alpha-chymotrypsin and Diabetes-Mellitus

The aim was to review evidence about diabetes secondary to hereditary pancreatitis, seeking novel diagnostic and treatment features.. Hereditary pancreatitis (HP) is an autosomal dominant condition, characterized by recurrent episodes of acute pancreatitis, progression to fibrosis, and chronic pancreatitis. Clinical presentation includes diabetes of the exocrine pancreas (DEP). HP prevalence ranges from 0.3 to 0.57 per 100,000 people, with up to 80% of these develop DEP. This condition often requires specific interventions: with regard to metabolic control, metformin is the first choice for those with mild DEP, and for those in advanced disease, insulin is considered the first-line therapy. Insulin analogues and insulin pump therapy are preferred due to the brittle glycemic pattern and risk of hypoglycemia. In case of exocrine insufficiency, pancreatic enzyme replacement therapy is recommended. Pancreatic polypeptide administration is a promising novel treatment feature. DEP due to HP appears to be a misdiagnosed condition. The requirement of specific management demonstrates the importance of this matter; therefore, appropriate recognition and classification are important.

Topics: Acute Disease; Carcinoma, Pancreatic Ductal; Chymotrypsin; Diabetes Complications; Diabetes Mellitus; Exocrine Pancreatic Insufficiency; Fibrosis; Humans; Pancreas, Exocrine; Pancreatic Neoplasms; Pancreatitis, Chronic; Recurrence; Risk Factors; Trypsin; Trypsin Inhibitor, Kazal Pancreatic

Topics: Amyloidosis; Animals; Arteriosclerosis; Arthritis, Rheumatoid; Blood Coagulation Disorders; Blood Coagulation Factors; Chymotrypsin; Chymotrypsinogen; Diabetes Mellitus; Emphysema; Fibrinolysis; Gastrointestinal Diseases; Humans; Kallikreins; Kidney Diseases; Muscular Dystrophies; Oligopeptides; Peptide Hydrolases; Substrate Specificity; Swine

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

Topics: Adult; Aged; Chymotrypsin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Receptors, Glucagon; Signal Transduction

Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort.. We performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model.. We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups.. We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.

Topics: Adolescent; Adult; Age of Onset; Asian People; Calculi; Chymotrypsin; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Gene-Environment Interaction; Genetic Predisposition to Disease; Genotype; Humans; Kaplan-Meier Estimate; Middle Aged; Mutation; Pancreatic Diseases; Pancreatitis, Alcoholic; Pancreatitis, Chronic; Smoking; Steatorrhea; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Young Adult

The imbalance of the calcium homeostasis in the lenticular tissues of diabetic patients is an important risk factor for development of cataract diseases. In the current study, the impact of elevated levels of calcium ions were investigated on structure and aggregation propensity of glycated lens crystallins using gel electrophoresis and spectroscopic assessments. The glycated proteins indicated significant resistance against calcium-induced structural insults and aggregation. While, glycated crystallins revealed an increased conformational stability; a slight instability was observed for these proteins upon interaction with calcium ions. Also, in the presence of calcium, the proteolytic pattern of native crystallins was altered and that of glycated protein counterparts remained almost unchanged. According to results of this study it is suggested that the structural alteration of lens crystallins upon glycation may significantly reduce their calcium buffering capacity in eye lenses. Therefore, under chronic hyperglycemia accumulation of this cataractogenic metal ion in the lenticular tissues may subsequently culminate in activation of different pathogenic pathways, leading to development of lens opacity and cataract diseases.

Topics: Animals; Benzothiazoles; Calcium; Cataract; Cattle; Chymotrypsin; Circular Dichroism; Cross-Linking Reagents; Crystallins; Diabetes Mellitus; Dynamic Light Scattering; Fluorescence; Glycosylation; Homeostasis; Ions; Kinetics; Lens, Crystalline; Molecular Weight; Protein Aggregates; Protein Conformation; Protein Stability; Proteolysis; Thiazoles; Tryptophan

Previous studies suggest that casein exerts various anti-diabetic effects. However, it is not known which casein proteins are bioactive, nor their effects on enteroendocrine cells. This study evaluated the effects of intact whole casein, intact individual proteins (alpha, beta and kappa casein) and hydrolysates on an enteroendocrine cell line. High content analysis accurately monitored changes in cell health and intracellular glucagon-like peptide-1 (GLP-1) content. Cheese ripening duration and GLP-1 secretory responses were also considered. Beta casein significantly stimulated enteroendocrine cell proliferation and all caseins were potent GLP-1 secretagogues (except kappa casein). Interestingly the GLP-1 secretory activity was almost always lost or significantly reduced upon hydrolysis with proteolytic enzymes. Only pepsin-derived beta casein hydrolysates had significantly increased potency compared with the intact protein, but this was diminished with prolonged hydrolysis. In conclusion casein proteins are not detrimental to enteroendocrine cells, and alpha and beta casein are particularly beneficial stimulating proliferation and GLP-1 secretion.

Topics: Caseins; Cell Line; Cell Proliferation; Chymotrypsin; Diabetes Mellitus; Enteroendocrine Cells; Glucagon-Like Peptide 1; Hydrolysis

Ongoing studies suggest an important role for iPLA2β in a multitude of biological processes and it has been implicated in neurodegenerative, skeletal and vascular smooth muscle disorders, bone formation, and cardiac arrhythmias. Thus, identifying an iPLA2βinhibitor that can be reliably and safely used in vivo is warranted. Currently, the mechanism-based inhibitor bromoenol lactone (BEL) is the most widely used to discern the role of iPLA2β in biological processes. While BEL is recognized as a more potent inhibitor of iPLA2 than of cPLA2 or sPLA2, leading to its designation as a "specific" inhibitor of iPLA2, it has been shown to also inhibit non-PLA2 enzymes. A potential complication of its use is that while the S and R enantiomers of BEL exhibit preference for cytosol-associated iPLA2β and membrane-associated iPLA2γ, respectively, the selectivity is only 10-fold for both. In addition, BEL is unstable in solution, promotes irreversible inhibition, and may be cytotoxic, making BEL not amenable for in vivo use. Recently, a fluoroketone (FK)-based compound (FKGK18) was described as a potent inhibitor of iPLA2β. Here we characterized its inhibitory profile in beta-cells and find that FKGK18: (a) inhibits iPLA2β with a greater potency (100-fold) than iPLA2γ, (b) inhibition of iPLA2β is reversible, (c) is an ineffective inhibitor of α-chymotrypsin, and (d) inhibits previously described outcomes of iPLA2β activation including (i) glucose-stimulated insulin secretion, (ii) arachidonic acid hydrolysis; as reflected by PGE2 release from human islets, (iii) ER stress-induced neutral sphingomyelinase 2 expression, and (iv) ER stress-induced beta-cell apoptosis. These findings suggest that FKGK18 is similar to BEL in its ability to inhibit iPLA2β. Because, in contrast to BEL, it is reversible and not a non-specific inhibitor of proteases, it is suggested that FKGK18 is more ideal for ex vivo and in vivo assessments of iPLA2β role in biological functions.

Topics: Animals; Apoptosis; Calcium; Cell Membrane; Chymotrypsin; Cytosol; Diabetes Mellitus; Dinoprostone; Drug Evaluation, Preclinical; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Glucose; Group VI Phospholipases A2; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Ketones; Mice; Myocardium; Naphthalenes; Pyrones; Sphingomyelin Phosphodiesterase; Time Factors

Abstinence is a prerequisite for the treatment of alcoholic chronic pancreatitis, but there are patients who have repeated attacks because of their inability to abstain and the consequent congestive effects of the continued alcohol intake on pancreatic juice. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for acinar cells and causes them to secrete pancreatic juice of low viscosity.. Twelve patients with alcoholic chronic pancreatitis, who were unable to abstain from drinking, were administered bromhexine hydrochloride for 6 months to assess its therapeutic efficacy.. Of 12 patients administered bromhexine, 8 (67%) reported symptomatic improvement, and all patients showed improvement in the levels of pancreatic enzymes. Pancreatic exocrine function also tended to improve, but no improvement of pancreatic endocrine function was detected. Although none of the pancreatic stones present in some patients disappeared, a protein plug present in one patient disappeared, accompanied by improvement in the irregular outline of the lumen of the main pancreatic duct.. Bromhexine hydrochloride may be a new for the morbidity of chronic pancreatitis, in which there is increased viscosity of the pancreatic juice and formation of a protein plug.

Topics: Bromhexine; Calculi; Chymotrypsin; Diabetes Mellitus; Expectorants; Feces; Female; gamma-Glutamyltransferase; Humans; Male; Middle Aged; Pancreas; Pancreatitis, Alcoholic; Radiography

How insulin binds to and activates the insulin receptor has long been the subject of speculation. Of particular interest are invariant phenylalanine residues at consecutive positions in the B chain (residues B24 and B25). Sites of mutation causing diabetes mellitus, these residues occupy opposite structural environments: Phe(B25) projects from the surface of insulin, whereas Phe(B24) packs against the core. Despite these differences, site-specific cross-linking suggests that each contacts the insulin receptor. Photoactivatable derivatives of insulin containing respective p-azidophenylalanine substitutions at positions B24 and B25 were synthesized in an engineered monomer (DKP-insulin). On ultraviolet irradiation each derivative cross-links efficiently to the receptor. Packing of Phe(B24) at the receptor interface (rather than against the core of the hormone) may require a conformational change in the B chain. Sites of cross-linking in the receptor were mapped to domains by Western blot. Remarkably, whereas B25 cross-links to the C-terminal domain of the alpha subunit in accord with previous studies (Kurose, T., et al. (1994) J. Biol. Chem. 269, 29190-29197), the probe at B24 cross-links to its N-terminal domain (the L1 beta-helix). Our results demonstrate that consecutive residues in insulin contact widely separated sequences in the receptor and in turn suggest a revised interpretation of electron-microscopic images of the complex. By tethering the N- and C-terminal domains of the extracellular alpha subunit, insulin is proposed to stabilize an active conformation of the disulfide-linked transmembrane tyrosine kinase.

Topics: Amino Acid Sequence; Animals; Azides; Blotting, Western; CHO Cells; Chymotrypsin; Cricetinae; Cross-Linking Reagents; Diabetes Mellitus; Dimerization; Disulfides; Exons; Humans; Insulin; Models, Biological; Models, Molecular; Molecular Sequence Data; Mutation; Phenylalanine; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptor, Insulin; Sequence Homology, Amino Acid; Trypsin; Ultraviolet Rays

Recent reports show a pro-oxidant activity of aminoguanidine. Aminoguanidine is able to generate hydrogen peroxide in the presence of Cu (II). These observations have been confirmed by the present studies in that aminoguanidine is, indeed, able to generate oxidants similar in reactivity to the hydroxyl radical and is also able to fragment BSA in a Cu (II)-dependent manner. Studies on glycated bovine serum albumin show that aminoguanidine can affect a number of parameters associated with the nonenzymatic glycation of protein. This includes an ability to decrease glucose attachment and levels of protein fluorescence termed glycophore, resulting from protein glycation. Aminoguanidine also increases the generation of dicarbonyl compounds by glycated protein. All of these effects on parameters of glycation appear to be Cu (II) dependent. Further studies show that one effect of protein glycation is to decrease its susceptibility to proteolysis. The reverse is true of protein oxidation, which has previously been shown to increase the susceptibility of proteins to proteolytic digestion. Evidence is presented suggesting that aminoguanidine is able to enhance the proteolytic digestion of glycated BSA, a protein shown to be protease resistant. Our observations are discussed within the context of current concepts of protein glycation in the development of diabetic complications and aminoguanidine's potential use as a prophylactic agent in diabetes mellitus.

Topics: Chymotrypsin; Diabetes Mellitus; Endopeptidases; Glycated Serum Albumin; Glycation End Products, Advanced; Guanidines; Hydrogen Peroxide; Oxidants; Pepsin A; Serum Albumin; Serum Albumin, Bovine; Trypsin

To compare the pancreatic exocrine and beta-cell function in the two variants of malnutrition-related diabetes mellitus (MRDM): fibrocalculous pancreatic diabetes (FCPD) and protein-deficient pancreatic diabetes (PDPD).. Fecal chymotrypsin (FCT) and fasting C-peptide levels were measured in 20 consecutive patients with FCPD and 19 with PDPD. FCPD was diagnosed by pancreatic calcification on ultrasonography, while the diagnosis of PDPD was made on the basis of low body mass index, severe diabetes requiring insulin therapy, and ketosis resistance on interruption of insulin. Twenty patients with type I diabetes and 32 healthy subjects served as control subjects.. Both FCPD and PDPD patients had diminished levels of FCT when compared with those of control subjects and patients with type I diabetes. However, FCT levels were significantly lower in subjects with FCPD (median 0.4 U/g, range 0-8.9 U/g), in comparison with those with PDPD (4.7 U/g, 0.6-40.5 U/g; P < 0.001). Of the FCPD patients, 13 of 20 (65%) had severe exocrine pancreatic deficiency (FCT < 1 U/g) vs. 3 of 19 (15.8%) PDPD subjects (P < 0.01). In comparison with control subjects, fasting serum C-peptide levels were significantly diminished in both MRDM groups. However, C-peptide levels in subjects with FCPD (mean +/- SE, 0.22 +/- 0.04 nmol/l) and PDPD (0.26 +/- 0.04 nmol/l) were comparable.. Among the two variants of MRDM, subjects with FCPD have severe pancreatic exocrine deficiency in comparison with those with PDPD, even though their C-peptide levels are comparably diminished. This suggests that the pathogenesis of these two entities may differ or that the genetic and/or environmental factors leading to exocrine damage are different.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Chymotrypsin; Diabetes Mellitus; Diabetes Mellitus, Type 1; Feces; Female; Glycated Hemoglobin; Humans; India; Insulin; Insulin Secretion; Islets of Langerhans; Male; Nutrition Disorders; Pancreas; Pancreatic Diseases; Reference Values; Statistics, Nonparametric

Loss of chymotrypsin binding capacity of alpha 2-macroglobulin in diabetic plasma on in vitro incubation, could be partially prevented by phenylmethyl sulphonyl fluoride and pepstatin A. Prior ten-fold dilution of plasma with 0.02 M phosphate buffer (pH 7.0) completely arrested the process. The phenomenon could not be reactivated by Ca2+, lecithin or bovine serum albumin. Diabetic plasma, like normal plasma, exhibited maximal hydrolytic activities on H-D-Pro-Phe-Arg-p-nitroanilide, H-D-Val-Leu-Arg-p-nitroanilide and H-D-Ile-Pro-Arg-p-nitroanilide. The hydrolytic activities were not significantly diminished on incubation of plasma at 37 degrees C for 12 hr, unlike alpha 2-macroglobulin activity. On gel chromatography on Sephadex G-200, part of the proteolytic activity in diabetic plasma coeluted with alpha 2-macroglobulin in the VO region. A second activity peak (absent in normal plasma) was eluted with a Ve/V0 value of 1.40. Possible role of free proteinases in diabetic plasma in the inactivation of alpha 2-macroglobulin is discussed.

Topics: alpha-Macroglobulins; Amino Acid Sequence; Chymotrypsin; Diabetes Mellitus; Endopeptidases; Humans; Molecular Sequence Data; Oligopeptides; Protease Inhibitors; Substrate Specificity

In 11 persons with normal pancreas function and 21 patients with chronic pancreatitis serum levels of insulin and C-peptide were measured under basal conditions and after maximal stimulation with glucose-tolbutamide-glucagon. Patients with the highest excretory deficiency in the secretin-pancreozymin test had the most marked impairment in endocrine function. In patients with manifest diabetes the exocrine capacity was reduced to an average of 10% of normal. The endocrine parameters correlated linearly with the exocrine ones, most markedly C-peptide reserve with pancreatic enzyme secretion.

Topics: Adult; C-Peptide; Chronic Disease; Chymotrypsin; Diabetes Mellitus; Female; Humans; Insulin; Male; Pancreas; Pancreatitis; Trypsin

Not infrequently exact diagnosis of chronic pancreatitis is possible only after step by step observation. The results of examination, analyses and treatment should be communicated from a general practitioner to a specialist, further to a specialized centre and vice versa. Screening tests and special examinations should be conducted in definite order. A surgical treatment is desirable in approximately 40% of clinically pronounced chronic pancreatitis. The best results are obtained by close cooperation between different specialists and the patient himself.

Topics: 4-Aminobenzoic Acid; Alcoholism; Amylases; Chloroquine; Chronic Disease; Chymotrypsin; Diabetes Mellitus; Feces; Humans; Isoenzymes; Ligation; Lipase; Nutritional Physiological Phenomena; Pancreatic Ducts; Pancreatitis; Patient Care Team

100 lenses from 98 consecutive patients with senile cataract were investigated histologically for pseudoexfoliation. The patients came from an area known for its high incidence of pseudoexfoliation. The examiner was not aware of the clinical examination at the time of histopathological study. Pseudoexfoliation was observed in 33 lenses. There seemed to be an increasing incidence of pseudoexfoliation with increasing age of the patients. Only 16 of the cases of pseudoexfoliation had been recorded preoperatively, but routine pupillary dilatation had not been carried out. The use of alpha-chymotrypsin at cataract extraction did not preclude histological diagnosis of pseudoexfoliation.

Topics: Age Factors; Aged; Cataract; Cataract Extraction; Chymotrypsin; Diabetes Mellitus; Eye Diseases; Female; Humans; Lens, Crystalline; Male; Middle Aged

Topics: Adrenalectomy; Amino Sugars; Amylases; Animals; Anti-Bacterial Agents; Chymotrypsin; Dactinomycin; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diazoxide; Insulin; Leucine; Nitroso Compounds; Pancreas; Proteins; Rats; Rats, Inbred Strains; Trypsin

Topics: Adipose Tissue; Adrenalectomy; Animals; Blood Glucose; Bromelains; Cattle; Chymotrypsin; Diabetes Mellitus; Dithiothreitol; Humans; Hypoglycemic Agents; Mercaptoethanol; Mice; Molecular Weight; Papain; Rats; Tissue Extracts; Trypsin

Topics: Cataract Extraction; Chymotrypsin; Diabetes Mellitus; Eye Injuries; Glaucoma; Humans; Intraocular Pressure; Methods; Middle Aged; Rupture; Visual Acuity

Topics: Adolescent; Adult; Aged; Animals; Blood Glucose; Blood Proteins; Chymotrypsin; Diabetes Mellitus; Diaphragm; Endopeptidases; Female; Glycosuria; Humans; Immune Sera; In Vitro Techniques; Injections, Intramuscular; Injections, Intravenous; Insulin; Insulin Antibodies; Insulin Resistance; Male; Middle Aged; Pituitary-Adrenal Function Tests; Rats

Topics: Adult; Aged; Aging; Basement Membrane; Cataract Extraction; Chymotrypsin; Cryosurgery; Diabetes Complications; Diabetes Mellitus; Humans; Lens, Crystalline; Middle Aged

Topics: Adult; Aged; Animals; Cattle; Chymotrypsin; Diabetes Mellitus; Electrophoresis, Disc; Female; Growth Hormone; Humans; Hypopituitarism; Insulin Antagonists; Male; Middle Aged; Nitrogen; Time Factors

Topics: Cardiovascular Diseases; Cholestasis; Chymotrypsin; Diabetes Mellitus; Gastritis; Humans; Liver Cirrhosis; Liver Neoplasms; Lung Diseases; Pancreatic Neoplasms; Pancreatitis; Trypsin Inhibitors

Topics: Animals; Blood Glucose; Chymotrypsin; Diabetes Mellitus; Male; Peptide Hydrolases; Rats; Trypsin

Topics: Anti-Bacterial Agents; Arthritis; Arthritis, Rheumatoid; Cataract; Cataract Extraction; Chymotrypsin; Diabetes Mellitus; Drug Therapy; Endophthalmitis; Eye Diseases; Eye Foreign Bodies; Humans; Lens, Crystalline; Ophthalmia, Sympathetic; Panophthalmitis; Postoperative Complications; Steroids; Uveitis; Vitreous Body