The effect of pharmacological agents on pancreatic incretory activity in patients with chronic pancreatitis

In chronic pancreatitis with moderate derangements of carbohydrate tolerance (detected by the double glucose test), the basal concentrations of insulin and C-peptide in blood are normal whereas in patients with secondary diabetes mellitus are lowered. Glucagonemia is increased in patients of both groups. Euphylline (applied as an inhibitor of nucleotide phosphodiesterase), calcium gluconate and the adrenomimetic drug isadrin consistently increased insulinemia and the blood level of C-peptide in patients with chronic pancreatitis both with moderate and appreciable derangements of glucose tolerance. In patients with secondary diabetes that developed in the presence of pancreatitis, these drugs did not influence glucagonemia. The clinical prospects of the making use of the stimulating action of euphylline, calcium gluconate and isadrin on the function of beta-cells of the pancreas in chronic pancreatitis patients are under discussion.     

酒精性慢性胰腺炎继发糖尿病的临床特点分析

目的：探讨酒精性慢性胰腺炎继发的糖尿病与成年隐匿性自身免疫糖尿病（ LADA）及2型糖尿病（T2DM）患者的临床资料、代谢指标及生化检查的差异。方法对2005~2014年于本院内分泌和消化科住院治疗的符合WHO糖尿病诊断标准的酒精性慢性胰腺炎继发的糖尿病患者24例,LADA患者30例及T2DM患者40例的病史,临床资料进行回顾性分析和比较。结果酒精性慢性胰腺炎继发糖尿病患者的体重指数（BMI）与LADA患者的差异无显著性,明显低于T2DM患者。酒精性慢性胰腺炎继发糖尿病的空腹C肽值要高于LADA组患者,低于T2DM患者,总胆固醇（ CHO）和低密度脂蛋白胆固醇（ LDL-C）水平低于LADA及T2DM患者,外周血管病变的发生低于T2DM患者。结论长期大量饮酒患者出现糖尿病,应注意鉴别有无酒精性慢性胰腺炎继发的糖尿病,该类患者体型偏瘦,CHO及LDL-C低于LADA及T2DM患者,易出现低血糖,但是无酮症倾向。     

急慢性胰腺炎后新发2型糖尿病的危险因素Meta分析

目的 系统评价急慢性胰腺炎患者新发2型糖尿病危险因素的相关研究.方法 计算机检索中英文数据库,筛选符合纳入标准的病例对照研究,病例组为急慢性胰腺炎患者中新发2型糖尿病的患者,对照组为急慢性胰腺炎患者中未并发2型糖尿病的患者,对纳入的研究进行质量评估,提取数据并采用Review Manager5.3进行Meta分析及系统...     

Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia.

We have used a continuous intravenous infusion of glucose (6 mg/kg/min), insulin (80 mU/min), epinephrine (6 mug/min), and propranolol (0.08 mg/min) to directly assess insulin resistance in 14 untreated adult onset diabetics with a mean (plus or minus SE) fasting plasma glucose level of 217 plus or minus 17 mg/100 ml. During the infusion endogenous insulin secretion is inhibited and steady-state plasma glucose and insulin levels are achieved after 90 min. Since similar steady-state levels of plasma insulin are achieved in all subjects, the plasma glucose concentration observed during the steady-state period is a measure of an individual's insulin resistance. Under these conditions, the mean (plus or minus SE) steady-state plasma glucose level of the 14 diabetic patients was 350 plus or minus 16 mg/100 ml, while that of 12 normal subjects was 121 plus or minus 4 mg/100 ml. Additional studies were performed in which control subjects and patients with diabetes had their fasting plasma glucose levels acutely raised or lowered to comparable levels before receiving the basic infusion mixture of glucose, insulin, epinephrine, and propranolol. The results of these studies indicated that differences in initial plasma glucose levels could not account for the different glucose responses of the two groups to the basic infusion. Finally, the mean (plus or minus SE) steady-state plasma glucose level of 104 plus or minus 17 mg/100 ml observed during the same basic infusion in five patients with fasting hyperglycemia (mean plus or minus SE, 142 plus or minus 12 mg/100 ml) secondary to chronic pancreatitis suggested that neither chronic hyperglycemia nor hypoinsulinemia per se necessarily lead to insulin resistance. These results demonstrate that marked insulin resistance exists in adult onset diabetics with fasting hyperglycemia. Since previous studies have documented the presence of insulin resistance in patients with chemical diabetes, the possibility exists that insulin resistance may be characteristic of adult onset diabetes mellitus.     

Hormonal mechanisms of carbohydrate metabolism disorders in chronic pancreatitis

The mechanisms of carbohydrate metabolism abnormality were studied in 128 patients suffering from chronic pancreatitis by means of simultaneous measurement in the blood of glucose, insulin, C-peptide and glucagon concentrations both on an empty stomach and after the glucose tolerance test (50 g glucose). Five types of the hormonal mechanisms of hyperglycemia were revealed, caused by derangement of beta-cells for the most part, more rarely by alpha-cells of the pancreas and impairment of interregulation of those cells in chronic pancreatitis. The rate of the hormonal mechanisms of carbohydrate metabolism abnormality was shown to depend on the gravity and duration of chronic pancreatitis whereas blood sugar and insulin response to intravenous injection of glucose in patients with chronic pancreatitis to have characteristic features in common to type I and II diabetes.     

Incretory changes in the pancreatic hormones in chronic pancreatitis

Radioimmunoassay was employed to study blood content of insulin, C-peptide and glucagon in 78 patients with chronic pancreatitis. It was revealed that during exacerbation, there was an increase in the content of insulin and glucagon and, to a lesser degree, in that of C-peptide. During remissions, part of the patients showed insular deficiency which increased with disease standing. When pancreatitis lasted from 1 to 5 years or from 5 to 10 years, diabetes mellitus was recorded in 9.4% of the patients and in 16% of the patients, respectively.     

Magnesium deficiency in patients with chronic pancreatitis identified by an intravenous loading test

Magnesium deficiency is a common clinical condition that may exist despite a normal serum magnesium concentration. Patients with chronic pancreatitis could develop magnesium deficiency due to either malabsorption, diabetes mellitus, or chronic alcoholism. Since serum levels of magnesium are a poor indicator of magnesium deficiency, the retention of a low-dose intravenous magnesium load (0.1 mmol/kg body weight) was determined in 13 patients with chronic pancreatitis (10 due to alcoholism) and eight healthy controls. Percentage magnesium retention was greater in patients with chronic pancreatitis than controls (59.8+/-37.3% S.D. versus 22.0+/-38.2% S. D.: P=0.038), and 10 of 13 patients showed evidence of magnesium deficiency. Routine evaluation of magnesium status could allow appropriate supplementation and conceivably symptomatic improvement in patients with severe chronic pancreatitis.     

The presence of retinopathy in patients with secondary diabetes following pancreatectomy or chronic pancreatitis

The incidence of diabetic retinopathy was evaluated by means of fluorescein angiography in 54 patients with diabetes secondary to chronic pancreatitis or to pancreatectomy. Thirty-one percent of the patients had background retinopathy; none had proliferative retinopathy. The percentage of patients with retinopathy was the same in groups with or without a family history of diabetes. There was no correlation between the degree of metabolic control, the levels of C-peptide, glucagon, growth hormone, and the presence of retinopathy. Retinopathy was correlated with the duration of diabetes. In conclusion, diabetes caused by pancreatitis or pancreatectomy has a significant prevalence of retinopathy, which has more benign characteristics and slower evolution than the retinopathy in patients with primary diabetes.     

Comparison of combined therapies in treatment of secondary failure to glyburide.

OBJECTIVE--To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS--A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment. RESULTS--Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients. CONCLUSIONS--The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.     

167例老年胰腺癌特点及与糖尿病、慢性胰腺炎的关系分析

目的 :分析 16 7例老年胰腺癌的临床特征 ,探讨胰腺癌与糖尿病、慢性胰腺炎之间的关系。方法 :对 16 7例胰腺癌和16 7例对照组进行回顾性对比分析 ,计算其相对危险度 (RR) ,评价胰腺癌与糖尿病、慢性胰腺炎的关系。结果 :(1)胰腺癌的临床表现以腹痛、黄疸、消瘦、腹胀和上腹不适为主 ,男性多见。无一例是早期胰腺癌。 (2 )在胰腺癌组中 2年内确诊糖尿病有4 5例 (2 6 .95 % ) ,对照组中有 4例 (2 .4 0 % ) ,两组有显著差异 (P <0 .0 1)。胰腺癌组中糖尿病病史两年以上有 12例 (7.19% ) ,对照组中有 14例 (8.38% ) ,两组无显著差异 (P >0 .0 5 )。 (3)胰腺癌组和对照组分别检出慢性胰腺炎 6例和 1例 ,两组无显著差异 (P >0 .0 5 )。结论 :老年人胰腺癌确诊相对较晚 ,常伴有糖尿病的发生 ,但糖尿病不是胰腺癌的危险因素 ,糖尿病是胰腺癌的继发性结果。慢性胰腺炎与胰腺癌发生无相关性。老年人出现血糖异常须警惕胰腺癌的发生。     

How low can you go? Chronic hypoglycemia versus normal glucose homeostasis.

BACKGROUND: Set point errors in glucose homeostasis that result in chronic, mild hyperglycemia in the setting of maturity onset diabetes of the young have been described. Similar set point errors may exist that result in chronic, asymptomatic glucopenia. CASE: A healthy 39-year-old female was referred for evaluation of chronic, persistent, and asymptomatic glucopenia that persisted over the prior several years with a record of numerous random plasma glucose concentrations between 35 and 45 mg/dL. She denied ethanol intake and family history of hypoglycemia or diabetes. She was not taking any medications known to cause hypoglycemia, and a urine sulfonylurea screen was negative. Fasting insulin and C-peptide levels were not elevated, and pancreatic imaging studies were normal. We hypothesized that this patient possessed an error in glucose metabolism that resulted in chronic, asymptomatic glucopenia. RESULTS: In a series of clinical studies, we demonstrated a nadir plasma glucose concentration of 35 mg/dL in the absence of symptoms during a 60-hour fast. C-peptide secretion was appropriately suppressed during symptomatic hypoglycemia with exogenous insulin infusion, and counterregulatory hormone secretion was intact during insulin-induced symptomatic hypoglycemia. Finally, the patient demonstrated an incremental increase in insulin concentration in response to minimal increases in plasma glucose during a sequential, stepped infusion of 10% dextrose. CONCLUSIONS: We conclude that this patient exhibits features of a set point error in glucose homeostasis that manifests as chronic, asymptomatic glucopenia. Although the mechanism for this condition remains to be elucidated, such set point errors do exist and should be considered in the differential diagnosis of chronic hypoglycemia.     

Chemical pancreatectomy treats chronic pancreatitis while preserving endocrine function in preclinical models

Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%–2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid–treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.     

Chronic pancreatitis

Chronic pancreatitis is the progressive and permanent destruction of the pancreas resulting in exocrine and endocrine insufficiency and, often, chronic disabling pain. The etiology is multifactorial. Alcoholism plays a significant role in adults, whereas genetic and structural defects predominate in children. The average age at diagnosis is 35 to 55 years. Morbidity and mortality are secondary to chronic pain and complications (e.g., diabetes, pancreatic cancer). Contrast-enhanced computed tomography is the radiographic test of choice for diagnosis, with ductal calcifications being pathognomonic. Newer modalities, such as endoscopic ultrasonography and magnetic resonance cholangiopancreatography, provide diagnostic results similar to those of endoscopic retrograde cholangiopancreatography. Management begins with lifestyle modifications (e.g., cessation of alcohol and tobacco use) and dietary changes followed by analgesics and pancreatic enzyme supplementation. Before proceeding with endoscopic or surgical interventions, physicians and patients should weigh the risks and benefits of each procedure. Therapeutic endoscopy is indicated for symptomatic or complicated pseudocyst, biliary obstruction, and decompression of pancreatic duct. Surgical procedures include decompression for large duct disease (pancreatic duct dilatation of 7 mm or more) and resection for small duct disease. Lateral pancreaticojejunostomy is the most commonly performed surgery in patients with large duct disease. Pancreatoduodenectomy is indicated for the treatment of chronic pancreatitis with pancreatic head enlargement. Patients with chronic pancreatitis are at increased risk of pancreatic neoplasm; regular surveillance is sometimes advocated, but formal guidelines and evidence of clinical benefit are lacking.     

Course and therapy of nonpancreatic complications of chronic pancreatitis]

Out of 647 patients with chronic recurrent pancreatitis followed up for 10-12 years 27 patients (4.2%) developed symptomatic gastroduodenal ulcers, 29 (4.5%) multiple gastroduodenal erosions. Ulcers and erosions emerged in patients with pronounced pancreatic bicarbonate insufficiency. Sucralfate treatment produced the best effect, while almagel plus vicalin were superior to gastrozepin. Relapses of ulcerogenesis were registered in 8 cases, multiple erosions in 11 cases, left pleural exudate in 8 cases in the presence of chronic pancreatitis exacerbation. Pancreatocardiac syndrome with cardialgias, a trend to arterial hypotonia, reduced voltage of ECG waves, occasional extrasystolic arrhythmia occurred in 45 patients (7%). It is shown that metabolic disorders of biogenic amines and lowered blood levels of insulin and C-peptide may underlie pathogenesis of pancreatocardiac syndrome.     

Decreased Insulin Binding to Lymphocytes from Diabetic Subjects

We have studied insulin binding to circulating lymphocytes isolated from 20 untreated adult, nonobese, nonketotic, diabetic subjects with fasting hyperglycemia, 20 normal subjects, and four patients with fasting hyperglycemia secondary to chronic pancreatitis. The results of these studies show that lymphocytes from diabetic patients have decreased ability to specificity bind insulin when compared to lymphocytes from normal subjects. For example, when lymphocytes from diabetic patients and a trace amount of [(125)I]insulin (3.3 x 10(-11) M) were incubated, binding was less than 50% of the value obtained with lymphocytes from normal subjects (2+/-0.2% vs. 4.2+/-0.4%). Furthermore, the data show that lymphocytes from diabetic patients have only 1,200 insulin receptor sites per cell compared to 2,200 sites per cell for lymphocytes from normal subjects. Competitive inhibition studies using unlabeled insulin indicate that the affinity for insulin of lymphocytes from both groups is comparable. Consequently the decreased insulin binding of diabetics' lymphocytes is primarily due to a decreased number of available receptors rather than decreased binding affinity. This decreased insulin binding is not due to chronic hyperglycemia since insulin binding to lymphocytes, obtained from four patients with fasting hyperglycemia secondary to chronic pancreatitis, was completely normal. The possibility that some factor present in the plasma of diabetic patients could cause decreased insulin binding also seems unlikely since we could demonstrate no in vitro effects of diabetics' plasma on insulin binding. Lastly, the proportion of lymphocytes which were thymus derived and bone marrow derived were the same in each of the study groups indicating that differences in lymphocyte subpopulations do not account for our results.IN CONCLUSION: (a) lymphocytes from nonobese, untreated, adult diabetic patients with fasting hyperglycemia demonstrate a decreased ability to bind insulin; (b) this decreased insulin binding to lymphocytes obtained from diabetic patients can be accounted for primarily by an absolute decrease in the number of available receptor sites per cell; and (c) these data suggest that this defect in insulin binding is a primary phenomenon.     

Fractional urinary clearance of immunoreactive lipase in chronic pancreatic disease

Using an immunoenzymatic method, we studied lipase in the serum and urine of 23 controls, 22 chronic pancreatitis patients in symptomatic remission, and in 9 patients with proven pancreatic cancer. Serum and urine lipase and its fractional urinary clearance were compared with those of amylase and immunoreactive trypsin. Lipase immunoreactivity was detectable in the urine of 81.5% of the studied subjects (controls: 82%, chronic pancreatitis: 86%, pancreatic cancer: 66%); its output was higher than the upper limit of controls in 31.8% of chronic pancreatitis and in only 1 of pancreatic cancer, and it was significantly correlated with the urinary output of trypsin (r = 0.487, P less than 0.001), but not with that of amylase. A significant correlation was found between urinary output and serum levels for lipase, but not for trypsin or amylase. Fractional clearance of lipase was of the same magnitude as that of trypsin but only 0.1% that of amylase. 19% of chronic pancreatitis and pancreatic cancer showed a fractional clearance of lipase above the upper limit of controls, compared with 45% for trypsin and 3.2% for amylase. No difference in urinary clearance of the three enzymes was found between chronic pancreatitis and pancreatic cancer. In conclusion, although of no diagnostic relevance in pain-free patients with chronic pancreatic disease, this measurement can provide information on the mechanisms of renal excretion of pancreatic enzymes.     

Trends in the incidence and significance of presentations to the emergency department due to acute pancreatitis.

INTRODUCTION: Acute pancreatitis is an important cause of abdominal pain that may be associated with significant morbidity for the patient and considerable workload for the hospital. Our impression has been that it is becoming increasingly common, perhaps in tandem with increased rates of other alcohol-related disease. METHODS: The medical records of all patients attending our emergency department with acute pancreatitis by Hospital Inpatient Enquiry coding over a 9-year period were examined to determine its incidence, aetiology and significance (Imrie severity of pancreatitis scoring, length of hospital stay and interventional workload). RESULTS: The incidence of acute pancreatitis (n=97, 40 male patients) increased approximately threefold over the study period (especially in the lattermost triennial period with 75 patients) in a fashion disproportionate to changes in our locality's population. Gallstone-related disease continues to be most prevalent although alcohol-related disease also became more common. Disease severity (length of hospital stay and Imrie score) was similar throughout with a mean length of hospital stay exceeding that of the majority of accident and emergency admissions. Seven acute complications of acute pancreatitis were noted while 34 chronic sequelae developed. Requirement for invasive intervention doubled (n=19 in first triennial period in the study vs 39 in the latter triennial period), although the relative need for endoscopic retrograde cholangiopancreaticography diminished with increased availability of magnetic resonance cholangiography imaging. Nine patients with gallstone-related acute pancreatitis suffered recurrent attacks while awaiting cholecystectomy. CONCLUSION: Acute pancreatitis is an increasingly frequent cause of hospital admission while the clinical significance of each incident remains high. The presentation of acute pancreatitis to the emergency department as an early declaration of symptomatic cholelithiasis is especially worrisome as it suggests a failing of recognition and/or effective referral of premonitory biliary complaints.     

Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention

Type 1 diabetes is caused by the immune-mediated destruction of islet insulin-secreting beta-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months or even years before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates and eventually result in clinical diabetes. A fraction of individuals with humoral immunological changes have clinical diabetes that initially is not insulin-requiring. The onset of diabetes in these patients is usually in adult life, and because their diabetes is at least initially not insulin-requiring, they appear clinically to be affected by type 2 diabetes. Such patients probably have the same disease process as patients with type 1 diabetes in that they have similar HLA genetic susceptibility as well as autoantibodies to islet antigens, low insulin secretion, and a higher rate of progression to insulin dependency. These patients are defined as being affected by an autoimmune type of diabetes not requiring insulin at diagnosis, which is also named latent autoimmune diabetes of the adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency, and in this respect, efforts should be made to protect residual C-peptide secretion. LADA can serve as a model for designing new strategies for prevention of type 1 diabetes but also as a target group for prevention in its own right.     

Pancreatic diabetes mellitus

Diabetes mellitus caused by pancreatic exocrine disease is a unique clinical and metabolic form of diabetes. The diagnosis of pancreatic diabetes caused by chronic pancreatitis may be elusive because it is occasionally painless and often not accompanied by clinical malabsorption until after hyperglycemia occurs. Diabetic patients with pancreatic calcification or clinically demonstrable pancreatic exocrine dysfunction will manifest the unique aspects of pancreatic diabetes described herein. Like other forms of diabetes, the primary hormonal abnormality in pancreatic diabetes is decreased insulin secretion. Patients with this disorder are unique in that they have low glucagon levels that respond abnormally to several physiological stimuli, blunted epinephrine responses to insulin-induced hypoglycemia, and malabsorption. In addition, they often have concomitant alcohol abuse with hepatic disease and poor nutrition. These characteristics result in increased levels of circulating gluconeogenic amino acids, decreased insulin requirements, a resistance to ketosis, low cholesterol levels, an increased risk of hypoglycemia while on insulin therapy, and the clinical impression of brittle diabetes. Retinopathy occurs at a rate equal to that of insulin-dependent diabetes but may be less severe in degree. Other complications of pancreatic diabetes have been less well studied but may be expected to be seen more frequently as these patients survive longer. The characteristics of pancreatic diabetes suggest that a conservative approach be taken in regard to intensive insulin therapy and tight blood glucose control.     

Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene.

Idiopathic chronic pancreatitis (ICP) is the leading cause of nonalcoholic chronic pancreatitis. This study examined a series of patients with ICP to determine the prevalence and role of mutations of the cystic fibrosis gene (CFTR) and of a trypsin inhibitor gene (PSTI). Genetic testing was done in 39 patients with ICP. In this series, 17 patients had CFTR mutations and 9 had PSTI mutations. Pancreatitis risk was increased 14-fold by having the N34S PST1 mutation, 40-fold by having two abnormal copies of CFTR, and 600-fold by having both. In patients with two CFTR mutations, extrapancreatic clinical findings and nasal bioelectric responses suggested reduced residual CFTR protein function. Thus, pancreatitis risk showed complex inheritance and was highest in individuals who have abnormalities in both the pancreatic ducts (CFTR) and acini (PSTI). These findings indicate that PSTI is a modifier gene for CFTR-related ICP and have implications for the classification, diagnosis, and pathogenesis of pancreatitis.