Subject(s)
Amylases/blood , COVID-19/complications , Diabetic Ketoacidosis/enzymology , Lipase/blood , SARS-CoV-2 , Adolescent , Adult , Aged , COVID-19/enzymology , Female , Humans , Male , Middle AgedABSTRACT
Fulminant type 1 diabetes mellitus progresses extremely rapidly and is accompanied by ketoacidosis. Patients with the disease present at emergency departments with non-specific symptoms, including fever, nausea, vomiting, and abdominal pain. Here, we present a case of fulminant type 1 diabetes mellitus where the patient was initially misdiagnosed with gastroenteritis and acute pancreatitis. A 50-year-old Japanese woman was referred to our hospital with coma and shock. She had presented with nausea, vomiting, abdominal pain and thirst from 5â¯days before admission, and had been misdiagnosed with gastroenteritis by her primary care physician. Upon examination, metabolic acidosis and remarkable elevation of pancreatic exocrine enzymes were found (amylase 4322â¯IU/L, lipase 1046â¯IU/L). Acute pancreatitis was initially suspected because of the high pancreatic enzyme levels and abdominal pain. However, her plasma glucose level was markedly elevated at 1357â¯mg/dL. The patient was diagnosed with fulminant type 1 diabetes mellitus. Computed tomography showed no radiological evidence of acute pancreatitis. In conclusion, fulminant type 1 diabetes mellitus is often referred to hospital with flu-like or gastrointestinal symptoms and elevation of serum pancreatic enzymes. Physicians must be sure not to misdiagnose it as gastroenteritis or acute pancreatitis.
Subject(s)
Amylases/blood , Diabetes Mellitus, Type 1/enzymology , Lipase/blood , Acute Disease , Biomarkers/blood , Diabetic Ketoacidosis/enzymology , Female , Humans , Middle AgedABSTRACT
BACKGROUND: Many studies indicated that mean platelet volume (MPV) and platelet distribution width (PDW) may be valuable in the diagnosis and management of clinical disorders; also, serum butyrylcholinesterase activity (BChE) was suggested to be linked to systemic inflammation and oxidative stress. Limited studies measured these readily available markers in children with diabetic ketoacidosis (DKA). Our objectives were to measure MPV, PDW and BChE in children with DKA; and to assess if any of these markers reflects the severity of DKA. METHODS: Our study included: 30 children with DKA (DKA group), 30 diabetic children (Non-DKA group) and 30 apparently healthy children (control group). MPV, PDW and BChE were measured in all children. Additional blood samples were withdrawn from the DKA group to assess these markers at discharge from hospital. RESULTS: MPV, PDW and BChE were significantly altered in the DKA group than the other two groups; and their levels improved significantly at discharge of the DKA group (p < 0.05). The three markers were found to equally to predict the presence of DKA, but MPV was the most suitable risk marker for DKA diagnosis (OR = 4.251, CI 95% =1.463-12.351, p = 0.003). Regarding their relation with DKA severity, they did not correlate significantly with arterial PH or serum HCO3- (p > 0.05). CONCLUSION: DKA in children is associated with changes in MPV, PDW and BChE activity, which improve after resolution of the condition. Elevated MPV can be a suitable risk marker for DKA. None of the studied markers correlated with the severity of DKA.
Subject(s)
Blood Platelets/enzymology , Butyrylcholinesterase/blood , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/enzymology , Mean Platelet Volume/methods , Adolescent , Biomarkers/blood , Blood Platelets/pathology , Case-Control Studies , Child , Diabetic Ketoacidosis/diagnosis , Enzyme Activation/physiology , Female , Humans , MaleABSTRACT
OBJECTIVE: Diabetic ketoacidosis in children is associated with vasogenic cerebral edema, possibly due to the release of destructive polymorphonuclear neutrophil azurophilic enzymes. Our objectives were to measure plasma azurophilic enzyme levels in children with diabetic ketoacidosis, to correlate plasma azurophilic enzyme levels with diabetic ketoacidosis severity, and to determine whether azurophilic enzymes disrupt the blood-brain barrier in vitro. DESIGN: Prospective clinical and laboratory study. SETTING: The Children's Hospital, London Health Sciences Centre. SUBJECTS: Pediatric type 1 diabetes patients; acute diabetic ketoacidosis or age-/sex-matched insulin-controlled. MEASUREMENTS AND MAIN RESULTS: Acute diabetic ketoacidosis in children was associated with elevated polymorphonuclear neutrophils. Plasma azurophilic enzymes were elevated in diabetic ketoacidosis patients, including human leukocyte elastase (p < 0.001), proteinase-3 (p < 0.01), and myeloperoxidase (p < 0.001). A leukocyte origin of human leukocyte elastase and proteinase-3 in diabetic ketoacidosis was confirmed with buffy coat quantitative real-time polymerase chain reaction (p < 0.01). Of the three azurophilic enzymes elevated, only proteinase-3 levels correlated with diabetic ketoacidosis severity (p = 0.002). Recombinant proteinase-3 applied to human brain microvascular endothelial cells degraded both the tight junction protein occludin (p < 0.05) and the adherens junction protein VE-cadherin (p < 0.05). Permeability of human brain microvascular endothelial cell monolayers was increased by recombinant proteinase-3 application (p = 0.010). CONCLUSIONS: Our results indicate that diabetic ketoacidosis is associated with systemic polymorphonuclear neutrophil activation and degranulation. Of all the polymorphonuclear neutrophil azurophilic enzymes examined, only proteinase-3 correlated with diabetic ketoacidosis severity and potently degraded the blood-brain barrier in vitro. Proteinase-3 might mediate vasogenic edema during diabetic ketoacidosis, and selective proteinase-3 antagonists may offer future vascular- and neuroprotection.
Subject(s)
Blood-Brain Barrier/metabolism , Brain Edema/enzymology , Diabetic Ketoacidosis/enzymology , Leukocyte Elastase/blood , Myeloblastin/blood , Peroxidase/blood , Brain Edema/etiology , Case-Control Studies , Cathepsin G/blood , Cell Culture Techniques , Child , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/enzymology , Diabetic Ketoacidosis/complications , Endothelial Cells/physiology , Female , Humans , MaleABSTRACT
BACKGROUND: Diabetic ketoacidosis (DKA) in children is associated with cerebrovascular-related complications. We recently reported that DKA facilitates leukocyte adherence to the brain microvascular endothelium. Adhered leukocytes can release enzymes that instigate vascular dysfunction. Our aims were to measure plasma levels of leukocyte-derived matrix metalloproteinases (MMPs) from DKA patients and to correlate plasma MMP concentrations with DKA severity. METHODS: Plasma was obtained from children with type 1 diabetes, either in DKA (n = 16) or insulin controlled (CON; n = 16). Antibody microarray and gelatin zymography were used to quantify plasma MMPs and their endogenous tissue inhibitors (TIMPs). MMP concentrations were correlated with DKA severity (blood pH). Quantitative PCR of leukocyte mRNA was used to help determine the origin of plasma MMPs. RESULTS: DKA was associated with altered plasma levels of ↓MMP-2 (P < 0.001), ↑MMP-8 (P < 0.001), ↑MMP-9 (P < 0.05), and ↑TIMP-4 (P < 0.001), as compared with CON. Elevated MMP-8 and MMP-9 were both positively correlated with DKA severity (P < 0.05). DKA was associated with increased leukocyte mRNA for MMP-8, MMP-9, and TIMP-4 (P < 0.005). CONCLUSION: MMPs are dynamically regulated during DKA. Plasma MMP-8 and MMP-9 concentrations correlate with DKA severity and are known to degrade brain microvascular endothelial cell tight junctions. Thus, leukocyte-derived MMPs might contribute to DKA-associated cerebrovascular complications.
Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetic Ketoacidosis/enzymology , Leukocytes/enzymology , Matrix Metalloproteinase 8/blood , Matrix Metalloproteinase 9/blood , Biomarkers/blood , Child , Diabetes Mellitus, Type 1/blood , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/etiology , Female , Gene Expression Regulation, Enzymologic , Humans , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 8/genetics , Matrix Metalloproteinase 9/genetics , RNA, Messenger/blood , Severity of Illness Index , Time Factors , Tissue Inhibitor of Metalloproteinases/blood , Tissue Inhibitor of Metalloproteinase-4ABSTRACT
The potential roles of serum butyrylcholinesterase (BChE) activity and platelet indices in type 1 diabetes (T1D) remain uncertain. We aimed to investigate the correlation among the platelet indices, serum BChE activity, and diabetic ketoacidosis (DKA). Sixty-one T1D patients, 29 patients with DKA, and 30 age- and sex-matched controls were enrolled. Mean platelet volume (MPV), platelet distribution width (PDW), and serum BChE activity were measured and evaluated at admission and after the treatment. The serum BChE activity was significantly lower in patients with DKA at admission to the hospital compared with non-DKA and control subjects; however, plasma glucose level, HbA1c level, MPV and PDW were significantly higher. Serum BChE activity, variables related to glycemic control, and platelet parameters were higher in non-DKA patients than in controls. Serum BChE activity was correlated with the serum HCO3 level (r = 0.375, p < 0.05) and plasma glucose level (r = -0.387, p < 0.05). Receiver operating characteristic curve analyses showed no difference between serum BChE activity and the platelet parameters with respect to the ability to reflect DKA. Logistic regression showed that increased PDW can act as a risk marker for the presence of DKA. Serum BChE activity and the platelet parameters returned to normal along with the plasma glucose levels when metabolic acidosis was well controlled. Serum BChE activity and the platelet parameters were significantly correlated with DKA. Measurement of PDW can provide complementary information and a risk biomarker reflecting the presence of DKA.
Subject(s)
Blood Platelets/enzymology , Blood Platelets/pathology , Butyrylcholinesterase/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/enzymology , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/enzymology , Biomarkers/blood , Blood Glucose/metabolism , Female , Humans , Male , Mean Platelet Volume/methods , Middle AgedABSTRACT
A 59-year-old Chinese male patient was admitted at diagnosis of type 1 diabetes with ketoacidosis. During the normalization of blood glucose with insulin, the patient developed acute hemolysis. The factors predisposing to hemolysis were not found, except the significantly diminished activity of glucose-6-phosphate dehydrogenase (G6PD). DNA analysis did not show any coding or intronic mutation in the G6PD gene. This is the first reported case of a Chinese patient in diabetic ketoacidosis with hemolysis induced by G6PD deficiency in the absence of mutations in the G6PD gene.
Subject(s)
Diabetes Mellitus, Type 1/enzymology , Diabetic Ketoacidosis/enzymology , Glucosephosphate Dehydrogenase Deficiency/metabolism , China , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Diabetic Ketoacidosis/etiology , Diabetic Ketoacidosis/genetics , Diabetic Ketoacidosis/pathology , Glucosephosphate Dehydrogenase/genetics , Glucosephosphate Dehydrogenase/metabolism , Glucosephosphate Dehydrogenase Deficiency/complications , Glucosephosphate Dehydrogenase Deficiency/genetics , Glucosephosphate Dehydrogenase Deficiency/pathology , Hemolysis , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: To investigate the clinical characteristics and different status of islet autoantibodies of rapid-onset type 1 diabetes in China with elevated serum pancreatic enzymes. METHODS: In accordance with the criteria Imagawa reported, 40 cases of acute-onset type 1 diabetics with ketosis or ketoacidosis were selected and 4 fell into the criteria of rapid-onset type 1 diabetes. Compared the clinical characteristics between fulminant (group F, n = 4) and nonfulminant (group NF, n = 36) type 1 diabetics. Same parameters were compared between the patients with diabetic symptoms within 1 week (group A, n = 11) and those beyond 1week (group B, n = 29). The percentage of elevated serum amylase were compared between patients with and without severe ketoacidosis. Islet autoantibodies, including glutamic acid decarboxylase antibody (GAD-Ab), protein tyrosine phosphatase antibody (IA-2Ab) and insulin autoantibody (IAA),, were detected by radioligand assays. RESULTS: We found 4 cases of rapid-onset type 1 diabetes in Chinese, accounted for 10% of acute-onset type 1 diabetes. Among 4 rapid-onset type 1 diabetics, 2 patients detected GAD-Ab positive. Patients with duration of diabetic symptoms within 1 week (group A) were found all with severe ketoacidosis and 10 of 11 patients were found serum amylase elevated and this group appeared higher blood glucose, lower PH and CO(2)CP, nearly normal HbA(1c) and more severe ketoacidosis, more patients with elevated amylase (P < 0.05) than those with duration of symptoms more than 1 week (group B). Patients with severe ketoacidosis (n = 20) owned higher percentage of elevated serum amylase than those with mild or moderate ketoacidosis (n = 20) (60% vs 20%, P < 0.05). CONCLUSION: (1) Rapid-onset type 1 diabetes cases are also observed in China. (2) Rapid-onset type 1 diabetes may be a group of syndromes with different etiology which immune and non-immune factors may both involved in. (3) Elevated pancreatic enzymes are not specific markers for rapid-onset type 1 diabetes, it may result from severe ketoacidosis and metabolic derangements.
Subject(s)
Autoantibodies/blood , Diabetes Mellitus, Type 1/enzymology , Diabetic Ketoacidosis/enzymology , Hyperamylasemia/etiology , Islets of Langerhans/immunology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/immunology , Female , Humans , Hyperamylasemia/immunology , MaleABSTRACT
The incidence of pancreatic enzyme elevations in children with diabetic ketoacidosis (DKA) compared with children with newly diagnosed diabetes without DKA was assessed in a prospective study. Pancreatic enzyme elevations, particularly hyperlipasemia, are common but not associated with significant symptomatology. Acute pancreatitis was diagnosed in 2% of children with DKA.
Subject(s)
Diabetic Ketoacidosis/enzymology , Hyperamylasemia/diagnosis , Lipase/blood , Acute Disease , Bicarbonates/blood , Child , Female , Humans , Hypertriglyceridemia/diagnosis , Male , Pancreatitis/diagnosis , Prospective StudiesSubject(s)
Amylases/blood , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/enzymology , Lipase/blood , Adult , Aged , Female , HumansABSTRACT
AIMS: Inappropriate production of nitric oxide (NO) may be responsible for the haemodynamic disturbances of diabetic ketoacidosis. We investigated whether this metabolic condition is associated with increased plasma nitrate (the stable oxidation product of NO) levels and NO synthase gene expression in lymphomonocytes. RESEARCH DESIGN AND METHODS: Plasma nitrate concentrations, lymphomonocyte-inducible nitric oxide synthase (iNOS) gene expression, tumour necrosis factor-alpha (TNF-alpha) and soluble thrombomodulin were measured in 11 Type 1 diabetic patients at baseline, during mild ketosis and after euglycaemia was re-established. RESULTS: During diabetic ketosis plasma nitrate concentrations were higher (18 (16-21) vs. 9 (7-11) micro mol/l; (95% lower-upper confidence interval) P < 0.05) than at baseline. At baseline lymphomonocyte iNOS mRNA expression and iNOS protein levels were undetectable, but in ketosis both were increased (both at P < 0.0001). After recovery from ketosis, NO3 concentration, iNOS mRNA, and iNOS expression (270 +/- 36%, mean +/- sd) decreased but not significantly. No significant changes were observed in either TNF-alpha or soluble thrombomodulin levels between the three conditions. CONCLUSIONS: Diabetic ketosis is associated with increased nitrate levels and the activation of iNOS expression in circulating lymphomonocytes, but it does not affect either the proinflammatory cytokine TNF-alpha or a marker of endothelial dysfunction such as thrombomodulin. Our data support the hypothesis that, during diabetic ketosis, alterations in NO homeostasis are present in circulating lymphomonocytes.
Subject(s)
Diabetes Mellitus, Type 1/enzymology , Diabetic Ketoacidosis/enzymology , Monocytes/enzymology , Nitric Oxide Synthase/metabolism , Adult , Blotting, Western , Diabetes Mellitus, Type 1/blood , Diabetic Ketoacidosis/blood , Female , Gene Expression , Humans , Male , Nitrates/metabolism , Nitric Oxide Synthase Type II , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Thrombomodulin/blood , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVES: Amylase and lipase estimations are the standard tests to diagnose acute pancreatitis (AP). Elevation of amylase and lipase < or = 3 times normal may be nonspecific, but elevation of either one > 3 times normal is reported to be diagnostic of AP. The aim of this study was to evaluate the incidence and magnitude of nonspecific elevations of amylase and lipase in diabetic ketoacidosis (DKA) and to correlate their elevation with known metabolic derangements of DKA. METHODS: A total of 150 consecutive episodes of DKA in 135 patients were evaluated for serum amylase, lipase, and biochemical markers of DKA on admission and 24 h later. Patients were divided according to the following: 1) Clearly nonspecific amylase elevation (CNSA): Amylase elevation < 3 times normal plus normal or < 3 times lipase; 2) Clearly nonspecific lipase elevation (CNSL): Lipase elevation < 3 times normal plus normal or < 3 times amylase; and 3) Probably nonspecific amylase or lipase elevation (PNSA or PNSL): > 3 times elevation of amylase or lipase or both with normal abdominal CT. RESULTS: Elevated amylase and lipase levels ranged from 111 to 1257 IU/L (normal 30-110 IU/L) and 25-529 IU/dl (normal < 24 IU/dl) (CT-proven AP = 16, excluded). Nonspecific amylase elevation (CNSA + PNSA) = 25 (16.6%) cases, CNSA in 10 (6.6% of all DKA or 27% of amylase elevations), and PNSA in 15 (10% of all DKA or 41% of amylase elevations). Nonspecific lipase elevation (CNSL + PNSL) = 36 (24%), CNSL in 23 (15.3% of all DKA or 47% of all lipase elevations), and PNSL in 13 (8.7% of all DKA or 26.5% of all lipase elevations). Multiple regression analyses showed significant correlation of pH and serum osmolality with amylase elevation. Lipase elevation showed positive correlation with serum osmolality alone. CONCLUSIONS: In DKA nonspecific elevations of amylase and lipase occur in 16-25% of cases. Amylase elevation is correlated with pH and serum osmolality, but lipase elevation is correlated with serum osmolality alone. Diagnosis of AP based soley on elevated amylase or lipase, even > 3 times normal, is not justifiable.
Subject(s)
Amylases/blood , Clinical Enzyme Tests , Diabetic Ketoacidosis/enzymology , Lipase/blood , Pancreatitis/diagnosis , Acute Disease , Diabetic Ketoacidosis/blood , Female , Humans , Hydrogen-Ion Concentration , Incidence , Male , Middle Aged , Osmolar ConcentrationABSTRACT
Diabetic ketoacidosis (DKA) is frequently associated with pancreatic enzyme abnormalities. In order to determine the main factors that lead to this increase, serum total amylase (TA), pancreatic amylase (PA), lipase (L) and leukocyte elastase (LE), an early predictor of acute pancreatitis, were measured in four groups of patients on admission. Group 1 consisted of 52 patients with DKA (age: 41.9 +/- 19.2 years; blood glucose (Glc): 27.4 +/- 11.5 mmol/L; pH: 7.20 +/- 0.16; plasma bicarbonate: 10.5 +/- 6.2 mmol/L; blood urea nitrogen (BUN): 0.60 +/- 0.44 g/L; HbA(1C): 12.5% +/- 2.8%). Group 2 consisted of 90 patients with poorly controlled non-ketotic diabetes (age: 53.4 +/- 16.0; Glc: 14.3 +/- 0.6; HCO(3)(-): 26.6 +/- 3.2; BUN: 0.38 +/- 0.20; HbA(1C): 11.3 +/- 2.1). Group 3 consisted of 22 patients with well-controlled diabetes (age: 53.7 +/- 12.8; Glc: 10. 1 +/- 5.2; HCO(3)(-): 27.4 +/- 3.8; BUN: 0.36 +/- 0.19; HbA(1C): 6.8 +/- 0.8). Group 4 (controls) comprised 27 non-diabetic patients (age: 46.0 +/- 15.0; Glc: 4.9 +/- 0.5; HCO(3)(-): 28.4 +/- 2.5; BUN: 0.30 +/- 0.16; HbA(1C): 5.2 +/- 0.7) (means +/- SD). Increased enzyme activities were more frequent in group 1 (TA: 30.7; PA: 27.0; L: 36.5; LE: 73%) than in groups 2 (TA: 8.9; PA: 7.1; L: 8.9; LE: 45. 5%), 3 (TA: 13.6; PA: 9.0; L: 18.1; LE: 31.8%) and 4 (TA: 7.0; PA: 3. 0; L: 0.0; LE: 29.6%). Mean serum enzyme activities were significantly different in the 4 groups (ANOVA, P < 0.01) and were higher in group 1 than in groups 2, 3 and 4 (Student's t-test; group 1 vs 2 or 3 or 4: P < 0.001). In groups 1 + 2 + 3 + 4 (all patients), the four enzymes correlated with one another and also with Glc, BUN and HCO(3)(-) (P < 0.001). In group 1, TA correlated negatively with HCO(3)(-) (P < 0.001) and pH (P < 0.05); PA and L correlated positively with Glc and BUN (P < 0.01) and negatively with HCO(3)(-) (respectively, p < 0.01 and 0.05). PA correlated positively with pH (P < 0.01); LE correlated with Glc (P < 0.05) and BUN (P < 0.01). In conclusion, this study suggests that the serum levels of pancreatic enzymes increase with the degree of diabetic disequilibrium, and mainly correlate with metabolic factors such as hyperglycaemia, dehydration and acidosis. Increased pancreatic enzyme activities in patients with DKA, even in combination with abdominal pain, should not be diagnosed as acute pancreatitis; this could be important, particularly for younger clinicians.
Subject(s)
Amylases/blood , Blood Glucose/metabolism , Diabetes Mellitus/blood , Diabetic Ketoacidosis/blood , Leukocyte Elastase/blood , Lipase/blood , Adult , Analysis of Variance , Bicarbonates/blood , Biomarkers/blood , Blood Urea Nitrogen , Diabetes Mellitus/enzymology , Diabetic Ketoacidosis/enzymology , Female , Humans , Isoenzymes/blood , Male , Middle AgedABSTRACT
We report three patients with diabetic ketoacidosis (DKA) who presented with striking elevations of serum lipase levels and less striking elevations of amylase and trypsinogen. All three had nausea and vomiting, but none had objective evidence of abdominal pain, and computed tomography scans of the pancreas were unremarkable. These cases suggest the association of asymptomatic enzyme elevations with DKA. We review the literature on this subject.
Subject(s)
Diabetic Ketoacidosis/enzymology , Lipase/blood , Amylases/blood , Biomarkers , Humans , Male , Middle Aged , Pancreas/enzymology , Trypsinogen/bloodABSTRACT
The relation between increase of amylasaemia and increase of lipasaemia was studied during ketoacidosis in 31 insulin-dependent diabetics. The effects of metabolic disturbances on amylase production during the acute phase of ketoacidosis were also evaluated. The greatest increase of amylasaemia was observed after 24 hours in 17 cases (55%), with return to normal values after 3 to 7 days. Amylasuria was closely correlated with amylasaemia (r = 0.7; P less than 0.01). No correlation was found between hyperamylasaemia and the degree of ketoacidosis, but there was a correlation between plasma osmolality and hyperamylasaemia (r = 0.44; P less than 0.02). The increase of lipasaemia, considered more specific of pancreatic damage, was closely correlated with that of amylasaemia (r = 0.63: P less than 0.01). The electrolyte disturbances associated with ketoacidosis are responsible for cellular damage with release of enzymes in many tissues. The hyperamylasaemia consecutive to pancreatic damage might be of similar origin and aggravated by splanchnic hypoperfusion.
Subject(s)
Amylases/blood , Diabetic Ketoacidosis/enzymology , Lipase/blood , Acute Disease , Adult , Diabetic Coma/enzymology , Female , Humans , Male , Middle Aged , Pancreatitis/enzymologyABSTRACT
Administration to normal rats of 100 mg of streptozotocin/kg body weight produced ketotic diabetic rats in which the affinity of carnitine palmitoyltransferase for malonyl-CoA was decreased by 10-fold and its activity was increased by 30%, but the injection of insulin brought the affinity and the activity back to normal within 4 h. Administration of 60 mg of streptozotocin/kg produced non-ketotic diabetic rats and caused a less substantial change in the affinity of carnitine palmitoyltransferase for malonyl-CoA. In the BB Wistar diabetic rat, the onset of diabetes also increased the activity of carnitine palmitoyltransferase and decreased its affinity for malonyl-CoA. Injection of insulin brought both of these values back to normal within 2 h. The total activity of mitochondrial carnitine palmitoyltransferase (outer + inner activities) was 40% greater in the BB Wistar diabetic rat, but treatment with insulin did not decrease the total activity to normal values within 2 h. The elevated activity and decreased affinity for malonyl-CoA found in fasting rats did not respond to short-term insulin treatment. The evaluation of a previous report that cycloheximide blocks the effects of starvation indicated that cycloheximide did not act by inhibiting protein synthesis, but produced its effect by preventing gastric emptying. Current data suggest that diabetes increases the activity of carnitine palmitoyltransferase and greatly diminishes the affinity of the enzyme for malonyl-CoA and that the severity of diabetes is associated with differences in the affinity of the enzyme for its inhibitor. Insulin acts on the outer carnitine palmitoyltransferase to reverse these effects very rapidly, but diabetes produces some change in the total activity that is not reversed by short-term treatment with insulin.
Subject(s)
Acyl Coenzyme A/metabolism , Acyltransferases/metabolism , Carnitine O-Palmitoyltransferase/metabolism , Insulin/pharmacology , Malonyl Coenzyme A/metabolism , Animals , Diabetes Mellitus, Experimental/enzymology , Diabetic Ketoacidosis/enzymology , Kinetics , Male , Rats , Rats, Inbred Strains , Streptozocin/administration & dosage , Time FactorsABSTRACT
The intestine is capable of shifting its major fuel source from glutamine in the fed animal to ketone bodies in the fasted animal. Glutaminase (EC 3.5.1.2), the entry enzyme of glutamine oxidation, was examined for its function as a determinant in the utilization of jejunal fuel during diabetes and fasting. Male Sprague-Dawley rats were made ketotic to varied degrees by either fasting or the induction of diabetes with graded doses of streptozotocin (SZ). Specific activity of glutaminase was decreased in the diabetic animals to 64% (p less than 0.05) of controls in the group receiving 110 mg/kg SZ and 82% of controls in the group receiving 65 mg/kg SZ and to 78% (p less than 0.05) of controls in the fasted animals. The activity of glutaminase in the small intestine was negatively correlated to the concentration of beta-hydroxybutyrate in the plasma (r = -0.97, p less than 0.025) and jejunum (r = -0.92, p less than 0.05) for the four groups of animals. Specific activity of glutaminase was decreased in all cell types isolated along the villus-crypt axis of the small intestine from diabetic and fasted rats compared with control rats. The quantity of glutaminase-protein was determined by a dot immunobinding assay using an antibody to purified glutaminase. The activity of glutaminase relative to immunoreactive glutaminase-protein was significantly decreased (p less than 0.05) to 53% of control values in the 110 mg/kg SZ group, 77% in the 65 mg/kg SZ group, and 70% in the fasted group. These data indicate that an inactivation of glutaminase-protein may play a role in the ability of the intestine to shift its fuel source from glutamine to ketone bodies during diabetes and fasting.