ceruletide and Diabetes-Mellitus--Type-1

Understanding the mechanisms by which cells sense and respond to injury is central to developing therapies to enhance tissue regeneration. Previously, we showed that pancreatic injury consisting of acinar cell damage+β-cell ablation led to islet cell transdifferentiation. Here, we report that the molecular mechanism for this requires activating protease-activated receptor-2 (PAR2), a G-protein-coupled receptor. PAR2 modulation was sufficient to induce islet cell transdifferentiation in the absence of β-cells. Its expression was modulated in an islet cell type-specific manner in murine and human type 1 diabetes (T1D). In addition to transdifferentiation, PAR2 regulated β-cell apoptosis in pancreatitis. PAR2's role in regeneration is broad, as mice lacking PAR2 had marked phenotypes in response to injury in the liver and in digit regeneration following amputation. These studies provide a pharmacologically relevant target to induce tissue regeneration in a number of diseases, including T1D.

Topics: Animals; Carbon Tetrachloride; Cell Death; Cell Lineage; Cell Proliferation; Cell Survival; Cell Transdifferentiation; Ceruletide; Diabetes Mellitus, Type 1; Extremities; Gene Expression Regulation; Glucagon; Homeodomain Proteins; Humans; Insulin; Insulin-Secreting Cells; Liver; Mice, Inbred C57BL; Mice, Knockout; Paired Box Transcription Factors; Pancreatitis; Receptor, PAR-2; Regeneration; Transcription Factors

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

Type I diabetes (T1D) is an autoimmune disease in which an immune response to pancreatic β-cells results in their loss over time. Although the conventional view is that this loss is due to autoimmune destruction, we present evidence of an additional phenomenon in which autoimmunity promotes islet endocrine cell transdifferentiation. The end result is a large excess of δ-cells, resulting from α- to β- to δ-cell transdifferentiation. Intermediates in the process of transdifferentiation were present in murine and human T1D. Here, we report that the peptide caerulein was sufficient in the context of severe β-cell deficiency to induce efficient induction of α- to β- to δ-cell transdifferentiation in a manner very similar to what occurred in T1D. This was demonstrated by genetic lineage tracing and time course analysis. Islet transdifferentiation proceeded in an islet autonomous manner, indicating the existence of a sensing mechanism that controls the transdifferentiation process within each islet. The finding of evidence for islet cell transdifferentiation in rodent and human T1D and its induction by a single peptide in a model of T1D has important implications for the development of β-cell regeneration therapies for diabetes.

Topics: Adult; Animals; Cell Transdifferentiation; Cells, Cultured; Ceruletide; Diabetes Mellitus, Type 1; Female; Glucagon-Secreting Cells; Humans; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Somatostatin-Secreting Cells

The pancreatic polypeptide (PP) response to a mixed meal was investigated in seven insulin-dependent diabetics without measurable signs of diabetic autonomic neuropathy, and in seven healthy subjects. Since acute changes in metabolic regulation might influence the meal-induced PP response, the insulin-dependent diabetic patients were studied during normo- and hyperglycemic experimental conditions at blood glucose levels of 5 and 15 mmol/l, respectively. The PP response was identical on the two occasions, the response being significantly smaller than in the healthy subjects. Thus, PP response is independent of short-term changes in metabolic control. Since the response was attenuated in the insulin-dependent diabetic patients, who had no otherwise measurable signs of neuropathy, the PP response to a meal could be a sensitive indicator of dysfunction of the reflex arc controlling PP secretion in insulin-dependent diabetic patients. Alternatively, the reduction in PP secretion in these patients reflects dysfunction of the PP secreting cells of the pancreas. Iv injection of cholecystokinin-8 elicited a small but significant increase in PP concentrations, while iv secretin did not increase PP concentrations at all in healthy subjects. These stimuli are therefore less suitable in the assessment of vagal neuropathy.

Topics: Adult; Blood Glucose; Ceruletide; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Food; Humans; Injections, Intravenous; Islets of Langerhans; Male; Pancreatic Polypeptide; Radioimmunoassay; Secretin; Time Factors; Vagus Nerve

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

Exocrine pancreatic function was studied by rapid intravenous injection and by prolonged intravenous infusion of a combination of secretin and caerulein in a group of patients with proven pancreatic disease and in controls. The aim was to compare the value of the two procedures of stimulation in the diagnosis of exocrine pancreatic insufficiency. Results showed that the pancreatic response to infusion of the stimulants discriminates normal from abnormal pancreatic function better than responses to rapid injection.

Topics: Adolescent; Adult; Ceruletide; Chronic Disease; Diabetes Mellitus, Type 1; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Secretin