graduate Technician, CONICET.     

Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats

Summary An intrinsic angiotensin system has been described in the pancreas, with angiotensin II specific receptors being present on both exocrine, endocrine and vascular cells. The aim of the present study was to evaluate the effects of angiotensin II on insulin secretion and blood flow regulation in the pancreas. Blood flows were determined with a microsphere technique. Infusion of angiotensin II induced a dose-dependent reduction in both whole pancreatic and islet blood flow, which was most pronounced in the former. Administration of enalaprilate, an inhibitor of angiotensin-converting enzyme, and saralasin, a non-selective angiotensin II receptor antagonist, preferentially increased islet blood flow. The effects of angiotensin II on insulin release were examined by measuring insulin concentrations in the effluents from isolated perfused pancreata. In these preparations, enalaprilate affected neither basal nor glucose-stimulated insulin release, whereas angiotensin II delayed the first phase of insulin release in response to glucose. The effect of angiotensin II was probably due to initial marked vasoconstriction. The retardation of insulin release could be avoided by adding angiotensin II to the perfusion medium 20 min before glucose administration, i. e. so that the vasoconstriction had disappeared when glucose-stimulation began. The present study suggests that the angiotensin-system is important in regulation of islet blood flow and points to a pivotal role of islet blood perfusion for an adequate insulin release. [Diabetologia (1998) 41: 127–133] Received: 7 April 1997 and in revised form: 27 August 1997     

Hyperresponse in calcium-induced insulin release from electrically permeabilized pancreatic islets of diabetic GK rats and its defective augmentation by glucose

Summary In spontaneously diabetic GK rats, insulin secretion from pancreatic beta cells in response to glucose is selectively impaired, probably due to deficient intracellular metabolism of glucose and impaired closure of K_ATP channels during glucose stimulation. By using electrically permeabilized islets of GK rats, we explored the functional modulations in exocytotic steps distal to the rise in [Ca^{2 +} ]i in the diabetic condition. At 30 nmol/l Ca^{2 +} (basal conditions) insulin release was similar between GK and non-diabetic control Wistar rats. In response to 3.0 μmol/l Ca^{2 +} (maximum stimulatory conditions), insulin release was significantly augmented in permeabilized GK islets (p < 0.01). Raising glucose concentrations from 2.8 to 16.7 mmol/l further augmented insulin release induced by 3.0 μmol/l Ca^{2 +} from permeabilized control islets(p < 0.001), but had no effect on that from permeabilized GK islets. The stimulatory effect of glucose on insulin release from permeabilized control islets was partly inhibited by 2,4-dinitrophenol, an inhibitor of mitochondrial oxidative phosphorylation (p < 0.01). The hyperresponse to Ca^{2 +} in GK islets may play a physiologically compensatory role on the putative functional impairment both in [Ca^{2 +} ]i rise and energy state in response to glucose in diabetic β cells, and may explain the relative preservation of insulin release induced by non-glucose depolarizing stimuli, such as arginine, from pancreatic islets in non-insulin-dependent diabetes mellitus. [Diabetologia (1995) 38: 772–778] Received: 17 September 1994 and in revised form: 29 December 1994     

Induction of rat muscle insulin resistance by epinephrine is accompanied by increased interstitial glucose and lactate concentrations

Summary Muscle glucose uptake and lactate release during β-adrenergic stimulation by epinephrine (epi) and β-adrenergic blockade by propranolol (prop) were investigated during an euglycaemic hyperinsulinaemic (30 pmol · kg^–1· min^–1) with or without added somatostatin (0.1 μg/min; pancreatic) clamp in female rats. To assess the interstitial insulin, glucose and lactate concentrations, microdialysis was done in the medial femoral muscle in both legs. The influence of muscle skeletal blood flow on interstitial insulin, glucose and lactate was examined with the microsphere technique, using ⁵⁷Co-microspheres. Epinephrine decreased glucose infusion rate by about 75 % (p < 0.0001) and increased concentrations of interstitial glucose by about 35 % (p < 0.001) and lactate by about 65 % (p < 0.01). Plasma insulin concentration increased during β-adrenergic stimulation by about 25 % (p < 0.05) whereas the interstitial insulin concentration was unchanged. Muscle blood flow in the hindlimb was considerably enhanced by about 130 %, (p < 0.001) by epinephrine. Infusion of propranolol totally abolished all the above effects induced by epinephrine. The data show that insulin resistance and vasodilation induced by β-adrenergic stimulation with epinephrine is accompanied by increased interstitial glucose as well as lactate concentrations in muscle. The increased interstitial glucose concentration is the result of a decreased cellular uptake of glucose together with an increased capillary delivery of glucose by vasodilation. It is concluded that the severe cellular resistance to insulin induced by epinephrine could not be overcome either by the increased insulin secretion or by vasodilation. [Diabetologia (1998) 41: 1467–1473] Received: 5 January 1998 and in final revised form: 6 July 1998     

The probability of pancreatitis after pancreatic parenchymatography with a non-ionic contrast medium. A sequentially designed clinical trial

Endoscopic retrograde pancreatography (ERP) with parenchymatous contrast filling may result in clinical pancreatitis. The aim of the present prospective trial was to assess the frequency of acute pancreatitis after pancreatic parenchymatography with a non-ionic contrast medium, metrizamide. For ethical reasons the examination was designed as a sequential study with clearly defined stopping rules. None of the 48 patients studied developed clinical pancreatitis. This indicates that the probability of pancreatitis after parenchymatography is less than 5%. A high degree of contrast filling was obtained both in patients with normal and in those with pathologic pancreatic ducts. The contrast filling of the ducts was associated with not more than a slight pain. The rise in serum amylase was considerable but was not associated with clinical pancreatitis and returned to preexamination levels within 48 h. The examination shows that the non-ionic contrast medium used is well tolerated in ERP.     

Effects of chronic TSH treatment on blood sugar,serum IRI and FFA levels of thyroidectomized dogs. Glucose and insulin tolerance tests

Summary The effects of TSH treatment (0.1 USPU/kg body weight/die, for 3–4 days) on the blood sugar, serum IRI and circulating FFA responses to glucose and insulin were studied. Blood sugar and serum FFA levels of the dogs, in basal conditions and at any time interval during the test were slightly modified by TSH treatment. The kinetics of insulin disappearance from blood was not affected while the mean serum IRI during the insulin tolerance test was moderately reduced, which suggests that insulin space is moderately raised by TSH. The serum IRI response to glucose (OGTT, IVGTT) was found to be significantly and intensely reduced. The possibility of an inhibitory action of TSH on the insulin response to glucose in dogs, excluding the participation of the thyroid, exerted via insulin space and secretion is discussed. This work, partly published in abstract form (I Congreso Latino-americano de Diabetes, Montevideo, October 22–25, 1972;VI Congreso Argentino de Biología, San Miguel de Tucumán, April 9–13, 1973, abstract # 131; 8th Congr. of the Int. Diabetes Fed., Bruxelles, July 15–20, 1973, abstract # 86), was sponsored by theConsejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Established Investigator,Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Postgraduate Fellow, University of Buenos Aires, Argentina.     

Lack of gastrointestinal glucagon response to hypoglycaemia in depancreatized dogs

Summary Fasting (24 h) normal dogs and depancreatized dogs were injected intravenously with highly purified porcine insulin (Actrapid) in the doses of 0.2 U/kg and 0.5 U/kg, respectively. Blood glucose decreased from 152±41 (SEM) mg/100 ml to 39±7 mg/100 ml in the depancreatized dog and from 95±3 mg/100 ml to 42±4 mg/100 ml in the normal animal. Using a specific antiserum for “pancreatic” glucagon, the circulating level of glucagon immunoreactivity did not rise from the basal value of 247±31 pg/ml in the depancreatized group whereas it rose significantly from 223±24 pg/ml to 321±41 pg/ml in the normal group. In contrast intravenous infusion of 7 g of arginine increased “pancreatic” glucagon immunoreactivity in both groups. Thus, extrapancreatic glucagon of the pancreatic type does not respond to hypoglycaemia but to arginine infusion.     

On the pathogenesis of maturity-onset diabetes mellitus

Conclusions At the 6th IDF Congress in Stockholm in 1967, a hypothesis for the pathogenesis of maturity-onset diabetes under the title ‘What is inherited — what is added?’ was put forward. Investigations over the past 10 years, on the whole, tend to confirm our concept that the capacity of the pancreatic beta-cell to respond to a standardized glucose infusion with insulin production, to a major degree, is genetically controlled. Therefore, our original idea that impaired insulin response to glucose is a marker of genetic diabetes in all its stages (prediabetes, chemical diabetes, manifest diabetes) seems plausible. Accordingly, a malfunction in the transmission of information about the blood glucose level in the extracellular fluid to those sites in the cells which regulate insulin release, would be the primary defect in genetic diabetes. Our studies suggest that, due to increased sensitivity of the liver to insulin in the portal vein, most prediabetics retain a relatively normal — although somewhat low — glucose tolerance. This compensatory mechanism becomes insufficient and glucose intolerance is precipitated, e.g., when the demand for insulin release is increased. This occurs when the sensitivity of the body for insulin diminishes as in the case of obesity, acromegaly and pregnancy and, maybe, also during the process of aging.     

肾综合征出血热患者胰腺功能变化的临床研究

将６５例确诊为肾综合征出血热（ＨＦＲＳ）的住院患者列为观察组，选１０例正常者为对照组，监测ＨＦＲＳ患者各期的空腹血糖、血淀粉酶，脂肪酶及胰岛素含量并随机选出３０例ＨＦＲＳ患者，于发热末期或少尿期行口服葡萄糖耐量试验及胰岛素释放试验（口服７５ｇ糖）。发现ＨＦＲＳ患者在发热期即出现血糖、血淀粉酶，脂肪酶及胰岛素水平升高，服糖后胰岛素释放减少，糖耐量减低。此变化在少尿期最显著，多尿期次灾，恢复期渐正常，     

Analogue analysis of oral glucose tolerance test and insulin secretion in acromegaly

Summary Carbohydrate metabolism and insulin secretion in acromegaly have been studied by means of simulation and analogue analysis of plasma insulin and blood glucose curves obtained during OGTT in 20 acromegalic patients, using a model planned in our laboratory. Patients were arbitrarily subdivided into three groups according to blood glucose level at 120 min. Patients (8) with blood glucose level below or equal to 140 mg/100 ml were assigned to the first group; those (8) with blood glucose level ranging from 140 to 200 mg/100 ml were assigned to the second group; the remaining 4 patients with blood glucose level exceeding 200 mg/100 ml were assigned to the third group. Analogue simulation has shown that: 1) hepatic glycogenolysis is decreased in all patients; 2) peripheral glucose utilization is also decreased in all patients; 3) in the first group of patients, B-cell responsiveness to glucose and to gut hormones is increased; 4) in the second group, B-cell responsiveness to glucose is increased, whereas responsiveness to gut hormones is unchanged; 5) in the third group, B-cells still respond well to blood glucose variations but are not capable of reacting to high glycemic levels if these are constant; B-cell responsiveness to gut hormones remains normal; 6) insulin disappearance rate for biological purposes is decreased in all patients. This study was supported by C.N.R. grant: reference n. 72.00636.04. Istituto di Biologia Animale dell’Università di Padova.     

Decreased cyclic AMP and Insulin responses to glucose in pancreatic islets of diabetic chinese hamsters

Summary The dose as well as the time kinetics of insulin and adenosine-3,5-monophosphate (cyclic AMP) responses to glucose were compared in pancreatic islets isolated from normal and diabetic Chinese hamsters. The insulin content in diabetic islets was about one-half that in normal islets. Insulin release in diabetic islets incubated for 10 min with glucose 60–1000 mg/l00 ml was from one-third to one-half that in normal islets. Glucose 1000 mg/l00 ml stimulated three-fold increases in insulin release without increasing the accumulation of [³H] cyclic AMP in either normal or diabetic islets prelabelled with [³H] adenine. However, in the presence of 1.0 mM of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), glucose 150 mg/l00 ml elicited significant increases of insulin release (+ 134%) and [³H] cyclic AMP accumulation in islets (+ 44%) and incubation medium (+ 48%) of islets of normal but not diabetic hamsters. Also, in perifusion experiments with 0.1 mM IBMX, glucose 500 mg/l00 ml produced threefold greater increases in insulin release and two-fold greater increases in efflux of cyclic AMP in normal than diabetic islets. By contrast with the lesser effects of glucose in diabetic islets, 1.0 mM IBMX increased islet and medium cyclic AMP, as well as insulin release, similarly in normal and diabetic islets. It is suggested that the impairment of glucose induced insulin release in islets of the diabetic Chinese hamster may be due to a defective interaction of glucose with the adenylate cyclase-cyclic AMP system in the pancreatic B cell.This work was presented in part at a meeting of the European Association for the Study of Diabetes, Sept. 1975, Munich, Germanyon leave from the Department of Endocrinology, Karolinska Hospital, Stockholm     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

Summary A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-²H₂]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl_b), glucose clearance at 600 pmol/l insulin concentration (Cl₆₀₀), basal glucose production (P_b), basal insulin sensitivity index (BSI = Cl_b/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSI_b) and first (PSI₁) and second-phase (PSI₂) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 ± 0.6 vs 0.76 ± 0.18 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; ISI: 0.40 ± 0.06 vs 0.13 ± 0.05 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; Cl₆₀₀: 333 ± 47 vs 137 ± 26 ml · min^–1· m^–2, p < 0.01; NGT vs NIDDM). P_b was not elevated in NIDDM (588 ± 169 vs 606 ± 123 μmol · min^–1· m^–2, NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI₁ was impaired in NIDDM (67 ± 15 vs 12 ± 7 pmol · min^–1· m^–2· mmol/l^–1, p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSI_b was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion. [Diabetologia (1998) 41: 1029–1039] Received: 17 September 1997 and in final revised form: 28 April 1998     

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

Summary Prolonged exposure of islets to fatty acids results in a lowered glucose set-point for insulin secretion. We examined the mechanism in islets cultured for 24 h with 0.25 mmol/l palmitate. As expected, insulin secretion at 2.8 and 8.3 mmol/l glucose was increased in the palmitate-treated islets as opposed to no change at 27.7 mmol/l glucose. Co-culturing with 0.05 μg/ml Triacsin C, an inhibitor of long chain acyl-CoA synthetase, blocked this effect. Glucose utilization and oxidation showed the same pattern as insulin secretion, with the step-up for both measurements being fully manifest at 2.8 mmol/l glucose. Glucokinase K_m and V_max measured in islet extracts were unaffected by the palmitate. In contrast, hexokinase V_max was increased by 25–35 % in both the cytoplasmic and mitochondrial-bound pools. Our data suggest prolonged exposure to fatty acids increased beta-cell hexokinase activity, thereby modifying the kinetics of glucose entry into the metabolic pathway and glucose-induced insulin secretion. The cellular mediator is likely an increased level of long chain fatty acyl-CoA esters. [Diabetologia (1997) 40: 392–397] Received: 5 November 1996 and in revised form: 7 January 1997