Pancreatic duct occlusion with Ethibloc. An experimental study in juvenile pigs

In the transplantation of vascularized pancreatic grafts severe problems are related to the exocclusion is an improved alternative to duct ligation in producing atrophy of the exocrine pancreas while leaving the endocrine pancreas intact. Fractional growth rate in duct-ligated and duct-occluded animals was reduced to 1/3 - 1/4 of that of sham operated controls. Fasting blood glucose, fasting insulin, sum of blood glucose and glucose elimination rate during an intravenous glucose tolerance test remained normal in the duct-ligated and Ethibloc-occluded animals. There was a diminished insulin response to a maximal glucose load. In spite of this, the glucose tolerance remained virtually normal. The volume of the pancreas was reduced to 1/3 of its normal size after both experimental procedures. Histologically, the islets appeared to remain normal, while the exocrine portion of the gland was replaced by fibrous tissue. No traces of the active compound, Ethibloc, remained after 4 weeks. This study shows that pancreatic duct occlusion with Ethibloc results in impairment of endocrine function. Consequently, Ethibloc duct occlusion does not seem to be a superior alternative to other methods of producing exocrine atrophy in organs intended for transplantation.     

Hypoglycémie spontanée et insuffisance rénale chronique.

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.     

Adipokine ganglioside GM2 activator protein stimulates insulin secretion

Recently, we identified ganglioside GM2 activator protein (GM2AP) as a novel adipokine, and revealed that treatment of cultured cells with GM2AP impairs insulin signal transduction. The aim of this study was to examine the impact of GM2AP on glucose metabolism in vivo. Injection of recombinant GM2AP in mice significantly lowered blood glucose levels in glucose tolerance tests. Administration of GM2AP to mice for 10 days increased serum insulin levels, whereas the contents of glucose, leptin and FFA were significantly decreased. Stimulation of calcium influx and insulin secretion by GM2AP was observed in hamster insulinoma HIT-T15 cells. Blockage of GM2AP function by specific antibodies inhibited GM2AP-induced insulin secretion. These results provide novel insights into the physiological functions of GM2AP in obesity.     

Myocardial Infarction and Carbohydrate Metabolism Relating to Diabetes Mellitus

Fifteen non-obese males with acute myocardial infarction and no diabetic history were evaluated for diabetes. During infarction, results of oral glucose tolerance tests were “diabetic” or “probably diabetic” in 10 of the 15 patients (67 percent). The plasma immuno-reactive insulin response in 12 patients (80 percent) was of a pattern observed in patients with maturity-onset diabetes. Six months after infarction, follow-up glucose tolerance tests in 12 surviving patients were diabetic or probably diabetic in three cases (25 percent). In seven of twelve patients (58 percent) had delay in the peaking of the plasma insulin response to an oral glucose tolerance test, a phenomenon that is observed in patients with maturity-onset diabetes.Glucose tolerance tests were abnormal in one of fourteen control subjects (7 percent). There was a delayed plasma insulin response to an oral glucose test in two of fourteen controls (14 percent).Patients with myocardial infarction have an increased incidence of diabetes mellitus.     

Glucose tolerance during long term treatment with a somatostatin analogue.

Seven patients with active acromegaly were treated with SMS 201-995, an analogue of somatostatin, for one year, the maximum dose being 100 micrograms three times a day. Three patients had impaired glucose tolerance before treatment, due to insulin resistance in two and insulin deficiency in one. In all patients treatment with the analogue slightly increased postprandial glucose concentrations and suppressed insulin concentrations for two to two and a half hours after each injection; growth hormone concentrations decreased progressively with treatment. The patient with impaired glucose tolerance due to insulin deficiency developed diabetes mellitus after four months'' treatment; concomitant treatment with glibenclamide resulted in a decreased glucose concentration and increased insulin concentration. This analogue of somatostatin had only minor side effects on glucose tolerance in patients with acromegaly and may be used in patients with impaired glucose tolerance provided that glucose concentrations are monitored closely.     

Inhibition of Ca2+-independent phospholipase A2 results in insufficient insulin secretion and impaired glucose tolerance

Islet Ca2+-independent phospholipase A2 (iPLA2) is postulated to mediate insulin secretion by releasing arachidonic acid in response to insulin secretagogues. However, the significance of iPLA2 signaling in insulin secretion in vivo remains unexplored. Here we investigated the physiological role of iPLA2 in beta-cell lines, isolated islets, and mice. We showed that small interfering RNA-specific silencing of iPLA2 expression in INS-1 cells significantly reduced insulin-secretory responses of INS-1 cells to glucose. Immunohistochemical analysis revealed that mouse islet cells expressed significantly higher levels of iPLA2 than pancreatic exocrine acinar cells. Bromoenol lactone (BEL), a selective inhibitor of iPLA2, inhibited glucose-stimulated insulin secretion from isolated mouse islets; this inhibition was overcome by exogenous arachidonic acid. We also showed that iv BEL administration to mice resulted in sustained hyperglycemia and reduced insulin levels during glucose tolerance tests. Clamp experiments demonstrated that the impaired glucose tolerance was due to insufficient insulin secretion rather than decreased insulin sensitivity. Short-term administration of BEL to mice had no effect on fasting glucose levels and caused no apparent pathological changes of islets in pancreas sections. These results unambiguously demonstrate that iPLA2 signaling plays an important role in glucose-stimulated insulin secretion under physiological conditions.     

Beta cell function, peripheral sensitivity to insulin and islet cell autoimmunity in cystic fibrosis patients with normal glucose tolerance

Beta cell function, peripheral sensitivity to insulin and specific pancreatic autoimmunity were studied in 30 youngsters with cystic fibrosis (CF) accurately selected in order to fulfill the criteria for normal glucose tolerance. With respect to weight-matched controls, patients with CF exhibited a significantly lower glucose tolerance and a globally preserved, although delayed, insulin response to oral glucose tolerance test, while first-phase insulin secretion after i.v. glucose was blunted. Peripheral sensitivity to insulin, assessed in vivo by both the euglycemic clamp technique and the number of insulin receptors, directly measured in circulating monocytes, was superimposable in patients and controls. Serum islet-cell antibodies were not found in any of the patients. In conclusion, disorders of beta cell function may be observed in CF patients even when glucose tolerance is within the normal range. Such abnormalities are not associated with changes in peripheral sensitivity to insulin and do not seem to depend on specific autoimmune events.     

Interaction of caerulein, glucose, and amino acids on insulin secretion from the perfused rat pancreas

The effect of caerulein on insulin response to graded amounts of glucose from the isolated perfused rat pancreas was investigated in the presence or absence of an amino acids mixture. Caerulein at a concentration of 0.1 ng/ml which is a submaximal concentration for an effect on exocrine pancreatic secretion potentiated insulin responses to glucose concentrations less than 200 mg/dl, but produced no further increase when added to a glucose stimulus over a 200 mg/dl. However, in the presence of amino acids the insulin response to 200 mg/dl glucose was significantly potentiated by the stimulation of 0.1 ng/ml caerulein. The effectiveness of caerulein as an insulinotropic agent depended on the glucose concentration only when amino acids were present. These results indicate that caerulein, at a concentration which stimulate pancreatic exocrine secretion, has a synergistic effect on insulin response to glucose and amino acids and therefore raises the possibility that endogenously released CCK may contribute to the entero-insular axis.     

Results of long-term biguanide therapy as a preventive measure in protodiabetes]

55 patients with pathological glucose tolerance received a long term treatment with buformin (200 mg daily). In 43 of the protodiabetics the duration of treatment was one year, in 29 of them two years and in 11 three years. The age of the patients was 38 years and the mean relative body weight was 118 per cent. The effect of buformin on glucose tolerance and insulin secretion was tested with the glucose infusion test before and after the periods of treatment. After one year we found in 58 per cent, after two years in 69 per cent and after three years in 64 per cent of the protodiabetics an improvement of glucose tolerance. In these groups the results showed a rise of the IRI in the low responder and a decrease of the IRI in the high responder. The good effects on glucose tolerance were not demonstrable in the compared groups with long-term treatment of diet only.     

Influence of vagotomy on glucose tolerance and on the responses of plasma insulin and exocrine pancreatic function followed glucose load or food ingestion in dogs]

A part of the intrapancreatic nerve fibres of dogs show 1-2 months after bilateral truncal vagotomy a decay of the medullary sheath; in addition, the histochemically demonstrable insulin content of the B-cells is reduced. These animals do no longer react to oral glucose administration or feeding a meat meal with a reflectoric early rise of plasma insulin concentration and of exocrine functional parameters (all the animals were bearing exocrine pancreas fistulas). The glucose tolerance and and the decrease of free fatty acids in serum were restricted. Also, the content of bicarbonate and protein in the pancreatic juice and the insulin secretion of vagotomized animals are strongly reduced in the subsequent test phase (up to 120 min) following oral or i.v. glucose administration and after feeding meat. The inhibition of exocrine volume secretion following i.v. glucose administration was enhanced by the intervention. The findings confirm the involvement of the N. vagus in the mechanisms of the enteroinsular axis that becomes active together with exocrine gastro- and duodenopancreatic reflexes to any kind of physiological enteral stimulation.     

Endogenous opiate modulators of insulin secretion in the obese

The effects of endogenous opiates on insulin response to oral glucose load were studied in obese subjects and in lean healthy volunteers. None of these having a family diabetes. After 3 days on an 1,800 cal./m2, 40% carbohydrate diet all subjects underwent two standard 75 g oral glucose tolerance tests (OGTT), one of which was accompanied by an i. v. administration of 10 mg of, an antagonist of opiates, the naloxone. In one group of obese impaired oral glucose tolerance test occurred. All obese, but not the lean healthy volunteers, showed: 1) increased basal plasma insulin levels, 2) higher insulin response to OGTT, 3) a decrease in insulin response to OGTT after naloxone administration, with significant differences at 60 min (p less than 0.01) and 90 min (p less than 0.025). In none of the subjects significant differences were observed in blood glucose levels after OGTT plus naloxone administration. These data suggest that increased endogenous opiates may affect insulin response to glucose in obese with impaired or normal oral glucose tolerance test. At present there seems to be no satisfactory explanation for unchanged blood glucose levels during OGTT with and without naloxone despite a decrease in insulin secretion in the obese patients.     

Secretin-stimulated amylase release into blood is impaired in type 1 diabetes mellitus.

BACKGROUND: Prior studies have provided data indicating the existence of close interaction between pancreatic endocrine and exocrine function, but few clinical studies have explored this relationship in depth. We compared pancreatic exocrine function non-endoscopically in individuals with type 1 diabetes mellitus, type 2 diabetes mellitus, and normal glucose tolerant controls, to assess the importance of local insulin production to pancreatic exocrine function. METHODS: The plasma amylase response to intravenous secretin challenge was measured in men with type 1 diabetes mellitus (n = 5), type 2 diabetes mellitus (n = 5), and normal controls (n = 3). Patients were characterized by their urinary excretion of c-peptide and albumin over 24 hours. Autonomic neuropathy was non-invasively assessed by measuring RR variation (with deep respiration on EKG). RESULTS: Post-secretin amylase responses were generally absent with low baseline levels in the patients with type 1 diabetes mellitus. Patients with type 2 diabetes mellitus and controls showed similar twofold increases over baseline after secretin administration. When normal glucose tolerant and type 2 diabetic patients were pooled and compared against type 1 diabetes mellitus, the differences were statistically significant (p < 0.03). Total amylase response correlated positively, but weakly, with 24 h urinary C-peptide excretion (r = 0.507; p < 0.112), but not with glycemic control, duration of diabetes, or indices of autonomic neuropathy. CONCLUSIONS: Patients with type 1 diabetes mellitus, but not type 2 diabetes mellitus, have reduced pancreatic exocrine function, supporting the concept of a local paracrine effect of insulin on pancreatic acinar cells. Further studies are needed to determine the clinical impact of this deficiency, and whether such patients with type 1 diabetes mellitus would benefit from therapy with pancreatic enzyme supplementation.     

The mechanism of insulin secretion after oral glucose administration. VII. Exocrine pancreatic function and plasma-IRI in dogs with chronic pancreatic fistulas.

During an intravenous glucose test, conscious dogs with exocrine pancreatic fistulas showed a reduction in the secretions of water, protein and of bicarbonate. This reduction is related to hyperglycemia and to IRI increase in the peripheral venous blood. After oral administration of glucose, however, a biphasic stimulation of the exocrine function was observed. During the first 15 minutes when insulin secretion increases independently of the blood glucose increase, all exocrine pancreatic functions are transiently stimulated, too. A second peak of the exocrine secretions is to be observed when glucose absorption and insulin secretion exhibit their maximum.     

Effects of truncal,selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Part II-Comparison of response to oral and intravenous glucose.

Paired oral and intravenous glucose tolerance tests were carried out in patients who had undergone truncal vagotomy and pyloroplasty, selective vagotomy and pyloroplasty, or highly selective vagotomy at least six months earlier. Intravenous glucose tolerance was similar in all three groups. Oral glucose elicited significantly higher concentrations of plasma insulin in patients who had undergone selective and highly selective vagotomy than in those treated by truncal vagotomy. When the same amount of glucose was given intravenously, however, plasma insulin concentrations were similar in all three groups of patients. The insulin secreted in response to intravenous glucose expressed as a percentage of that secreted in response to oral glucose was 112% for truncal vagotomy, 51% for selective vagotomy, and 52% for highly selective vagotomy. Truncal vagotomy thus led to a diminished insulin response to oral glucose, which was probably due to impaired release of small-bowel hormones.     

Intravenous glucose tolerance, insulin response to glucose, peripheral sensitivity to insulin, and serum lipoproteins in post-myocardial infarct patients with normal fasting blood glucose

Intravenous glucose tolerance (IVGTT), basal insulin and insulin response to glucose infusion (GIT), insulin sensitivity, and lipoprotein patterns were determined in non-obese post-coronary subjects, 3-6 months after myocardial infarction. Twelve had decreased and 31 normal IVGTT. The control group comprised 31 subjects with normal IVGTT, who did not display any signs of coronary disease. The post-coronary patients were not taking any drugs except for furosamide, which was shown not to influence insulin response to GIT or glucose tolerance. Decreased IVGTT in the post-coronary patients could be ascribed to decreased insulin response and insulin resistance. These two derangements are considered as hereditary markers in glucose intolerance and type 2 diabetes. Accordingly, our findings suggest that glucose intolerance in subjects with myocardial infarcts has the same background. The post-coronary patients demonstrated elevated triglycerides (TG) and cholesterol in total serum and in very low density lipoproteins (VLDL), the lipoprotein patterns being almost identical in post-coronary patients with or without decreased IVGTT. No relationship was found in the control and post-coronary groups between IVGTT, basal insulin, stimulated insulin (KI, IP), and insulin sensitivity (KG), on the one hand, and total or VLDL TG or any other lipoprotein particle, on the other. Thus, the derangements in glucose, insulin, and serum triglyceride metabolism were independent abnormalities (risk factors) in these non-obese post-coronary patients.     

First-phase insulin release in adult cystic fibrosis patients: correlation with clinical and biological parameters.

Adult patients with cystic fibrosis (CF) are at high risk for developing insulin-dependent diabetes mellitus. Therefore, the fast insulin release (FIR) to intravenously administered glucose was measured in 23 adult CF patients. The influence of the clinical parameters and type of gene deletion on the amplitude of the FIR, defined by the sum of the 1st- and 3rd-minute insulin concentrations was analyzed. In 11 of the 18 normoglycemic patients with exocrine pancreatic insufficiency and the 3 nontreated diabetic CF patients studied, an FIR value lower than the 3rd percentile was found. The female patients had higher mean FIR values than the male patients (62.8 +/- 39.6 vs. 27.9 +/- 17.9 mU/l; p < 0.05). No influence of age, body mass index, or pulmonary or liver involvement on the FIR was found. Subjects heterozygous for the delta F508 deletion had a similar insulin response as homozygous patients. The FIR level correlated negatively with the basal glucose level (r = 0.4; p < 0.001). In conclusion, 61% of the adult nondiabetic CF patients with exocrine pancreatic insufficiency presented a loss in acute insulin response, which could not be predicted by clinical or genetic parameters.     

Insulin secretion, glycosylated haemoglobin and islet cell antibodies in cystic fibrosis children and adolescents with different degrees of glucose tolerance.

In comparison with 12 weight-matched controls, 39 children and adolescents with cystic fibrosis (CF) showed higher fasting glycaemic levels and both delayed and enhanced blood glucose responses to OGTT. Glycaemic response was normal in 30/39 patients (76.9%), impaired in other 7 cases (18%) and diabetic in the remnant two (5.1%). Fasting insulin levels and total insulin output during OGTT did not differ in patients and controls, but insulin peak in CF group was delayed and sustained. In the whole CF series mean HbA1c was higher than in controls but no difference was found between patients with normal and those with impaired glucose tolerance. Islet cell antibodies were absent in the entire CF group. In conclusion, our results confirm the raised prevalence in CF of glucose tolerance abnormalities, which do not seem to depend on auto-immune factor involvement. Delayed insulin response to OGTT can be considered a very early expression of beta cell impairment in the course of CF. In our experience HbA1c assay did not constitute a sensitive and specific screening test for detection of the C patients with glucose intolerance.     

Plasma Insulin during Remission in Juvenile Diabetes Mellitus

Three juvenile diabetics in partial remission were studied before and after the recurrence of overt diabetes. The remissions were partial because glucose tolerance never returned to normal. However, it improved sufficiently to cause the discontinuance of insulin therapy for at least four months.The insulin output in response to double glucose tolerance tests was increased during remission. The degree of remission seemed to be related to the magnitude of the insulin response to glucose. In two of the patients the increase was low and the response very slight. The third patient, however, had a delayed hyper-response and his carbohydrate tolerance during the remission was much more improved than those of the other patients.     

Seasonal variations in plasma glucose and insulin concentrations after glucose loading in the edible dormouse (Glis glis L.).

Glucose tolerance tests made in the Edible dormouse showed annual variations in B cell secretory capacity, associated with glucose tolerance changes. 1. During autumn and winter, the B cell is sensitive to glucose, and insulin regulates the high peripheral consumption of this hexose. 2. At the beginning of spring, insulin secretion decreases and glucose tolerance is impaired. In June, the B cell response si low or absent and a poor tolerance to glucose still persists. 3. The variations in B cell activity can be related to changing energy requirements during the year.