ceruletide and Diabetes-Mellitus--Type-2

The clinical relevance of pancreatic exocrine insufficiency (PEI) in diabetic patients is unclear mostly because established function tests are invasive and expensive or lack sensitivity and specificity. A modified version of the noninvasive 13C-mixed triglyceride breath test (13C-MTGT) has recently been shown to detect moderate PEI reliably in patients with chronic pancreatitis. Its sensitivity and specificity in other patient groups are unknown. We therefore aimed to clarify the significance of this test for patients with diabetes mellitus (DM).. A secretin cerulein test and a modified 13C-MTGT were performed in 14 patients with DM (10 patients with type 1 DM) and 10 healthy volunteers.. Secretin cerulein test showed significantly lower outputs of amylase, trypsin, and lipase in DM compared with healthy volunteers (P < 0.05). Likewise, 13C-MTGT showed significantly lower maximal and cumulative 13C-exhalation in DM (P < 0.005). Stimulated lipase output correlated with cumulative 13C-exhalation (P < 0.05). However, when compared with normal values, only 2 patients with diabetes had abnormally low lipase output, whereas cumulative 13C-exhalation was pathologically decreased in 8 patients, including those with decreased lipase output.. The noninvasive 13C-MTGT can detect mild to moderate PEI in DM. However, the specificity of the 13C-MTGT is low in these patients probably because nonpancreatic mechanisms contribute to decreased intestinal lipolysis.

Topics: Adult; Aged; Breath Tests; Carbon Isotopes; Ceruletide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Middle Aged; Pancreas, Exocrine; Pancreatic Function Tests; Quality of Life; Reproducibility of Results; Secretin; Sensitivity and Specificity; Surveys and Questionnaires; Triglycerides; Young Adult

Diabetes mellitus type 2 and chronic pancreatitis are regarded as risk factors for pancreatic cancer. Pancreatic duct glands (PDGs) were recently described as a new compartment of the major duct in humans and mice. To evaluate the influence of diabetes and chronic pancreatitis on PDGs, cerulein was injected i.p., repetitively over 10 weeks, in mice exhibiting obesity and a type 2 diabetes-like syndrome (B6.V-Lep(ob/ob)) and in lean littermates. By using 5-bromo-2'-deoxyuridine (BrdU), a label-retaining cell population was characterized in PDGs. Cerulein administration led to more BrdU(+) cells in PDGs of obese mice compared with lean mice. The observed increase was specific to PDGs, because BrdU incorporation in cells of the pancreatic duct was not increased. In addition, the expression of distinct tumor markers in PDGs was characterized by Muc5ac, S100P, regenerating islet-derived 3β, 14-3-3 σ, and prostate stem cell antigen immunochemistry. Type 2 diabetes-like syndrome, accompanied by chronic pancreatitis, enhanced nuclear localization of S100P. Both risk factors for pancreatic cancer also induced the production of Muc5ac and the nuclear localization of S100P [corrected]. These results demonstrate that diabetes and chronic pancreatitis jointly enhance BrdU incorporation and production of pancreatic cancer-specific proteins in PDGs. The observed alterations suggest that pancreatic tumors might originate from the newly discovered histomorphological structures, called PDGs, which could represent a target for future anticancer therapies.

Topics: Animals; Bromodeoxyuridine; Carcinoma, Pancreatic Ductal; Ceruletide; Diabetes Mellitus, Type 2; Humans; Male; Metaplasia; Mice; Mice, Obese; Mucins; Neoplasm Proteins; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis, Chronic; Risk Factors

CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas.. We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure.. Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation.. In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein.

Topics: Animals; Animals, Genetically Modified; Body Weight; Carboxylesterase; Ceruletide; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Gene Expression; Gene Order; Glucose; Islets of Langerhans; Mice; Mutation; Pancreas, Exocrine; Phenotype

Patients affected by diabetes mellitus are reported to have an increased incidence of gallbladder abnormalities. The pathophysiologic mechanisms for this phenomenon are unclear. In the present study ultrasonography was used to determine gallbladder emptying in response to a meal or separate cephalic or hormonal stimulation in 21 diabetic patients and 10 healthy subjects. Gallbladder emptying and refilling after a meal were similar in diabetic patients and healthy subjects. When diabetics were divided according to the presence or absence of cardiac autonomic neuropathy (AN), a significant reduction of gallbladder emptying in response to cephalic stimulation was found in diabetics with AN (P less than 0.01 in comparison with diabetics without AN or healthy subjects). A dose-response curve of gallbladder emptying in response cerulein, a cholecystokinin analog, at concentrations of 0.25, 1, and 4 micrograms/kg/min was evaluated. No differences of gallbladder emptying were found in the three groups of subjects, indicating that gallbladder sensitivity to hormonal stimulation is not changed in diabetic patients with or without AN. Diabetic patients with AN have a significant reduction of gastric acid output and pancreatic polypeptide (PP) secretion in response to cephalic stimulation (P less than 0.05 in comparison with diabetic patients without AN or healthy subjects). Cerulein-induced PP secretion was similar in all three groups of subjects (P greater than 0.05). This study indicates that in diabetic patients with AN, gallbladder emptying as well as gastric acid and PP secretions induced by neural stimulation are markedly reduced in comparison to diabetics without AN.

Topics: Adult; Autonomic Nervous System Diseases; Ceruletide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Food; Gallbladder; Gastric Acid; Humans; Male; Pancreatic Polypeptide; Peristalsis; Ultrasonography

Secrepan (Eisai Co. Tokyo, Japan) was administered to 9 healthy volunteers and 36 patients with non-insulin dependent diabetes mellitus (NIDDM) to clarify the effect of secretin on the pancreatic B-cell, by determining the changes in blood of insulin (IRI). Whereas IRI in healthy subjects showed a monophasic change, reaching a peak (delta IRI = 43 +/- 7.3 microunits/ml, M +/- SE) 5 min after secretin loading and returning to the basal level in 15 min, NIDDM patients on diet therapy (delta IRI = 40.2 +/- 7.6 microunits/ml) showed no significant difference from the control group, but NIDDM patients on sulfonylurea (SU) (15.5 +/- 2.4 microunits/ml) and those on insulin therapy (5.3 +/- 1.4 microunits/ml), both showed a significant depression in responsiveness. Further, the changes in insulin secretion after atropine administration in healthy subjects and the changes in IRI response to Secrepan in vagotomized patients were also determined. As a result, data which preclude the possibility of association of the vagus nerve and cholinergic nerve with the stimulation of insulin secretion by secretin were obtained, and a direct action of secretin on the cell of islets of Langerhans was suggested. The maximum IRI response after a secretin load had a significant positive correlation with the IRI response after a 75-gm GTT and the content of C-peptide immunoreactivity in 24-hour urine. Therefore, insulin response to a secretin load can be useful in assessing endogenous insulin secretion and provides a pertinent clinical guide for the selection of an appropriate therapy for diabetes mellitus.

Topics: Adult; Atropine; C-Peptide; Ceruletide; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Secretin; Sincalide; Vagotomy