cholecystokinin and Diabetes-Mellitus

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

Although some controversy exists, diabetic patients generally are thought to have a two- to threefold increased risk of cholesterol gallstones. From previous studies there is no convincing evidence for a supersaturated bile in diabetics, whereas several reports indicate that impaired gall-bladder emptying could be one of the important factors in the increased incidence of gallstones in diabetics. However, studies of gall-bladder motility in diabetics have yielded conflicting results, probably because of substantial heterogeneity in the patients studied, emptying stimulus and technique used to assess gall-bladder motor function. The mechanism of the gall-bladder emptying abnormality in diabetics is not completely understood, although it has been proposed that it could represent a manifestation of denervation caused by visceral neuropathy. Based on normal post-prandial cholecystokinin release, it can be ruled out that impaired cholecystokinin release is the mechanism responsible for reduced gall-bladder emptying in diabetics. Other possible explanations for impaired gall-bladder contraction in diabetics include a decreased sensitivity of the smooth muscle of the gall-bladder to plasma cholecystokinin, and/or decreased cholecystokinin receptors on the gall-bladder wall.

Topics: Cholecystokinin; Cholelithiasis; Diabetes Complications; Diabetes Mellitus; Gallbladder; Gastrointestinal Motility; Humans; Muscle, Smooth; Postprandial Period; Receptors, Cholecystokinin

Topics: Appetite; Cholecystokinin; Corticotropin-Releasing Hormone; Diabetes Mellitus; Endorphins; Gastrointestinal Hormones; Hormones; Humans; Peptides

Topics: Cholecystokinin; Diabetes Mellitus; Endocrine Glands; Endocrine System Diseases; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Male; Somatostatin; Thyroid Diseases

Cerebral capillary endothelium forms a barrier limiting and controlling the movement of ions and solutes between blood and brain. Recent anatomical, physiological and biochemical studies have suggested the possibility that capillary function may be directly controlled by neuronal structures. Alterations in neuronal systems involved in the regulation of microcirculation may account for microvascular dysfunctions which occur in different pathologic conditions.

Topics: Acetylcholine; Aging; Animals; Biological Transport, Active; Blood-Brain Barrier; Brain; Capillaries; Capillary Permeability; Cerebrovascular Circulation; Cholecystokinin; Diabetes Mellitus; Dopamine; Endothelium; Histamine; Hypertension; Hypoxia, Brain; Locus Coeruleus; Microcirculation; Neural Pathways; Neurons; Norepinephrine; Receptors, Neurotransmitter; Serotonin; Substance P; Vasoactive Intestinal Peptide

Information concerning GEP hormones has progressively advanced since the initial discovery of a GEP hormone, secretin, in 1902. Studies in this area flourished with the advent of radioimmunoassay, and have provided an understanding of the secretion, regulation, metabolic actions, and role in certain diseases of major GEP hormones. Measurement of GEP hormones has achieved importance in clinical medicine and allowed understanding of the pathophysiology of several clinical disorders. The decade to come should witness additional advances in this rapidly expanding field.

Topics: Chemical Phenomena; Chemistry; Cholecystokinin; Diabetes Mellitus; Diarrhea; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Motilin; Neoplasms; Neurotensin; Pancreatic Polypeptide; Peptic Ulcer; Secretin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Chenodeoxycholic Acid; Cholecystokinin; Cholelithiasis; Dehydration; Diabetes Mellitus; Duodenal Ulcer; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Motilin; Pancreatic Neoplasms; Secretin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Carbohydrate Metabolism; Cholecystokinin; Diabetes Mellitus; Digestion; Gastrointestinal Hormones; Glucagon; Humans; Radioimmunoassay; Secretin; Somatostatin; Vasoactive Intestinal Peptide

Topics: Abdomen; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Diabetes Mellitus; Hepatomegaly; Humans; Jaundice; Laparotomy; Mental Disorders; Pain; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Prednisolone; Prognosis; Radioisotopes; Radionuclide Imaging; Secretin; Selenium

Topics: Cholecystokinin; Diabetes Mellitus; Gastrointestinal Hormones; Glucagon; Humans; Intestinal Secretions; Pancreatic Hormones; Peptides; Secretin

Topics: Animals; Biogenic Amines; Carcinoid Tumor; Cholecystokinin; Chromaffin System; Diabetes Mellitus; Digestive System; Digestive System Physiological Phenomena; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Intestines; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Secretin; Syndrome

Topics: Animals; Cholecystokinin; Diabetes Mellitus; Duodenum; Gastrins; Gastrointestinal Hormones; Glucose; Glucose Tolerance Test; Humans; In Vitro Techniques; Islets of Langerhans; Rats; Secretin; Serotonin; Tissue Extracts

Topics: Acute Disease; Amylases; Bicarbonates; Cholecystokinin; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Humans; Insulin; Islets of Langerhans; Lipase; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Secretin

Topics: Animals; Arginine; Blood Glucose; Cholecystokinin; Cyclic AMP; Diabetes Mellitus; Dietary Proteins; Digestive System Physiological Phenomena; Gastrins; Glucagon; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Portal System; Postgastrectomy Syndromes; Regional Blood Flow; Secretin; Serotonin

Topics: Cholecystokinin; Diabetes Mellitus; Fatty Acids, Essential; Gastrins; Gastrointestinal Hormones; Glucagon; Glucose; Humans; Islets of Langerhans; Secretin

Topics: Amino Acids; Animals; Autonomic Nervous System; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Dietary Carbohydrates; Dietary Proteins; Gastrectomy; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Glucagon; Glucose; Humans; Hypoglycemia; In Vitro Techniques; Insulin; Insulin Secretion; Intestinal Mucosa; Islets of Langerhans; Microcirculation; Portal System; Secretin

Topics: Autoantibodies; Autoimmune Diseases; Cholecystokinin; Diabetes Mellitus; Gastrins; Gastrointestinal Hormones; Glucagon; Glucose; Humans; Insulin; Secretin; Trace Elements

To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes.. A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design.. Forty-three overweight patients with Type 2 diabetes (age 18-65 y, body mass index (BMI) 27.2-48.2 kg/m2).. Body weight, BMI, body fat, waist and hip circumference, waist/hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin/glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite.. Subjects given cimetidine (n = 19) and placebo (n = 24) lost 5.0 +/- 2.2 kg (mean +/- s.d.) and 1.3 +/- 1.1 kg, respectively. Significant reductions were observed in appetite, body fat (29.9 +/- 6.6% to 25.3 +/- 7.4%), waist circumference (111.5 +/- 10.3 cm to 107.4 +/- 10.6 cm), waist/hip ratio (0.96 +/- 0.08 to 0.94 +/- 0.08), and systolic and diastolic blood pressure (reductions of 6.9 +/- 11.4 mm Hg and 6.0 +/- 6.6 mm Hg, respectively) in cimetidine group only. Significant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin/glucose ratio, plasma triglycerides and a significant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only.. Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Constitution; Cholecystokinin; Cholesterol, HDL; Cimetidine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Histamine H2 Antagonists; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Triglycerides; Weight Loss

Diabetes mellitus induces neuropsychiatric comorbidities at an early stage, which can be ameliorated by exercise. However, the neurobiological mechanisms underlying this ameliorative effect remain unclear. The present study was conducted in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which develop diabetes with age, and aimed to investigate whether social and anxiety-like behaviors and neurobiological changes associated with these behavioral phenotypes were reversed by voluntary exercise and whether those were maintained in the later stage. We investigated the effects of exercise at different diabetic stages in OLETF rats by comparing with control rats. Three groups of OLETF rats were used: sedentary rats, rats exercising on a wheel for two weeks at 4-5 weeks of age (early voluntary exercise), and those exercising at 10-11 weeks of age (late voluntary exercise). In the elevated plus-maze test, both early and late voluntary exercises did not affect anxiety-like behavior. In the social interaction tests, both early and late voluntary exercises ameliorated impaired sociability, novel exploration deficits, and hypoactivity in OLETF rats. Both early and late voluntary exercises reversed the increases in cholecystokinin-positive neuron densities in the infralimbic cortex and hippocampal cornu ammonis area 3 in the OLETF rats, although they did not affect the area-reduction in the medial prefrontal cortex and the increase in cholecystokinin-positive neuron densities in the basolateral amygdala. These suggest that voluntary exercise has therapeutic effects on impaired sociability and novel exploration deficits associated with cholecystokinin-positive neurons in specific corticolimbic regions in OLETF rats, and those are maintained after early exercise.

Topics: Animals; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Neurons; Rats; Rats, Inbred OLETF; Social Behavior

Topics: Adult; Aged; Anti-Obesity Agents; Appetite Regulation; Blood Glucose; Cholecystokinin; Cholesterol, HDL; Diabetes Mellitus; Female; Hemoglobins; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Obesity; Phenotype; Receptors, Cholecystokinin; Reference Values; Satiation; Signal Transduction; Triglycerides

To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents.. A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep(ob) /Lep(ob) mice for 28 days, and metabolic variables were assessed.. Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lep(ob) /Lep(ob) mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups.. The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Topics: Acetylation; Animals; Anti-Obesity Agents; Cholecystokinin; Diabetes Mellitus; Diet, High-Fat; Drug Synergism; Drug Therapy, Combination; Energy Intake; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Infusions, Subcutaneous; Islet Amyloid Polypeptide; Male; Mice, Mutant Strains; Obesity; Peptides; Random Allocation; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Glucagon; Weight Loss

Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

Topics: Animals; Chemokines, CC; Chemotaxis; Cholecystokinin; Diabetes Mellitus; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Intercellular Adhesion Molecule-1; Kidney; Macrophages; Male; Mice; Mice, Knockout; NF-kappa B; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Tumor Necrosis Factor-alpha

Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.. The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.. (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.. These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

Topics: Animals; Cholecystokinin; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Glucose; Homeostasis; Insulin Resistance; Male; Mice; Mice, Obese; Obesity; Sincalide

Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity.

Topics: Animals; Cell Lineage; Cell Separation; Cholecystokinin; Diabetes Mellitus; Enteroendocrine Cells; Flow Cytometry; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Green Fluorescent Proteins; Humans; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Transgenic; Neurotensin; Obesity; Peptide YY; Promoter Regions, Genetic

An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/ob) mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.

Topics: Animals; Cell Count; Cell Survival; Cells, Cultured; Cholecystokinin; Diabetes Mellitus; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Organ Size; Up-Regulation

To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin/IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1beta and IL-6 but not TNF-alpha. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1beta. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1beta and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-1RA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by up-regulating brain expression of IL-1beta antagonists.

Topics: Animals; Brain; Cells, Cultured; Cholecystokinin; Diabetes Mellitus; Eating; Exploratory Behavior; Humans; Hypoglycemic Agents; Immune System; Insulin-Like Growth Factor I; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Sialoglycoproteins; Signal Transduction; Tumor Necrosis Factor-alpha; Vagus Nerve; Vanadium Compounds

Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lepob) and leptin-resistant (Lepdb) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We hypothesize that myocytes from Lepob and Lepdb obese mice would not respond normally to neurotransmitters.. Cholecystectomy was performed on 39 lean, 19 Lepob, and 20 Lepdb 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40).. Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lepdb mice compared to controls (P < .001). Resting myocyte lengths from Lepob and Lepdb mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh.. These data suggest that gallbladder myocytes from obese mice are (1) foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin.

Topics: Acetylcholine; Animals; Blood Glucose; Body Weight; Cholecystokinin; Diabetes Mellitus; Female; Gallbladder; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Contraction; Myocytes, Smooth Muscle; Obesity

We compared the antinociceptive activity of a kappa-opioid agonist, U-50488H, in streptozotocin-induced diabetic mice with that in non-diabetic mice. Subcutaneously administered U-50488H (3 and 10 mg kg(-1)) showed a more potent antinociceptive effect, as evaluated by the tail-pressure method, in diabetic mice than in non-diabetic mice. Increased antinociceptive activity of U-50488H observed in diabetic mice was also observed in mice given U-50488H intrathecally (3 and 10 microg). However, there were no differences observed between diabetic and non-diabetic mice given U-50488H intracerebroventricularly (3 and 10 microg). Although the antinociceptive effect of U-50488H (3 mg kg(-1), s.c.) in non-diabetic mice was increased by treatment with PD135158 (100 ng, i.c.v.), a cholecystokininB (CCKB) antagonist, the antinociceptive activity of U-50488H which was enhanced in diabetic mice was not influenced by PD135158. Moreover, the increased antinociceptive activity of U-50488H (3 mg kg(-1), s.c.) in diabetic mice diminished when desulfated octapeptide of cholecystokinin (3-100 ng, i.c.v.), a CCKB agonist, was administered. These results suggested that diabetic mice were selectively hyper-responsive to spinal kappa-opioid receptor-mediated antinociception. The function of the analgesia inhibitory system in which cholecystokinin is used as a transmitter might be diminished in diabetic mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Cholecystokinin; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Pain; Streptozocin

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

Topics: Animals; Cholecystokinin; Diabetes Mellitus; In Vitro Techniques; Pancreas; Rats; Rats, Inbred Strains

The present study was undertaken to investigate postprandial responses of cholecystokinin (CCK) and pancreatic polypeptide (PP) and their interrelationship in patients with diabetes mellitus (DM) with and without autonomic neuropathy (AN). Twenty-two patients with DM (seven with AN and 15 without AN) and 14 age-matched healthy controls were studied. AN was diagnosed according to several tests of cardiovascular autonomic function. CCK and PP plasma levels were measured by specific radioimmunoassays before and at several time points after the oral administration of a test meal. Basal CCK plasma levels in DM patients were normal, whereas basal PP plasma levels were increased (139 +/- 18 vs 72 +/- 7 pg/ml; P < 0.01). Integrated postprandial CCK response was increased in DM patients (208 +/- 27 vs 110 +/- 14 pmol/liter/2 hr; P < 0.05), mainly due to the patients with AN. Postprandial PP response was increased in DM patients without AN (37,273 +/- 5241 vs 13,418 +/- 3299 pg/ml/2 hr; P < 0.001) but not in those with AN (8887 +/- 3461 pg/ml/2 hr). Moreover, PP response was closely (P < 0.002) correlated with the degree of AN. A direct and linear correlation between postprandial CCK and PP responses was found in healthy controls (r = 0.78; P < 0.005) but not in DM patients. We conclude that the CCK response to a meal is increased in diabetic patients with AN, whereas the PP response is increased only with an intact autonomic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cholecystokinin; Diabetes Mellitus; Diabetic Neuropathies; Eating; Female; Humans; Male; Middle Aged; Pancreatic Polypeptide; Radioimmunoassay; Statistics, Nonparametric; Time Factors

The reduced decrease of plasma alpha-amino nitrogen after hormonal stimulation of the pancreas has been characterized as a valid and simple test of pancreatic function. Aim of this study was to reassess the clinical value of the alpha-amino nitrogen test and to evaluate the role of different modes of hormonal secretion. Therefore, we have investigated the relationship of plasma alpha-amino nitrogen responses and pancreatic secretion, stimulated by either bolus injection (n = 25) or continuous infusion (n = 32) of cholecystokinin-pancreozymin in patients with and without exocrine pancreatic insufficiency as determined by the secretin-pancreozymin test. Of the 57 patients referred to the secretin-pancreozymin-test, 18 had pancreatic insufficiency, each 9 in the group with continuous and bolus stimulation.. Basal alpha-amino nitrogen concentrations were almost identical in patients with and without impaired pancreatic function (2.66 +/- 0.12 mmol/l vs. 2.73 +/- 0.08 mmol/l [SEM]; p > 0.05). Both, the bolus dose and infusion of cholecystokinin induced similar (log-normally distributed) maximum decreases of alpha-amino nitrogen concentrations (-SD; mean; + SD: 3.6; 9.0; 22.3% vs. 6.0; 10.5; 18.5%, respectively) in the patients without exocrine pancreatic insufficiency. This was in tendency more pronounced compared to those with impaired pancreatic secretion (cholecystokinin bolus; 2.7; 5.2; 9.9%; infusion: 5.0; 7.7; 11.6%). The difference (+/- exocrine pancreatic insufficiency) was significant (p < 0.05) for the infusion mode only. Moreover, the time course of alpha-amino nitrogen concentration-profiles was more homogenous after hormone infusion as compared to bolus stimulation. Sensitivities to detect exocrine pancreatic insufficiency by the alpha-amino nitrogen test were < 50% with either test modification.. The decrease of plasma alpha-amino nitrogen after stimulation with cholecystokinin is no accurate indicator of exocrine pancreatic function, regardless of whether hormonal stimulation is by bolus or by infusion.

Topics: Adult; Aged; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Exocrine Pancreatic Insufficiency; Humans; Infusions, Intravenous; Middle Aged; Pancreatic Function Tests; Pancreatic Juice; Pancreatitis; Reference Values; Secretin

To further elucidate the mechanism of impaired gallbladder emptying in diabetics with and without neuropathy, gallbladder function was assessed by ultrasonography following a medium-chain triglyceride (lipomul, 1.5 mg/kg) infusion into the duodenum and compared to that during intravenous infusion of cholecystokinin in diabetic women. Results were compared with five healthy control women. Mean (+/- SD) maximal percent gallbladder volume in diabetics following lipomul was reduced to 49 +/- 8% and after intravenous cholecystokinin to 47 +/- 9%, which was less than those in controls, 21 +/- 9% and 24 +/- 6%, respectively, but not significantly different. Further analysis of gallbladder emptying to lipomul differentiated two subgroups of diabetics: one subgroup (N = 5) had emptying comparable to controls (responders), while the other (N = 5) had very modest emptying (nonresponders). Two of the patients in the latter group had normal gallbladder emptying during exogenous cholecystokinin and their response would be compatible with visceral neuropathy. Blood levels of cholecystokinin, measured by bioassay, following lipomul and exogenous cholecystokinin were similar in controls and diabetics. Presence of diabetic neuropathy did not correlate with impaired gallbladder emptying. Follow up at 6 and 12 months of the three nonresponder diabetics revealed that no gallstones had developed and that two of them became responders to exogenous cholecystokinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Autonomic Nervous System Diseases; Cholecystokinin; Cholelithiasis; Corn Oil; Diabetes Mellitus; Diabetic Neuropathies; Female; Follow-Up Studies; Gallbladder; Gallbladder Emptying; Humans

A bioassay using dispersed pancreatic acini was used to measure fasting plasma cholecystokinin (CCK) concentrations in 105 patients with various kinds of gastrointestinal diseases, 17 patients with diabetes mellitus, and 6 healthy volunteers. High plasma CCK bioactivities were observed in patients with obstructive jaundice, choledocolithiasis, and primary biliary cirrhosis. Twenty-three samples with high CCK bioactivities were assayed by the same bioassay after the addition of a specific CCK antagonist and by a CCK radioimmunoassay in order to determine whether the high CCK-like bioactivity was due to circulating CCK or other factors. High CCK bioactivities were partially inhibited by the specific CCK antagonist, CR-1409, but the activities were not totally abolished. The residual bioactivities (not inhibited by CR-1409) correlated with plasma bile acid concentrations. The inhibitable CCK bioactivities correlated with plasma CCK levels obtained by radioimmunoassay. Although the bioassay using dispersed pancreatic acini has several advantages for measuring plasma CCK, this method overestimates CCK bioactivities in patients with high plasma bile acid concentrations.

Topics: Animals; Bile Acids and Salts; Biological Assay; Cholecystokinin; Diabetes Mellitus; Gastrointestinal Diseases; Humans; Pancreas; Proglumide; Radioimmunoassay; Rats; Rats, Inbred Strains

Insulinemia, concentration of C-peptide and glucagon in the blood was studied in chronic hepatitis patients showing moderate tolerance disorders to glucose and diabetes mellitus developed against the background of chronic pancreatitis. Both groups showed hyperglucagonemia. Basal hypoinsulinemia and reduction of the C-peptide level revealed only in patients suffering of chronic pancreatitis with secondary diabetes mellitus. Reduced reaction of beta-cells of the pancreas to physiologic stimulation by pancreosozymin were observed also in less significant disorders of tolerance to glucose. The authors discuss the significance of changes in the sequential development of different degrees of disorders of the carbohydrate metabolism in patients with chronic recurrent pancreatitis.

Topics: C-Peptide; Carbohydrate Metabolism; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Glucagon; Humans; Insulin; Islets of Langerhans; Pancreatitis; Recurrence

Topics: Biological Assay; Brain; Cholecystokinin; Cholestasis; Chronic Disease; Diabetes Mellitus; Humans; Intestinal Mucosa; Pancreatitis; Radioimmunoassay; Specimen Handling; Tissue Distribution

Contractile motility of the gallbladder and plasma cholecystokinin (CCK) responses to egg yolk administration were studied in 28 diabetic patients and 12 normal subjects. The patients were divided into three groups: group A (n = 10) had no diabetic neuropathy, group B (n = 8) had diabetic neuropathy with little autonomic neuropathy, and group C (n = 10) had advanced diabetic autonomic neuropathy. In groups A and B, contraction of the gallbladder after egg yolk administration was not significantly different from that of normal subjects. However, in group C, gallbladder contraction was impaired (p less than 0.01-0.05), compared with that in normal subjects. After the administration of egg yolk, plasma CCK levels increased from 12.4 +/- 4.5 to 25.3 +/- 12.0 pg/ml in normal subjects. In group A, plasma CCK levels increased from 17.9 +/- 8.5 to 39.3 +/- 14.2 pg/ml, and in group B, from 15.2 +/- 5.1 to 38.3 +/- 9.9 pg/ml. In group C, however, plasma CCK levels increased from 33.1 +/- 13.9 to 72.4 +/- 31.9 pg/ml, and fasting CCK levels and responses to egg yolk were significantly higher than those in normal subjects and in groups A and B (p less than 0.01-0.05). In conclusion, this study showed that in a group of diabetic patients with autonomic neuropathy, gallbladder contraction was impaired despite the exaggerated CCK response to egg yolk.

Topics: Adult; Autonomic Nervous System Diseases; Cholecystokinin; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Egg Yolk; Fasting; Female; Gallbladder; Humans; Male; Middle Aged

Topics: Cholecystokinin; Chronic Disease; Diabetes Mellitus; Hepatitis, Viral, Human; Humans; Liver Circulation; Pancreatitis; Pentagastrin; Plethysmography, Impedance

Gastrin/CCK immunoreactivity appears to be widely distributed throughout the mammalian CNS, being most abundant in the cerebral cortex [Vanderhaeghen et al. 1975; Straus et al. 1977; Beinfeld et al. 1981]. Besides its putative role as a co-transmitter in dopaminergic neurotransmission [Hökfelt et al. 1980], cholecystokinin is apparently involved in the central regulation of appetite and satiety [Gibbs et al. 1973; Antin et al. 1975; Parret and Batt 1980; Smith 1980; Smith and Gibbs 1981] Furthermore, it has been shown that the brain concentration of the peptide is decreased in genetically obese mice as compared to non-obese animals [Strauss and Yalow 1979]. The sand rat (Psammomys obesus) is a desert rodent which tends to become diabetic when it is fed with normocaloric diet and restricted in movement [Haines et al. 1965; Hahn et al. 1971]. However, the usefulness of this animal as a paradigm of diabetes is now being revised, since because in its typical expression this metabolic dysfunction appears to be an obesity syndrome [Rice and Robertson 1980]. Therefore, it seems to be necessary to study the distribution of gastrin/CCK-immunoreactive nerve cells in the brain of normal and diabetic (obese) sand rats to get further information about mechanism underlying the development of this form of diabetes.

Topics: Animals; Arvicolinae; Cell Count; Cerebral Cortex; Cholecystokinin; Diabetes Mellitus; Gastrins; Immunoenzyme Techniques; Neurons; Obesity; Rabbits

It has been claimed that plasma cholecystokinin (CCK) concentrations are raised in patients with pancreatic insufficiency. We have measured plasma CCK concentrations in 32 patients with pancreatic insufficiency (22 alcoholic pancreatitis and 10 cystic fibrosis) and in 30 normal subjects by radioimmunoassays using antibodies with different specificities. Antibody 1703 binds to COOH-terminal forms of CCK containing at least 14 amino acid residues and does not cross-react with gastrins. Antibody T204 binds to all CCK-peptides containing the sulfated tyrosyl region and shows low cross-reactivity with sulfated gastrins but no binding to nonsulfated gastrins. Antibody 5135 binds to all COOH-terminal CCK-peptides and shows full cross-reactivity with gastrins. In patients with pancreatic insufficiency, plasma CCK concentrations (1.2 +/- 0.1 pmol/liter, antibody 1703; 2.0 +/- 0.2 pmol/liter, antibody T204; 12.5 +/- 1.4 pmol/liter, antibody 5135) were not significantly different from those in normal subjects (1.1 +/- 0.1 pmol/liter, antibody 1703; 2.2 +/- 0.3 pmol/liter, antibody T204; 10.5 +/- 0.9 pmol/liter, antibody 5135). Furthermore, plasma CCK concentrations in patients with pancreatic insufficiency due to alcoholic pancreatitis (1.2 +/- 0.1 pmol/liter, antibody 1703; 1.9 +/- 0.2 pmol/liter, antibody T204; 14.0 +/- 1.9 pmol/liter, antibody 5135) were not significantly different from those in patients with cystic fibrosis (1.2 +/- 0.2 pmol/liter, antibody 1703; 2.4 +/- 0.4 pmol/liter, antibody T204, 9.1 +/- 1.0 pmol/liter, antibody 5135). Cross-reactivity with gastrin accounted for almost all CCK-like-immunoreactivity measured with antibody 5135.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Alcoholism; Antibodies; Antibody Specificity; Binding Sites, Antibody; Cholecystokinin; Cross Reactions; Cystic Fibrosis; Diabetes Mellitus; Exocrine Pancreatic Insufficiency; Female; Gastrins; Humans; Male; Middle Aged; Pancreatitis; Radioimmunoassay

Topics: Adolescent; Adult; Amylases; Cholecystokinin; Diabetes Mellitus; Female; Humans; Insulin; Male; Pancreas; Pancreatic Function Tests

These studies, therefore, allow a model of how CCK and insulin regulate the acinar pancreas in a coordinated manner (Fig. 27). CCK, after its secretion by gut cells, interacts with a specific receptor on the cell surface and then increases intracellular free Ca2+. Ca2+, in turn (1) interacts with the secretory granules leading to zymogen release, (2) stimulates protein synthesis, and (3) increases glucose transport. The model is supported on the finding of specific high affinity CCK receptors on acini and by the localization of CCK to the plasma membrane in EM autoradiographs. Insulin, secreted from the pancreatic islets, also interacts with a specific receptor on the cell surface. Either via a messenger generated by this reaction, or via insulin's subsequent direct interaction with intracellular organelles, such as the Golgi-endoplasmic reticulum, protein synthesis is initiated and glucose transport is increased. Then a series of events is initiated to increase cell growth, amylase content, and sensitivity to CCK. These studies, therefore, indicate that the control of acinar cell function is a product of cooperative intrahormonal interactions.

Topics: Amylases; Animals; Cholecystokinin; Diabetes Mellitus; Humans; Membrane Proteins; Molecular Weight; Pancreas; Pancreatic Juice; Receptor, Insulin; Receptors, Cell Surface; Ribonucleases

The role of extracellular Ca2+ in mediating the stimulatory effect of cholecystokinin octapeptide (CCK8) on [3H]phenylalanine incorporation into protein was studied in isolated pancreatic acini from streptozotocin-diabetic rats. The stimulatory effect of CCK8 (10(-10) M) on [3H]phenylalanine incorporation was completely abolished by preincubating acini with either 10(-4) M lanthanum or 10(-3) M manganese. At these concentrations neither compound altered the basal rate of amino acid incorporation, and both compounds inhibited CCK-mediated Ca2+ influx without affecting either basal or CCK-mediated 45Ca2+ efflux. Lanthanum (10(-4) M) also blocked the stimulatory effect of the cholinergic analogue carbachol (10(-5) M) on amino acid incorporation but did not alter the stimulatory effect of insulin (1.67 x 10(-8) M). Vasoactive intestinal polypeptide and 12-O-tetradecanoyl-phorbol-13-acetate failed to increase the incorporation of [3H]phenylalanine into acinar protein. These findings suggest that CCK and other pancreatic secretagogues that act via Ca2+ enhance protein synthesis by increasing cell membrane permeability to Ca2+ and provide additional evidence that this may be an important mechanism by which CCK regulates pancreatic exocrine function.

Topics: Animals; Biological Transport; Calcium; Carbachol; Cholecystokinin; Cycloleucine; Diabetes Mellitus; Insulin; Islets of Langerhans; Kinetics; Lanthanum; Male; Manganese; Peptide Fragments; Phenylalanine; Protein Biosynthesis; Rats; Rats, Inbred Strains; Sincalide

Topics: Animals; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Digestion; Eating; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Humans; Hypothalamus; Insulin; Insulin Secretion; Intestinal Absorption; Nutritional Physiological Phenomena

Topics: Adult; Antipyrine; Biotransformation; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Hepatitis; Humans; Liver; Metabolic Clearance Rate; Pancreatitis

Topics: Adolescent; Adult; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 1; Humans; Middle Aged; Pancreas; Pancreatic Function Tests; Secretin

Topics: Amylases; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 1; Glycosuria; Isoenzymes; Pancreas; Salivary Glands; Secretin

Fasting serum trypsin concentration and pancreatic trypsin output, stimulated by secretin and cholecystokinin-pancreozymin, were measured in 18 patients with insulin-dependent diabetes, to assess a possible correlation between these two indices of exocrine pancreatic function. Serum trypsin concentration was subnormal in 13, and pancreatic trypsin output was decreased in 14 patients, but there was no significant correlation between the two measurements. There was no correlation between serum trypsin and residual beta cell function measured by plasma C-peptide immunoreactivity (CPR). After an interval of four years serum trypsin measurements were repeated in 11 subjects. All individual trypsin levels were lower than the previous results, the difference being highly significant (t = 9.0; p < 0.001). Serum trypsin concentration therefore represents a qualitative index of reduced exocrine pancreatic function in diabetes, but has no value in quantitating the degree of deficiency.

Topics: Adolescent; Adult; Cholecystokinin; Diabetes Mellitus; Fasting; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pancreas; Secretin; Trypsin

A follow-up investigation of 20 patients, surgically treated for acute haemorrhagic necrotising pancreatitis, was performed in an average of 2 3/4 years after the operation. Twelve patients showed manifest diabetes mellitus, four further cases had a suspicious oral glucose tolerance test. Only one patient was insulin dependent. A secretin-pancreozymin test performed in 15 patients showed a dissociated or global pancreatic insufficiency in 13 cases. The extent of the endocrine and exocrine functional disturbance did not correlate with the extent of surgery. Postoperative functional defects were readily improved therapeutically in most cases. Only in patients who continued to consume alcohol were there digestive disturbances. The results indicate that the functional state of the remaining pancreas does not only depend on the extent of surgery but also on the extent of already existing or persisting toxic inflammatory damage and on the regenerative capacity of the remaining parenchyma.

Topics: Acute Disease; Cholecystokinin; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Necrosis; Pancreatic Diseases; Pancreatitis; Postoperative Complications; Secretin

Topics: Cholecystokinin; Chronic Disease; Diabetes Mellitus; Glucagon; Humans; Insulin; Male; Pancreatitis; Secretin

We studied insulin responses to glucose with and without cholecystokinin-pancreozymin and aminophyllin infusions in normal, chronic pancreatitic and genetic (maturity-onset) diabetic subjects. Glucose was given alone as separate 5 and 10 g boluses followed by infusion at 250 mg/min. and 500 mg/min., respectively. Chronic pancreatitis patients and genetic diabetic patients had decreased Imax values, indicating a decreased insulin reserve. Sensitivity to glucose was normal in pancreatitic subjects, but the diabetic subjects had a raised G50 value, compatible with glucoreceptor dysfunction. Infusions of aminophyllin enhanced insulin responses (Imax) to glucose injection in normal subjects and to a lesser degree in pancreatitic subjects, but decreased sensitivity to glucose (increase in G50) in both groups. Although the Imax value in pancreatitic subjects was significantly lower than in the control subjects during the glucose plus aminophyllin infusion, the blood glucose concentration in the pancreatitic subjects was nonetheless decreased. This suggests that pancreatitic subjects have increased endogenous insulin sensitivity. Aminophyllin had no effect in diabetic subjects. Crude cholecystokinin-pancreozymin changed the shape of the glucose/insulin dose response curve in normal, pancreatitic and diabetic subjects. These findings further suggest that the defect in insulin secretion in pancreatitic subjects is partly situated at the cyclic adenosine monophosphate stage of insulin release. Crude cholecystokin-pancreozymin seems to affect insulin release at a point beyond the cyclic adenosine monophosphate stage.

Topics: Adult; Aminophylline; Cholecystokinin; Chronic Disease; Cyclic AMP; Diabetes Mellitus; Gastrointestinal Hormones; Glucose; Humans; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Pancreatitis; Receptors, Drug

Topics: Animals; Cholecystokinin; Diabetes Mellitus; Humans; Insulin; Pancreatitis; Rats; Secretin

After a review of the literature the author's results of testing pancreatic function in 445 patients with different diseases are reported. The activities of serum amylase and lipase were estimated before and after stimulation with secretin and pancreozymin; at the same time exocrine secretions of the pancreas were collected in the duodenum and analyzed. Serum enzyme activity did not change markedly after stimulation in pronounced pancreatic insufficiency. Measuring the enzyme activity thus helped to make the diagnosis only in a few cases with chronic pancreatitis and pancreatic carcinoma. In all other patients there was no correlation between changes of serum enzyme activities and changes of exocrine pancreatic function. Pathological test results, that means an increase in enzyme activity after stimulation, were found not only in patients with established or suspected pancreatic diseases, but also in many other subjects. Thus the diagnostic relevance of these tests seems to be rather limited, since it does not prove or exclude with sufficient specificity or adequate probability the presence of pancreatic diseases; it therefore cannot be recommended for screening purposes.

Topics: Amylases; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Enzymes; Gastrointestinal Diseases; Humans; Kidney Failure, Chronic; Lipase; Liver Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

In this study, 37 guinea pigs were classified, on the basis of histologic examination of the pancreas, into three categories: nondiabetic, latent diabetic, and overt diabetic. In order to compare the exocrine pancreatic function in these three groups of animals, pancreatic secretion was collected from each animal following an intravenous infusion of secretin and pancreozymin. Pancreatic enzyme activity, bicarbonate concentration, and the total volume of pancreatic secretion were all significantly decreased in guinea pigs with overt diabetes, but not in those with latent diabetes mellitus. Pancreatic histologic changes characteristic of both latent and overt diabetes were beta-cell hyperplasia and generalized fatty degeneration of the acini. Only the animals with overt diabetes showed total degranulation and severe vacuolation of theta-cells. The same type of exocrine pancreatic dysfunction observed in guinea pigs with spontaneous overt diabetes mellitus is found in human diabetics, and is particularly common in the juvenile type. The guinea pig, therefore, appears to be a suitable animal model for the study of human juvenile diabetes mellitus.

Topics: Amylases; Animals; Bicarbonates; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Disease Models, Animal; Guinea Pigs; Islets of Langerhans; Lipase; Male; Pancreas; Secretin; Trypsin

A dynamic study of scintigraphy of the pancreas using 75Se-selenomethionine in diabetic patients was performed. Patients were selected who complained of abdominal pain or diarrhea or both and whose pancreatic exocrine functions were thought to be disturbed. Selenium-75-selenomethionine (3 muCi/kg body weight) was injected intravenously and radioactivity (cpm) was recorded by a scinticamera for 10 min successively up to 120 min. After 20-30 min the increase of radioactivity in the selected area of the displayed pancreas usually reached a plateau. Pancreozymin (1 Harper unit/kg) and secretin (1 harper unit/kg) were administered intravenously and decrease of radioactivity in the same area was followed for 60 min to examine pancreatic exocrine function. After 75Se-selenomethionine injection, the angle of the initial increase of radioactivity, the height of the plateau, and the reactive decrease of radioactivity after pancreozymin and secretin were analyzed in each case. Radioactivity recorded on data tape was reproduced for each 10-min period on a cathode-ray tube display. Areas of interest were selected for dynamic analyses. To supplement the diagnosis by visual image of a scintigram of the pancreas, the scintigram was quantified in the present study and the dynamic curves of radioactivity in the selected area of the displayed pancreas were studied for a total of 3 hr. Application of the dynamic study of the pancreas scintigraphy and the additional data analyses seemed useful for the early detection of pancreatic exocrine dysfunction in diabetic patients in whom the ordinary laboratory pancreatic exocrine function tests gave uncertain results.

Topics: Adult; Aged; Cholecystokinin; Diabetes Mellitus; Female; Humans; Male; Methionine; Middle Aged; Pancreas; Pancreatic Juice; Radioisotopes; Secretin; Selenium

The effects of repeated injections of 75 U crude cholecystolinin-pancreozymin (CCK-PZ) at increasing plateau glucose concentrations achieved by glucose infusion were studied in 15 controls, 8 chronic pancreatitics and 8 mild maturity onset diabetics. In control subjects CCK-PZ alone caused minor insulin release but proportinally greater secretion with increasing blood glucose concentrations. Chronic pancreatitis patients who had normal responses to intravenous glucose responded normally to the CCK-PZ but at significantly higher plateau glucose levels. Diabetics had no response to IV glucose boluses of 5 g or 10 g, but with glucose infusions of 250-500 mg/min had almost normal insulin responses to CCK-PZ. The responses to CCK-PZ plus glucose were greater than either stimulus alone, indicating an interaction between these and the beta cell. These studies suggest that the gut homone-receptor in the beta cell is intact in maturity onset diabetes and chronic pancreatitis, whether the glucose receptor is normal or defective. The peptide-responsible in the crude CCK-PZ is not secretin, glucagon or gut glucagon, but may be gastric inhibitory polypeptide (GIP) since pure CCK-PZ has no insuli releasing properties.

Topics: Adult; Blood Glucose; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Glucose; Humans; Insulin; Male; Middle Aged; Pancreatitis; Stimulation, Chemical

We have developed a sensitive, specific and reproducible radioimmunoassay for cholecystokinin (CCK) with which basal levels of CCK of between 400-800 pg/ml have been measured in normal man, in patients with diabetes and with duodenal ulcer disease, and in normal dogs. After a meal, circulating levels of CCK rose to 1000-1200 pg/ml in human subjects. Release of CCK was more rapid in diabetic and duodenal ulcer patients than in normal subjects, but elevated postprandial levels persisted much longer in normal subjects. Patients with the Zollinger-Ellison syndrome had elevated values of cholecystokinin which rose after a meal. Lack of correlation between elevated basal levels of gastrin and CCK in patients with the Zollinger-Ellison syndrome suggest that the hypercholecystokininemia may be absolute. The disappearance half-time of exogenous CCK was about 21/2 minutes in normal subjects as well as in diabetic and duodenal ulcer patients. Studies in dogs demonstrated no uptake of basal levels of cholecystokinin by the kidney; on infusion of exogenous CCK-33, the kidney extracted 43% of the total CCK presented and 56% of the integrated CCK. We conclude that: 1) circulating basal and postprandial levels of CCK may be measured in a reproducible fashion; 2) postprandial release of CCK is more rapid in diabetic and duodenal ulcer patients than in normal man; 3) the disappearance half-time of exogenous CCK in man and dogs is about 21/2 minutes; 4) the kidney is a major site for uptake of CCK.

Topics: Animals; Cholecystokinin; Diabetes Mellitus; Dogs; Duodenal Ulcer; Food; Gastrins; Half-Life; Humans; Kidney; Radioimmunoassay; Zollinger-Ellison Syndrome

Topics: Acute Disease; Adult; Aged; Alcoholism; Biliary Tract Diseases; Blood Glucose; Cholecystokinin; Cholelithiasis; Chronic Disease; Diabetes Mellitus; Europe; Female; Glucagon; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreatitis; Recurrence; Sex Factors; Stimulation, Chemical; United States

Topics: Alcoholism; Amylases; Bicarbonates; Blood Group Antigens; Calcinosis; Cholecystokinin; Chronic Disease; Coronary Disease; Diabetes Mellitus; Dietary Proteins; Ethnicity; Female; Glucose; Humans; Intestinal Absorption; Male; Pancreas; Pancreatic Cyst; Pancreatic Juice; Pancreatitis; Secretin; South Africa; Sucrose

Topics: Animals; Cholecystokinin; Depression, Chemical; Diabetes Mellitus; Glucagon; Glucose; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Pancreas; Radioimmunoassay; Rats; Stimulation, Chemical; Tolbutamide

Topics: Cholecystokinin; Depression, Chemical; Diabetes Mellitus; Fatty Acids, Nonesterified; Glucagon; Glycerol; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Secretin; Stimulation, Chemical

Topics: Arginine; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Insulin; Male; Radioimmunoassay; Secretin; Stimulation, Chemical

Topics: Adult; Animals; Biological Assay; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Dogs; Gastrins; Humans; Immunoassay; Insulin; Insulin Secretion; Methods; Middle Aged; Portal Vein; Secretin; Stimulation, Chemical

Topics: Adult; Aged; Calculi; Cholecystokinin; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Time Factors

Topics: Adult; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Female; Glucagon; Hormones; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Prediabetic State; Secretin; Tolbutamide

Topics: Adolescent; Adult; Age Factors; Celiac Disease; Child; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Diabetes Mellitus; Feces; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain; Pancreas; Pancreatitis; Time Factors

Topics: Amino Acids; Cholecystokinin; Diabetes Mellitus; Fatty Acids, Nonesterified; Gastrins; Glucagon; Glycolysis; Humans; Insulin; Insulin Secretion; Oxygen Consumption; Secretin

Topics: Animals; Blood Glucose; Cholecystokinin; Diabetes Mellitus; Dogs; Fatty Acids, Nonesterified; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Rabbits; Secretin; Serotonin; Stimulation, Chemical

Topics: Adult; Calculi; Cholecystokinin; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Jejunum; Male; Methods; Middle Aged; Pancreas; Pancreatectomy; Pancreatitis; Secretin

Topics: Adult; Aged; Cholecystokinin; Cholestasis; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Secretin

Topics: Adolescent; Adult; Aged; Cholecystokinin; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Pancreas; Secretin

Topics: Adult; Amylases; Bicarbonates; Calcinosis; Celiac Disease; Cholecystokinin; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Intubation, Gastrointestinal; Male; Middle Aged; Pancreatic Juice; Pancreatitis; Secretin

Topics: Adult; Aged; Alkaline Phosphatase; Amylases; Blood; Blood Glucose; Blood Proteins; Blood Sedimentation; Cholecystokinin; Diabetes Mellitus; Diagnosis, Differential; Electrophoresis; Feces; Gastrointestinal Hormones; Glucose Tolerance Test; Humans; Middle Aged; Pancreatitis; Secretin

Topics: Adolescent; Amylases; Blood Chemical Analysis; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 1; Gastrointestinal Hormones; Humans; Insulin; Lipase; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin