Difference in the influence of maternal and paternal NIDDM on pancreatic beta-cell activity and blood lipids in normoglycaemic non-diabetic adult offspring

Summary The 75-g oral glucose tolerance test was performed in 38 normoglycaemic (World Health Organization criteria) non-diabetic volunteers, aged 31–40 years, of whom 20 had a non-insulin-dependent diabetic (NIDDM) mother and 18 had an NIDDM father. At the time of the study the offspring of NIDDM mothers had a somewhat higher body mass index (BMI) (males: 26.5 ± 1.0 (mean ± SEM), females: 27.5 ± 1.5 kg/m²) than the offspring of NIDDM fathers (males: 23.4 ± 0.9, females: 24.2 ± 1.2 kg/m²). There was no difference in the time-course of glycaemia; however the serum concentrations of immunoreactive insulin (IRI), C-peptide and proinsulin were significantly higher in offspring of NIDDM mothers than in offspring of NIDDM fathers: area under the curve (AUC) serum IRI: 0.928 ± 0.091 vs 0.757 ± 0.056 nmol · l^–1· h^–1, p = 0.019; serum C-peptide: 6.379 ± 0.450 vs 4.753 ± 0.242 nmol · l^–1· h^–1, p = 0.004; serum proinsulin: 172 ± 40 vs 51 ± 7 pmol · l^–1· h^–1, p = 0.008). Serum IRI correlated with BMI, but C-peptide and proinsulin did not, and after accounting for BMI by covariance analysis they remained significantly higher in offspring of NIDDM mothers. In this group serum proinsulin was significantly higher in male than in female offspring (AUC serum proinsulin: 289 ± 68 vs 77 ± 27 pmol · l^–1· h^–1, P = 0.015). Male offspring of NIDDM mothers also had significantly higher serum triglyceride levels than females of the same group and than offspring of NIDDM fathers. The offspring (male and female) of NIDDM mothers had slightly lower serum apolipoprotein A-I levels than the offspring of NIDDM fathers. Significant correlations were found between serum triglycerides, HDL-cholesterol and apolipoprotein B, and serum concentrations of pancreatic beta-cell peptides, mostly in the offspring of NIDDM mothers; however, they did not display unequivocal association with gender within this group. The data are consistent with clinical observations of a greater risk of NIDDM transmission from the mother than from the father, and may suggest that male offspring are more exposed to this risk than female offspring. [Diabetologia (1996) 39: 831–837] Received: 2 June 1995 and in final revised form: 19 January 1996     

Serum pancreatic stone protein in pancreatic diseases

Summary Serum pancreatic stone protein (PSP) was determined in sera of pancreatic and nonpancreatic diseases using enzyme immunoassay specific to human PSP to study the diagnostic and pathophysiological significance of PSP. Serum PSP in acute pancreatitis (mean±SD=1075.4±2849.1 ng/mL,n=33) was significantly higher than that in controls (78.6±31.8 ng/mL,n=37,p<0.01), chronic pancreatitis (156.8±82.8 ng/mL,n=32,p<0.05), and pancreatic cancer (148.468.8 ng/mL,n=26,p<0.05). No significant difference was found between noncalcified and calcified chronic pancreatitis. Serum PSP levels were significantly higher in chronic renal failure under hemodialysis (1796.0±1492.9 ng/mL) than in other diseases such as peptic ulcer, liver cirrhosis, gallstone, and diabetes mellitus. Low but significant correlation was obtained between serum PSP and serum immunoreactive trypsin (r=0.22,p<0.05). Increased serum PSP levels in acute pancreatitis and chronic renal failure suggest that serum PSP levels reflect reflux from pancreatic secretion, release from damaged pancreatic acinar cells, or retention in circulation, and can be useful for diagnosis of acute pancreatitis, but not chronic calcified pancreatitis.     

Free fatty acids in serum of patients with acute necrotizing or edematous pancreatitis

Serum concentrations of free fatty acids (FFA) were assayed in 20 patients with acute necrotizing pancreatitis (ANP). Pancreatic and peripancreatic fat necrosis was verified on operation and/or by contrast-enhanced computed tomography. For comparison, 20 patients with acute edematous pancreatitis (AEP) were examined. On admission, FFA serum levels were 1.14±0.12 (SEM) mmol/L in ANP and, thus, significantly (p<0.03) higher than in AEP (0.78±0.09 mmol/L). The two groups also differed in the later course: in ANP, the FFA values remained raised (d 5–11∶0.86±0.13 mmol/L;p>0.05 vs day 1), whereas in AEP, the FFA concentrations normalized within 1 wk (d 2–4∶0.52±0.11 mmol/L; d 5–11∶0.39±0.05 mmol/L;p<0.05 vs day 1 andp<0.01 vs ANP). Serum FFA correlated positively with C-reactive protein levels (r _s=0.42;p<0.01), but has less discriminating potency between ANP and AEP. In AEP, the initial peak may correspond to the disease out-burst itself and to unspecific stress. In ANP, the higher and sustained elevation of FFA may predominantly mirror the ongoing pancreatic parenchymal and extrapancreatic fat necrosis, and be pathophysiologically relevant, especially in view of significantly reduced serum albumin levels in ANP.     

Change of the endocrine function of the pancreas in patients with chronic pancreatitis]

There was a study of 19 chronic pancreatitis patients (10 male and 9 female), 11 chronic pancreatitis and pancreatogenic diabetes mellitus patients (8 male and 3 female) and 12 type 2 diabetes mellitus patients (4 male and 8 female) at the age of 30-60 as well as 15 control group subjects at the same age range. The content of the C-peptide and such peptides as INCINE, PAMG-cine and PAMG-tin in the blood serum was subjected to the immunoradiometric assay. It was discovered that there is a trend to the increased C-peptide level in CP patients while the C-peptide level in CP patients with diabetes mellitus was smaller than that in the control group; the C-peptide level in CP patients with type 2 diabetes mellitus was higher as compared to that in the control group. It was shown that erythrocytes of CP patients are less sensitive to insulin action and do not respond to the presence of insulinomimetic peptides under examination during the glucose uptake test. CP patients with diabetes mellitus and type 2 diabetes mellitus patients are more sensitive to the action of insulin and peptides applied. Synthetic insulinomimetic peptides can serve as a means for discovering the functional cell deficiency under the glucose uptake test.     

Serum ribonuclease activity in the diagnosis of pancreatic disease

The present study evaluated serum ribonuclease activity (SRA) in patients with inflammatory and neoplastic pancreatic diseases. RNase determination was carried out using t-RNA (T) fromE. coli MRE 600 at pH 7.4 and polycytidylic acid (poly-C) (P) at pH6.6 as RNA substrates with RNase A from bovine pancreas as reference enzyme. Healthy volunteers had a SRA of T: 160±12 and P: 482 ±24 ngeq/mL (mean±SEM(n)). In patients with acute interstitial pancreatitis (AIP), SRA was similar to healthy controls (T: 166 ±14; P: 474 ±30 ngeq/mL). Patients with acute necrotizing pancreatitis (ANP) had increased SRA (T: 278 ±49; P: 791 ± 145 ngeq/mL,p 0.01, compared to controls). SRA values were also increased in patients with chronic pancreatitis (CP) with T: 224± 15 ngeq/mL (p<0.01) and in patients with pancreatic carcinoma (PCA) with T: 331 ±35(p 0.001 vs controls, p<0.01 vs CP). Increased SRA was detected in patients with renal insufficiency (T: 2576± 195 ngeq/mL, p<0.001). Diagnostic discrimination between AIP and ANP was achieved in 69% using T-SRA (sensitivity 31%, specificity 88%), and in 78% using P-SRA (sensitivity 54%, specificity 92%). Discrimination between CP and pancreatic carcinoma was possible in 68% (sensitivity 67%, specificity 71%). The diagnostic value of serum RNase is limited because of its low sensitivity, but increased T-SRA above a cutoff of 250 ngeq/mL and increased P-SRA above a cutoff of 620 ngeq/mL are specific for detecting pancreatic necrosis in the absence of renal impairment. The kidney is a major site for SRA clearance.     

Does acute ingestion of large amounts of alcohol cause pancreatic injury? A prospective study

Summary The contribution of ethanol to the pathogenesis of acute pancreatitis has been questioned for a long time. The authors asked whether acute ingestion of large amounts of alcohol may lead to pancreatic injury, as assessed by serum amylase levels, clinical picture, and abdominal ultrasound. Therefore, all patients (N=112) admitted to our medical emergency ward with the diagnosis of alcohol intoxication were evaluated prospectively during a 12-mo period. Of these, 78 (56 M, 22 F; mean age 36±15) could be evaluated. The other 44 were excluded because of incomplete data (n=18), mixed intoxications (n=8), repeated admission (n=9), incorrect diagnosis on admission (n=7), and chronic pancreatitis (n=2). Serum ethanol, amylase, and GOT were measured. Serum ethanol was 246±122 mg/dL (3–500 mg/dL), amylase 83±44 U/L (27–361 U/L), and GOT 25±37 U/L (5–271 U/L) without significant differences among the genders. No correlation between serum ethanol and serum amylase levels could be detected.     

Differences in Plasma Insulin Responses in Urban and Rural Indians: A Study in Southern-Indians

Fasting and 2 h post glucose plasma immunoreactive insulin (fasting IRI and 2 h IRI) responses were measured in urban (n = 149) and rural (n = 40) individuals with normal glucose tolerance during an epidemiological survey. In this survey, 900 urban and 1038 rural subjects were screened for glucose intolerance by capillary blood sampling. The respective response rates were 91% and 88%. We had planned to collect venous blood for IRI estimation, i.e. from 180 urban and 200 rural subjects. The compliance for the same was poor from the rural subjects and therefore the number available for IRI estimation was small. The mean ± SD ages of the urban and rural groups were similar (35.3 ± 9.9 and 38.6 ± 13.1 years, respectively). The rural population had lower body mass index (BMI) and subscapular:triceps ratio compared to the urban group (p < 0.001). The total calorie consumption was lower and physical activity was higher in rural population. Fasting and 2 h insulin values in urban population were 16.6 ± 9.4 mU I^?1 and 60.6 ± 42.5 mU I^?1 and in rural 6.7 ± 5.1 mU I^?1 and 32.4 ± 27.8 mU I^?1, respectively; the values being significantly lower in the rural population (p < 0.001). Multiple regression analysis showed that in urban population the fasting insulin was correlated to the BMI and the 2h IRI to 2 h glucose, BMI and the subscapular:triceps ratio. In the rural population, similar results were obtained, except in that the 2 h IRI was influenced by the gender also. This study showed that the fasting IRI and 2 h IRI responses in normoglycaemic urban and rural populations differed widely, probably related to the differences in body mass and adiposity distribution. The higher IRI concentrations in normoglycaemic urban subjects suggest a relative insulin resistance and this may be a contributory factor for the higher prevalence of diabetes in urban Indians.     

Stimulated gastrointestinal hormone release and gallbladder contraction during continuous jejunal feeding in patients with pancreatic pseudocyst is inhibited by octreotide

Summary Background. Continuous enteral feeding, the old-new therapeutic modality in the treatment of patients with acute pancreatitis and those with complications is considered to bypass the cephalic, the gastric, and (at least in part) the intestinal phase of pancreatic secretion. The aim of this study was to test the GI hormonal changes and gallbladder motility during CJF in patients with pancreatic pseudocysts following acute pancreatitis, with or without octreotide pretreatment. Patients and Methods. In 15 patients with pancreatic pseudocysts, an 8-French (8F) nasojejunal catheter was positioned into the jejunum distal to the ligament of Treitz during duodenoscopy. On test d 1, blood samples were taken for CCK, gastrin, insulin-like immunoreactivity (IRI), glucagon, and glucose measurements prior to and at 20, 40, 60, and 120 min following jejunal saline infusion at a rate of 2 mL/min. The gallbladder volumes were determined simultaneously by ultrasonography. On test d 2, CJF (175 kcal/h) was started by the same route and at the same infusion rate. Analogous measurements were performed as indicated above. On test d 3, 100 μg of octreotide was administered subcutaneously and the previous procedure was repeated. The plasma level of CCK and glucagon and the serum levels of IRI and gastrin were determined by bioassay and radioimmunoassay (RIA), respectively. Results. Significant changes in hormone levels were not observed during jejunal saline perfusion. However, the levels of CCK (5.7±0.9 pmol), gastrin (10.6±1.3 pmol/L), IRI (27.2±5.8 μIU/mL), glucagon (322.8±32.4 pg/mL), and glucose (5.8±1.0 mmol/L) were significantly increased at 20 min during CJF vs the saline controls (2.0±0.3 pmol, 6.8±1.1 pmol/L, 7.8±0.4 μIU/mL, 172.8±33.4 pg/mL, and 4.5±0.5 mmol/L, respectively) and remained elevated at 40, 60, and 120 min. Octreotide pretreatment eliminated the increases in CCK, gastrin, IRI, and glucagon levels observed during CJF alone. The significant decrease in gallbladder volume during CJF was also prevented by octreotide pretreatment. Conclusion. Continuous jejunal feeding (CJF) elicited significant increases in gastrointestinal (GI) regulatory hormone (cholecystokinin [CCK], gastrin, IRI, and glucagon) levels and evoked a consecutive gallbladder contraction. These biological responses are eliminated by octreotide pretreatment. Further clinical studies are needed to assess the eventual therapeutic effect of octreotide during CJF in patients with pancreatic pseudocyst.     

INSULIN-LIKE GROWTH FACTOR AND ITS CARRIER PROTEIN IN HYPOPITUITARY AND HYPOTHYROID CHILDREN AND ADULTS

Utilizing radioligand assays for the somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP), we have compared their serum levels in normal subjects with those in patients with hypopituitarism and hypothyroidism. The mean (±SEM) serum IGF concentration in children (n= 32, 2–13 yr, 929 ± 46 μU/ml) was virtually identical to that in adults (n= 20, 18–50 yr, 916·29 μU/ml), while CP levels in the former (1·8 ± 0·1 mg/ml) were significantly lower (P < 0·01) than in the latter (2·9 ± 0·1 mg/ml). Both serum IGF and CP were significantly decreased (P < 0·001) in hypopituitary children (n= 5, 6–8 yr, 377 ± 52 μU/ml and 0·9 ± 0·1 mg/ml respectively). Likewise, serum IGF and CP were significantly reduced (P < 0·05) in hypothyroid children (n= 10, 1–15 yr, 497 ± 24 μU/ml and 0·8 ± 0·1 mg/ml respectively) and adults (n= 12, 25–55 yr, 723 ± 40 μU/ml and 1·8 ± 0·2 mg/ml respectively). Growth hormone therapy (4 days) significantly increased (P < 0·05) serum IGF in hypopituitary children (336 ± 80 to 559 ± 59 μU/ml) but did not change the CP level (0·7 ± 0·2 to 0·7 ± 0·1 mg/ml). Thyroxine therapy (4–8 months) significantly increased (P < 0·05) both serum IGF and CP levels in hypothyroid children (497 ± 24 to 666 ± 38 μU/ml, and 0·8 ± 0·1 to 1·0 ± 0·1 mg/ml respectively) but had no effect in adults (723 ± 40 to 937 ± 132 μU/ml, and 1·8 ± 0·2 to 2·1 ± 0·2 mg/ml respectively). These studies indicate that growth retardation in children with hypopituitarism and hypothyroidism is associated with significant reductions in serum IGF and CP levels that are corrected, at least in part, by adequate hormone replacement therapy.     

Beta-blockers in hypertensive non-insulin-dependent diabetics: Comparison between penbutolol and propranolol on metabolic control and response to insulin-induced hypoglycemia

Summary In a single blind randomized study the effects of a 4-week administration of propranolol (160 mg/day) and penbutolol (40 mg/day) on metabolic control and insulin-induced hypoglycemia were tested in 8 non-insulin-dependent diabetics with diastolic blood pressure between 95 and 110 mmHg. The recovery from hypoglycemia was not delayed by either drug; hypoglycemic nadir and Conard’sK did not change significantly. Symptoms of hypoglycemia were inhibited to a lesser extent and pulse rate decrease was lower after penbutololvs baseline (65±2.4vs 77±2.4 beats/min, p<0.01) than after propranololvs baseline (61±1.06vs 77±2.4 beats/min p<0.001). Both drugs produced similar and significant effects on blood pressure both systolic and diastolic. There were no significant effects on fasting plasma glucose concentration, HbA_tc, IRI, urinary C-peptide, triglycerides, total and HDL cholesterol and FFA. IRG decreased after penbutololvs baseline 60 min after insulin injection (170±30.8vs 125±15.4 pmol/l, p<0.05). These results indicate that the use of beta-blockers, in particular penbutolol, for mild to moderate hypertension may be considered the treatment of choice also in non-insulin-dependent diabetics at the therapeutic doses employed.     

Metabolic Abnormalities in Offspring of NIDDM Patients with a Family History of Diabetes Mellitus

NIDDM appears to be an inherited condition. Our aim was to identify early metabolic abnormalities in non-diabetic offspring with one NIDDM parent and with a strongly positive (n = 58, age 27.8 ± 7.0 years) or a negative family history (n = 38, age 27.4 ± 6.7 years) of diabetes. These were compared with 31 offspring of non-diabetic parents (age 26.9 ± 5.5 years). After an overnight fast, blood was taken for glucose, insulin, C-peptide, insulin receptors, and lipids. All the subjects underwent a 75 g oral glucose tolerance test. The positive family history group had significantly higher fasting levels of triglycerides (1.09 ± 0.24 vs control subjects: CS: 0.93 ± 0.16 mmol l⁻¹, p < 0.001), insulin (102.8 ± 46.4 vs CS: 77.5 ± 32.4 pmol l⁻¹, p < 0.01) and C-peptide (0.69 ± 0.22 vs CS: 0.61 ± 0.19 nmol l⁻¹, p < 0.05) and lower numbers of insulin receptors per red cell (9.1 × 10³ (4.5–18.1, 95 % confidence intervals) vs CS: (11.2 × 10³ (6.3–19.9)), p < 0.01, despite similar blood glucose levels. After a glucose challenge (120 min), the increases in both insulin and C-peptide concentrations were significantly greater in the positive family history group (289.2 ± 214.1 pmol l⁻¹, 2.23 ± 1.48 nmol l⁻¹), respectively, than in CS (192.4 ± 170.3 pmol l⁻¹, p < 0.05) (1.54 ± 0.99 nmol l⁻¹ p < 0.01), respectively. No significant differences were found in fasting and post-challenge glucose levels. The negative family history group had significantly lower numbers of insulin receptors 9.4 × 10³ (4.1–15.2) compared with CS (p < 0.05). Insulin sensitivity was significantly reduced in the positive family history group (41.6 %) compared with control subjects (51.9 %), p < 0.01. The results strongly support the familial basis of the disease.     

An enteral therapy containing medium-chain triglycerides and hydrolyzed peptides reduces postprandial pain associated with chronic pancreatitis

Background/Aim: Pain in patients with chronic pancreatitis is difficult to manage. We examined if an enteral formulation containing medium-chain triglycerides (MCT) and hydrolyzed peptides would (1) minimally stimulate the exocrine pancreas by blunting cholecystokinin release and (2) decrease pain in patients with chronic pancreatitis. Methods: In the first part of the study, on separate days, 6 healthy controls consumed a standard enteral formulation, an enteral formulation containing MCT and hydrolyzed peptides, and a high-fat meal. Baseline and postprandial plasma cholecystokinin (CCK) concentrations were analyzed. Subsequently, 8 patients with chronic pancreatitis were enrolled and instructed to complete a visual analog pain assessment for a baseline period of 2 weeks followed by three cans per day of the enteral formulation containing MCT and hydrolyzed peptides for 10 weeks. Results: Mean CCK levels for our control subjects were 0.46 ± 0.29 pM at baseline, 10.75 ± 0.45 pM in response to the high-fat meal, and 7.9 ± 1.25 pM in response to the standard enteral formulation. Of note, CCK levels were 1.43 ±0.72 pM in response to the enteral supplement containing MCT and hydrolyzed peptides. In patients with chronic pancreatitis, the average improvement in pain scores from baseline to the conclusion of the study was 61.8% (p = 0.01). This corresponded to a clinical improvement in 6 of the 8 patients. Conclusions: A complete enteral supplement containing MCT and hydrolyzed peptides minimally increases plasma CCK levels. This therapy may be effective in reducing postprandial pain associated with chronic pancreatitis.     

Blood concentrations of polymorphonuclear leucocyte elastase and interleukin-6 are indicators for the occurrence of multiple organ failures at the early stage of acute pancreatitis

We studied potential indicators of severe acute pancreatitis by measuring the blood concentrations of various cytokines, polymorphonuclear leucocyte elastase (PMN-E), acute phase reactants, pancreatic amylase (P-AMY), pancreatic elastase-1 (E-1) and white blood cell (WBC) counts in patients with acute pancreatitis. In addition, the presence of multiple organ damage was assessed. Subjects consisted of 22 patients with acute pancreatitis including severe (n= 11), moderate (n= 4) and mild (n= 7) cases. A significant positive correlation was observed between the number of organs damaged and the peak concentrations of interleukin (IL)-6, PMN-E, C-reactive protein (CRP) and pancreatic secretory trypsin inhibitor (PSTI). Among these markers, blood concentrations of PMN-E and IL-6 rapidly increased and peaked at the early phase of acute pancreatitis whereas CRP and PSTI did not. The elevation of PMN-E and IL-6 was greater the more severe the symptoms. However, no significant correlation was observed between the number of organs damaged and the maximum serum concentrations of P-AMY and E-1, or the WBC count, which have been considered to be markers of pancreatitis. These results suggest that PMN-E and IL-6 concentrations are useful indicators of severity and prognosis and their determination facilitates the selection of appropriate treatment in the early stages of disease to prevent the aggressive progression of acute pancreatitis.     

Predictive value of complement activation fragments C3a and sC5b‐9 for development of severe disease in patients with acute pancreatitis

Background: Complement activation has been shown to occur in patients with acute pancreatitis. However, the diagnostic potential of complement activation products in plasma for predicting severe disease remains unclear to date. Methods: The daily levels of the complement anaphylatoxin C3a and the soluble terminal complement complex sC5b‐9 were determined by ELISA in plasma of patients with mild (n?=?16) or severe (n?=?14) acute pancreatitis during the first week after onset of symptoms, and in healthy control subjects (n?=?14). Results: Both C3a and sC5b‐9 were significantly elevated during the first 7 days in plasma of patients with severe acute pancreatitis (C3a: 459.3?±?407.5?ng/mL (mean?±?s); sC5b‐9: 617.9?±?297.7?ng/mL), as compared to patients with mild disease (C3a: 172?±?149.5?ng/mL; sC5b‐9: 306.7?±?167.3?ng/mL) or controls (C3a: 102.3?±?19.7?ng/mL; sC5b‐9: 40.64?±?19.7?ng/mL; P?P?Conclusion: In patients with acute pancreatitis, the plasma levels of complement C3a and sC5b‐9 measured daily during the first week after onset of symptoms represent highly specific and sensitive parameters for the prediction of severe acute pancreatitis.     

The effect of interleukin-6 on bacterial translocation in acute canine pancreatitis

Summary Background. Bacterial translocation from the gut to mesenteric lymph nodes and other extraintestinal sites is an important source of infection in acute pancreatitis. Impaired host immunity is known to promote bacterial translocation. Interleukin-6 (IL-6) is a multifunctional cytokine that regulates the immune response, acute phase reaction, and hematopoiesis. Methods. Twenty-four mongrel dogs (18–29 kg) were studied in four equal groups. In Groups I and II, acute pancreatitis was induced by direct pressure injection of 4% taurocholate and trypsin into the pancreatic duct at laparotomy. Groups III and IV had only laparotomy. Group I and III dogs were given IL-6 (50 μg/kg/d, sq) daily starting 24 h after operation and Group II and IV dogs received an equal volume of saline administered at similar time. All animals had blood drawn for culture, complete blood count (CBC), platelets, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and amylase on d 0, 1, 4, and 7. On d 7, mesenteric lymph nodes (MLN), spleen, liver, pancreas, and cecum were harvested for pathology study and for cultures of aerobic and anaerobic bacteria. Quantitative cecal cultures of aerobic and anaerobic bacteria were obtained. Results. All Group I and Group II dogs had severe pancreatitis. The increase of plasma CRP in Group I was sustained throughout treatment (1.3±0.3 on d 0 vs 3.1±0.3*, 3.0±0.3*, and 2.9±0.3* and d 1,4, and 7, respectively). Plasma CRP was increased in Group II on d 1 and d 4 (1.3±0.3 mg/dL on d 0 vs 3.6±0.3* mg/dL on d 1, and 3.1±0.3* on d 4, *p<0.05). There were no differences in white blood cell (WBC) count, differential, platelets, and ESR between Groups I and II. Bacterial translocation to MLN was lower in Group I (1/6) than in Group II (6/6) (p<0.05). All 6 dogs in Group II had bacterial spread to distant sites compared to 2 of 6 dogs in Group I (p=0.066). Both MLN and other distant organ cultures were negative in Group III and only 1 of 6 MLN cultures was positive in Group IV. Conclusions. IL-6 treatment decreases bacterial translocation to MLN and may be beneficial in reducing septic complications in acute pancreatitis.     

Ethnic Differences in Secretion,Sensitivity, and Hepatic Extraction of Insulin in Black and White Americans

Hyperinsulinaemia and abnormalities in hepatic insulin extraction commonly coexist in ethnic groups with severe insulin resistance. Therefore, we compared the effects of ethnicity on glucose/insulin/C-peptide dynamics, hepatic insulin extraction, and insulin sensitivity in healthy black (n = 32) and white (n = 30) Americans. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified, frequently sampled, intravenous glucose tolerance (FSIVGT) tests were performed in each subject. Insulin sensitivity index (S₁) was calculated using the MINIMOD method described by Bergman et al. Basal and post-stimulation hepatic insulin extraction were calculated by the molar ratios of C-peptide and insulin concentrations during the basal steady state and areas under the post-stimulation hormone curves, respectively. Apart from a slightly greater mean serum glucose peak response after oral glucose in the whites, mean glucose levels were identical in the blacks and whites during both stimulations. In contrast, serum insulin levels at basal and during both stimulations were significantly greater (2–3 fold) in the blacks than whites. However, the corresponding C-peptide responses were identical in both groups. The basal and postprandial hepatic insulin extraction were 33% and 45% lower in the blacks when compared to whites, respectively. The mean S₁ was significantly (p < 0.02) lower in the blacks (4.93 ± 0.46) than the whites (7.17 ± 0.88 × 10^?4 (mU l^?1)^?1). We conclude that ethnicity may be a major determinant of the mechanism of peripheral hyperinsulinaemia and insulin insensitivity in black and white Americans.     

Presence of SPINK-1 variant alters the course of chronic pancreatitis

Background and Aims: There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type‐1 (SPINK‐1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK‐1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence of the SPINK‐1/N34S variant in patients with CP, and to understand the impact of the SPINK‐1 mutation on the natural history of CP. Methods: A retrospective‐prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene‐1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK‐1/N34S mutation. Results: Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK‐1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort. Most of the patients who were positive for the SPINK‐1/N34S mutation had IP and were Caucasian (69.2%). The patients with the SPINK‐1/N34S mutation had a younger age of onset (32.9 ± 10.2 vs 40.1 ± 13.6 years; P = 0.108) than those with IP and no mutation. Over a median follow up of 9.6 years, the patients with the SPINK‐1/N34S mutation had a significantly greater number of acute flares each year, as compared to those without the mutation (11.8 ± 1.5 vs 4 ± 0.98; P = 0.0001). Conclusions: The prevalence of the SPINK‐1/N34S mutation in patients with CP is 5.4%, and is approximately 37.1% in patients with IP. These mutations are more prevalent in Caucasian patients with CP. The SPINK‐1/N34S mutation predisposes to early onset IP and more frequent acute flares of pancreatitis that might ultimately lead to pancreatic insufficiency. The patients with IP and borderline alcohol history should be considered for testing for genetic analysis, including SPINK‐1 mutations, initially restricted to clinical trials.     

Effects of chronic TSH treatment on blood sugar,serum IRI and FFA levels of thyroidectomized dogs. Glucose and insulin tolerance tests

Summary The effects of TSH treatment (0.1 USPU/kg body weight/die, for 3–4 days) on the blood sugar, serum IRI and circulating FFA responses to glucose and insulin were studied. Blood sugar and serum FFA levels of the dogs, in basal conditions and at any time interval during the test were slightly modified by TSH treatment. The kinetics of insulin disappearance from blood was not affected while the mean serum IRI during the insulin tolerance test was moderately reduced, which suggests that insulin space is moderately raised by TSH. The serum IRI response to glucose (OGTT, IVGTT) was found to be significantly and intensely reduced. The possibility of an inhibitory action of TSH on the insulin response to glucose in dogs, excluding the participation of the thyroid, exerted via insulin space and secretion is discussed. This work, partly published in abstract form (I Congreso Latino-americano de Diabetes, Montevideo, October 22–25, 1972;VI Congreso Argentino de Biología, San Miguel de Tucumán, April 9–13, 1973, abstract # 131; 8th Congr. of the Int. Diabetes Fed., Bruxelles, July 15–20, 1973, abstract # 86), was sponsored by theConsejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Established Investigator,Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Postgraduate Fellow, University of Buenos Aires, Argentina.     

Comparison of effects of quinapril and metoprolol on glycaemic control, serum lipids, blood pressure, albuminuria and quality of life in non-insulin-dependent diabetes mellitus patients with hypertension. Swedish Quinapril Group

Objective

To compare the long-term effects of the angiotensin-converting enzyme (ACE)-inhibitor quinapril and the cardioselective beta-adrenergic blocking agent metoprolol on glycaemic control, with glycosylated haemoglobin (HbA_1c) as the principal variable, in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension.

Design

A randomized, double-blind, double-dummy, multicentre study during 6 months preceded by a 4 week wash-out and a 3 week run-in placebo period. Quinapril (20 mg) and metoprolol (100 mg, conventional tablets) were given once daily. No change was made in the treatment of diabetes (diet and hypoglycaemic agents).

Subjects

Seventy-two patients fulfilling the criteria were randomized and entered the double-blind period. Twelve patients did not complete the study. Sixty patients, 26 on quinapril and 34 on metoprolol, were available for the final analysis.

Main outcome measures

The effect was assessed by changes in HbA_1c, the fasting serum glucose and the post-load serum glucose, C-peptide and insulin levels during the oral glucose tolerance test.

Results

In the quinapril group, the fasting serum glucose, oral glucose tolerance and the C-peptide and insulin responses, determined as the incremental area under the curves (AUC), showed no change, but the mean HbA_1c level increased from 6.2 ± 1.1% to 6.5 ± 1.3% (P < 0.05). In the metoprolol group, the rise in the mean level of HbA_1c, from 6.3 ± 1.0% to 6.8 ± 1.3% (P < 0.01), tended to be more marked than after quinapril, although there was no significant difference between the increments. The mean fasting serum glucose showed an increase from 9.1 ± 1.9 mm to 10.1 ± 2.8 mm (P < 0.01) which correlated significantly with the duration of diabetes (P < 0.01) and the increase in fasting serum triglycerides (P < 0.001). Moreover, in the metoprolol group we found significant decreases in the oral glucose tolerance as well as C-peptide and insulin responses to the glucose load.

Conclusions

Treatment with quinapril for 6 months appears to have advantages over metoprolol in NIDDM patients with hypertension. Although treatment with quinapril or metoprolol over 6 months was concomitant with a rise in the HbA_1c, increased fasting blood glucose, decreased oral glucose tolerance and decreased C-peptide and insulin responses to a glucose challenge were observed only in patients treated with metoprolol.

     

Metal-activated C-peptide facilitates glucose clearance and the release of a nitric oxide stimulus via the GLUT1 transporter

Aims/hypothesis Proinsulin C-peptide has been implicated in reducing complications associated with diabetes and also in improving blood flow. We hypothesised that incubation of erythrocytes with C-peptide would improve the ability of these cells to release ATP, a stimulus for nitric oxide production. Methods Erythrocytes obtained from rabbits (n = 11) and both healthy and type 2 diabetic humans (n = 7) were incubated with C-peptide in the absence and presence of Fe²⁺ and Cr³⁺, and the resulting ATP release was measured via chemiluminescence. This release was also measured in the presence and absence of phloretin, an inhibitor of GLUT1, and also of mannose, a glycolysis inhibitor. To determine glucose transport, ¹⁴C-labelled glucose was added to erythrocytes in the presence and absence of the C-peptide–metal complex and the aforementioned inhibitors. Results The release of ATP from the erythrocytes of patients with diabetes increased from 64 ± 13 to 260 ± 39 nmol/l upon incubation of the cells in C-peptide. The C-peptide activity was dependent upon binding to Fe²⁺, which was extended upon binding to Cr³⁺. The increase in ATP release from the erythrocytes is due to metal-activated C-peptide stimulation of glucose transfer into the erythrocytes via the GLUT1 transporter. In the presence of C-peptide complexed to Cr³⁺, the amount of glucose transferred into the erythrocyte increased by 31%. Conclusions/interpretation When complexed to Fe²⁺ or Cr³⁺, C-peptide has the ability to promote ATP release from erythrocytes. This release is due to an increase in glucose transport through GLUT1.